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Isolation and physiological actions of gastric inhibitory polypeptide Pederson, Raymond Arnold 1971

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THE ISOLAT ION AND P H Y S I O L O G I C A L A C T I O N S OF G A S T R I C INHIBITORY P O L Y P E P T I D E BY RAYMOND ARNOLD P E D E R S O N B . ED.; U N I V E R S I T Y OF C A L G A R Y , 1 9 6 4 a, I A T H E S I S S U B M I T T E D IN P A R T I A L F U L F I L M E N T OF ^ THE R E Q U I R E M E N T S FOR THE DEGREE OF DOCTOR OF P H I L O S O P H Y IN THE D E P A R T M E N T OF P H Y S I O L O G Y WE A C C E P T T H I S T H E S I S AS C O N F O R M I N G TO THE R E Q U I R E D STANDARD S U P E R V I S O R E X T E R N A L E X A M I N E R THE U N I V E R S I T Y OF B R I T I S H C O L U M B I A J U N E , 1971 In present ing th i s thes is in p a r t i a l f u l f i lmen t o f the requirements for an advanced degree at the Un ivers i ty of B r i t i s h Columbia, I agree that the L ibrary sha l l make i t f r ee l y ava i l ab le for reference and study. I fu r ther agree that permission for extens ive copying of th i s thes i s f o r s cho la r l y purposes may be granted by the Head of my Department or by h i s representat ives . It i s understood that copying or pub l i ca t i on o f th i s thes i s f o r f i nanc i a l gain sha l l not be allowed without my wr i t ten permiss ion. Department of ~TA.y&j ¥ The Un ivers i ty of B r i t i s h Columbia Vancouver 8, Canada Date 3^6/?/ ABSTRACT IT IS KNOWN THAT HUMORAL MECHANISMS FOR THE INHIBIT ION OF GASTRIC SECRET ION AND MOTOR A C T I V I T Y OPERATE FROM THE DUODENUM. THE GASTROINTEST INAL HORMONES C H O L E C Y S T O K I N I N -PANCREOZYMIN ( C C K - P Z ) AND S E C R E T I N HAVE BEEN IMPLICATED AS THE HORMONES RELEASED IN SOME OF THESE PROPOSED MECHANISMS. DE S P I T E THE FACT THAT CCK-PZ AND S E C R E T I N ARE PROBABLY INVOLVED IN GASTRIC INHIBITORY MECHANISMS, THEY FALL SHORT OF FUL P LL L IN G THE ORIGINAL D E F I N I T I O N OF E N T E R 0 G A S T R 0 N E AS THE INHIBITORY P R I N C I P L E RELEASED FROM THE DUODENUM BY THE PRESENCE THERE OF F A T . IMPURE PREPARATIONS OF CCK-PZ ARE KNOWN TO ST IMULATE H + SECRET ION IN THE DOG WHEN GIVEN ALONE AND TO INHIBIT H + SECRET ION ST IMULATED BY G A S T R I N . IN IT IAL STUDIES IN - TH IS THES IS COMPARING THE E F F E C T S OF 2 P U R I T I E S OF CCK-PZ ON GASTRIC SECRET ION PROVIDED EV IDENCE FOR THE E X I S T E N C E OF A GASTRIC INHIBITOR D I S T I N C T FROM CCK-PZ AND S E C R E T I N IN P A R T I A L L Y P U R I F I E D CCK-PZ P R E P A R A T I O N S . IT WAS CONCLUDED FROM THESE S T U D I E S THAT IN P A R T I A L L Y P U R I F Y I N G CCK-PZ, AN INHIBITORY MATERIAL COULD HAVE BEEN REMOVED. TH IS C O N C L U -SION WAS SUPPORTED BY THE F INDING THAT A S IDE FRACTION FROM THE P U R I F I C A T I O N OF CCK-PZ, WITH NO S I G N I F I C A N T CCK OR S E C R E T I N A C T I V I T Y , P O S S E S S E D POTENT INHIBITORY A C T I V I T Y FOR GASTRIN P E N T A P E P T I D E - S T I M U L A T E D H + AND P E P S I N SECRET ION IN THE DOG. THE S IDE FRACTION REFERRED TO IN THIS T H E S I S AS EG STAGE I BECAME THE STARTING POINT FOR SEVERAL P U R I F I -CATION PROCEDURES. P U R I F I C A T I O N OF THE INHIBITORY MATERIAL I I M l L E O T O T H E D I S C O V E R Y T H A T I T WAS A P O L Y P E P T I D E D I S T I N C T IN I T S C H E M I C A L F E A T U R E S F R O M C C K - P Z , N O T A B L Y B Y T H E A B S E N C E O F T H E A M I N O A C I D P R O L I N E . T H E P U R E I N H I B I T O R Y M A T E R I A L , G A S T R I C I N H I B I T O R Y P O L Y -P E P T I D E ( G . I . P . ) , W H E N A V A I L A B L E , WAS S H O W N TO P O S S E S S NO S E C R E T IN A C T 1V I T Y , N E G L I G I B L E C C K A C T I V I T Y , A N D T O H A V E N O P Y R O G E N I C OR V A S 0 D E P R E S S O R E F F E C T S . G . I . P . WAS U S E D IN S T U D I E S T O D E T E R M I N E I T S P O T E N C Y A S AN I N H I B I T O R O F G A S T R I C S E C R E T I ON A N D M O T O R A C T I V I T Y IN T H E D O G . S T U D I E S W E R E C A R R I E D O U T IN W H I C H . G . I . P . W A S S H O W N T O B E A H I G H L Y P O T E N T I N H I B I T O R O F H + A N D P E P S I N S E C R E T I O N F R O M B l C K E L P O U C H E S A N D M O T O R A C T I V I T Y F R O M V A G A L L Y D E N E R V A T E D A N T R A L P O U C H E S S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I D E A N D T H E W H O L E G A S T R I N M O L E C U L E . A N O T H E R O B J E C T I V E WAS TO D E T E R M I N E I F G . I . P . WAS E F F E C T I V E A S A N I N H I B I T O R O F G A S T R I C S E C R E T I O N A G A I N S T S T I M U L A N T S T H A T W E R E R E S I S T A N T TO I N H I B I T I O N B Y C C K - P Z A N D S E C R E T I N , E . G . H I S T A M I N E . R E S U L T S O F T H E S E E X P E R I M E N T S P R O V E D G . I . P . TO B E A B O U T H A L F A S E F F E C T I V E A N I N H I B I T O R O F H + , P E P S I N A N D F U N D I C M O T O R A C T I V I T Y D U R I N G H I S T A M I N E I N F U S I O N A S C O M P A R E D W I T H E X P E R I M E N T S IN W H I C H G A S T R I N P E N T A P E P T I D E WAS T H E S T I M U L A N T . T H E R A N G E O F E F F E C T I V E N E S S O F G . I . P . A S A G A S T R I C I N H I B I T O R WAS E X T E N D E D TO V A G A L L Y — S T I M U L A T E D H + A N D P E P S I N S E C R E T I O N W I T H P O T E N C Y O F I N H I B I T I O N E Q U A L L I N G T H A T F O U N D IN H I S T A M I N E S T U D I E S . AS A R E S U L T O F S T R U C T U R A L S I M I L A R I T I E S B E T W E E N G . I . P . A N D G L U C A G O N , S T U D I E S W E R E C A R R I E D O U T TO D E T E R M I N E I F G . I . P . M I M I C K E D T H E H Y P E R G L Y C E M I C OR P A N C R E A T I C I N H I B I T O R Y I V ACTIONS KNOWN TO BE POSSESSED BY GLUCAGON. T H I S WAS FOUND NOT TO BE THE CASE. IN ADDITION TO I N H I B I T I N G STIMULATED GASTRIC SECRETION AND MOTOR A C T I V I T Y , G . I . P . WAS SHOWN TO I N H I B I T FUNDIC POUCH H + SECRETION, P E P S I N SECRETION AND MOTOR A C T I V I T Y IN THE UNSTIMULATED CONDITION. IT IS CONCLUDED THAT SINCE G . I . P . F U L F I L L S THE PHYSIO-LOGICAL REQUIREMENTS AS AN E F F I C I E N T GASTRIC INHIBITOR AND MIMICS THE ACTIONS OF FAT IN THE DUODENUM, IT IS AN E X C E L -LENT CANDIDATE FOR THE HUMORAL AGENT RELEASED FROM THE DUODENUM BY FAT AND PERHAPS BY HYDROCHLORIC ACID AND HYPER-TONIC SOLUTIONS* HOWEVER, RESERVATIONS MUST BE HELD AS TO ITS STATUS AS A HORMONE UNTIL IT IS DETECTED IN BLOOD AND T I S S U E S . T A B L E OF CONTENTS PAGE A B S T R A C T . . . I I L I S T OF T A B L E S vi I I L I S T OF F I G U R E S xi ACKNOWLEDGEMENTS xiv INTRODUCTION . . . . 1 METHODS 1 8 O P E R A T I V E PROCEDURES 1 8 I CHRON I C D O G S 1 8 I I ACUTE CATS 21 I I I ACUTE G U I N E A P I G S 22 IV ACUTE R A B B I T S 2 3 C O L L E C T I O N AND A N A L Y S E S OF SAMPLES 2 3 I C O L L E C T I O N OF G A S T R I C S E C R E T I O N . . . . 2 3 A . B I C K E L POUCH C O L L E C T I O N - DOG . . . . 2 3 B. G A S T R I C REMNANT C O L L E C T I O N - DOG . . 2 4 C . WHOLE STOMACH C O L L E C T I O N - CAT . . . 2 4 D. P E R F U S I O N OF ANTRAL POUCH ANO MEASUREMENT OF ANTRAL MOTOR A C T I V I T Y I N THE DOG 2 4 E . MEASUREMENT OF F U N O I C POUCH MOTOR A C T I V I T Y I N THE DOG 2 6 F . MEASUREMENT OF GALL BLADDER A C T I V I T Y I N THE DOG 2 6 I I A N A L Y S E S OF S A M P L E S 2 7 A . G A S T R I C S E C R E T I O N 2 7 A ) E S T I M A T I O N OF H + C O N C E N T R A T I O N . . 2 7 B ) E S T I M A T I O N OF P E P S I N . . . . . . . 2 7 B. P A N C R E A T I C S E C R E T I O N . . . . . . . . 2 8 A ) VOLUME 2 8 B ) P R O T E I N OUTPUT 2 8 C . E S T I M A T I O N OF BLOOD GLUCOSE . . . . . 2 8 ASSAY METHODS 2 8 I A S S A Y OF C H O L E C Y S T O K I N I N A C T I V I T Y I N G A S T R I C I N H I B I T O R Y P R E P A R A T I O N S . . . . 2 8 II A S S A Y OF E N T E R O G A S T R O N E A C T I V I T Y . . . . 3 2 II I A S S A Y OF S E C R E T I N A C T I V I T Y • • 3 2 IV A . A S S A Y FOR BLOOO P R E S S U R E CHANGES • • 3 4 B. A S S A Y FOR P Y R O G E N I C E F F E C T S 3 4 SOURCE OF HORMONE P R E P A R A T I O N S 3 4 A N A L Y S I S OF DATA 36 v V I P A G E R E S U L T S 3 8 I M U L T I P A R A M E T E R STUDY ON THE E F F E C T S OF THE I N T R A V E N O U S I N F U S I O N OF TWO P R E P A R A T I O N S C O N T A I N I N G C H O L E C Y S T O K I N I N -P A N C R E O Z Y M I N ( C C K - P Z ) 3 8 A . T H E E F F E C T OF C C K - P Z ON I N T R A -G A L L BLADDER P R E S S U R E 3 9 B. THE E F F E C T OF C C K - P Z ON A N T R A L MOTOR A C T I VI TY 39 C . THE E F F E C T OF C C K - P Z ON P E P S I N O U T P U T FROM BlCKEL P O U C H E S . . . . . . . . 39 D . THE E F F E C T OF C C K - P Z ON H+ S E C R E T I O N FROM BlCKEL P O U C H E S . 44 II C O M P A R I S O N OF TWO P R E P A R A T I O N S C O N T A I N -I N G C C K - P Z I N T E R M S OF G A S T R I C S E C R E T O R Y I N H I B I T I O N 44 I I I P R E P A R A T I O N , A S S A Y AND G A S T R I C INHIBITORY A C T I O N S OF E G S T A G E I 51 A . E F F E C T S OF E G I ON G A S T R I C S E C R E T I O N AND MOTOR A C I T V I T Y . . 57 A ) B I C K E L POUCH H + S E C R E T I O N . . . . 57 B ) B I C K E L POUCH P E P S I N S E C R E T I O N . . 60 B. E F F E C T S OF E G I ( G 2 5 ) ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y S T I M U -L A T E D BY ENDOGENOUS G A S T R I N . . . . 64 A ) B I C K E L POUCH H"*" S E C R E T I O N . . . . 64 B ) B I C K E L POUCH P E P S I N S E C R E T I O N . . 64 c) A N T R A L MOTOR A C T I V I T Y . . . . . . 64 IV P R E P A R A T I O N AND A S S A Y OF E G S T A G E II • 69 V P U R I F I C A T I O N OF E G S T A G E II TO E G S T A G E Ml 73 VI E F F E C T OF PURE G A S T R I C I N H I B I T O R Y P O L Y -P E P T I D E ON B I C K E L POUCH A C I D AND P E P S I N S E C R E T I O N AND A N T R A L M O T I L I T Y S T I M U -L A T E D BY G A S T R I N P E N T A P E P T I D E 7 3 A ) B I C K E L POUCH H+ S E C R E T I O N . . . . 7 4 B) B I C K E L POUCH P E P S I N S E C R E T I O N . . 74 c) A N T R A L MOTOR A C T I V I T Y 8 1 V I I E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P -T I D E ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N ( S H G - I ) 8 1 A ) B I C K E L POUCH H + S E C R E T I O N . . . . 8 7 B) B I C K E L POUCH P E P S I N S E C R E T I O N • . 87 c) A N T R A L MOTOR A C T I V I T Y 9 2 V I I I E F F E C T OF G . I . P . ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E 9 2 V I I PAGE V I I I ( C O N T . ) A ) B I C K E L POUCH H + S E C R E T I O N . . . . 96 B ) B I C K E L POUCH P E P S I N S E C R E T I O N . . 100 c) B I C K E L POUCH MOTOR A C T I V I T Y . . . 100 I X E F F E C T OF G . I . P . ON I N S U L I N - S T I M U L A T E D G A S T R I C S E C R E T I O N 104 A ) G A S T R I C REMNANT H * S E C R E T I O N . . 109 B ) G A S T R I C REMNANT P E P S I N S E C R E T I O N . 109 X E F F E C T OF G . I . P . ON H+ S E C R E T I O N AND VOLUME OF P A N C R E A T I C J U I C E I N THE A N A E S T H E T I Z E D CAT D U R I N G THE I N F U S I O N OF G A S T R I N P E N T A P E P T I D E 109 A ) E F F E C T OF G . I . P . ON H+ S E C R E T I O N FROM THE CAT STOMACH S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 115 B) E F F E C T OF G . I . P . ON VOLUME OF P A N C R E A T I C J U I C E D U R I N G THE I N F U S I O N OF G A S T R I N P E N T A P E P T I D E . 115 X I E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON F A S T J N G BLOOD G L U C O S E L E V E L S . . . . 117 A ) BLOOD G L U C O S E L E V E L S I N E X P E R I M E N T S I N V O L V I N G THE I N H I B I T I O N OF GASTRIN P E N T A P E P T I D E — S T I M U L A T E D H + S E C R E -T I O N . 117 B ) C O M P A R I S O N OF E Q U I M O L A R I N J E C T I O N S OF GLUCAGON AND G . I . P . ON BLOOD G L U C O S E L E V E L S I N THE DOG AND THE R A B B I T 117 X I I E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON B I C K E L POUCH P E P S I N OUTPUT S T I M U L A T E D BY S E C R E T I N . . . . . 119 X I I I E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y I N THE U N S T I M U L A T E D DOG 124 A ) B I C K E L POUCH H+ OUTPUT 124 B ) B I C K E L POUCH P E P S I N OUTPUT . . . 124 c) A N T R A L AND B I C K E L POUCH MOTOR A C T I V I T Y 124 D I S C U S S I O N 127 B I B L I O G R A P H Y 153 L I S T OF T A B L E S T A B L E PAGE I. E F F E C T OF I N T R A V E N O U S I N F U S I O N OF C C K - P Z ON I N T R A - G A L L B L A D D E R P R E S S U R E 4-0 I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF C C K - P Z ON AN T R A L M O T I L I T Y 4-2 I I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF C C K - P Z ON P E P S I N S E C R E T I O N 4 5 IV. E F F E C T OF I N T R A V E N O U S I N F U S I O N OF C C K - P Z ON H + OUTPUT 4 7 V . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF C C K - P Z ON H + OUTPUT S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E . 52 V I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ON H + OUTPUT S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E . . . 5 8 V I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ON P E P S I N OUTPUT S T I M U L A T E D BY G A S T R I N P E N T A P E P T I OE 61 V I I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ( G 2 5 ) ON H + OUTPUT S T I M U L A T E D BY P E R F U S I O N OF A N T R A L P O U C H E S WITH 0 . 1 $ ACH • 6 5 IX. E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ( G 2 5 ) ON P E P S I N OUTPUT S T I M U L A T E D BY P E R F U S I O N OF AN T R A L P O U C H E S WITH 0 . 1 $ ACH 6 7 X . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ( G 2 5 ) ON A N T R A L M O T I L I T Y S T I M U L A T E D BY P E R F U S I O N OF AN T R A L P O U C H E S WITH 0 . 1 $ ACH 7 0 X I . H + OUTPUT I N R E S P O N S E TO THE I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E 7 5 X I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ( 1 . 0 JUG/KG/HR) ON H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 76 X I I I . P E P S I N S E C R E T I O N I N R E S P O N S E TO I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E 7 8 X I V . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ( 1 . 0 XJG/KG/HR) ON P E P S I N OUTPUT S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E . . . 7 9 V I I I I X T A B L E PAGE X V . ANTRAL M O T I L I T Y R E S P O N S E TO I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E 8 2 X V I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ( 1 . 0 AJG/KG/HR) ON A N T R A L M O T I L I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 8 3 X V I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ( 2 . 0 AJG/KG/HR) ON H + O U T P U T , P E P S I N OUTPUT AND A N T R A L M O T I L I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E . . . . . 8 5 X V I I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H + OUTPUT S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N I 8 8 X I X . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N I 9 0 X X . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON ANT R A L M O T I L I T Y S T I M U L A T E D BY S Y N T H E T I C HUMAN GASTR I N I 93 X X I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H+ OUTPUT S T I M U L A T E D BY H I S T A M I N E D I H Y D R O -C H L O R I D E ( 1 0 . 0 AIG/KG/HR ) 9 7 X X I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON hT*" OUTPUT S T I M U L A T E D BY H I S T A M I N E D I H Y D R O -C H L O R I D E ( 5 . 0 / J G / K G / H R ) 9 8 X X I I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E ( 1 0 . 0 J UG/KG/HR ) 101 X X I V . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E ( 5 . 0 J U G/KG/HR ) 1 0 2 X X V . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON F U N D I C M O T I L I T Y S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E ( 1 0 . 0 / J G/KG/HR ) . . . . . . 1 0 5 X X V I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON FUND I C M O T I L I T Y S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E ( 5 . 0 / J G/KG/HR ) 1 0 6 X X V I I . C O M P A R I S O N OF THE A C T I O N OF G . I . P . ON H4" S E C R E T I ON S T I M U L A T E D BY I N S U L I N H Y PO-G L Y C A E M I A . . 1 1 0 X T A B L E P A G E X X V I I I . C O M P A R I S O N OF THE A C T I O N OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY I N S U L I N H Y P O G L Y C A E M I A 1 1 2 X X I X . E F F E C T OF G . I . P . ON H + OUTPUT AND VOLUME OF P A N C R E A T I C J U I C E D U R I N G THE I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A -P E P T I D E I N THE CAT 1 1 6 XXX. E F F E C T OF E Q U I M O L A R I N J E C T I O N S OF GLUCAGON AND G . I . P . ON F A S T I N G BLOOD GLU C O S E L E V E L S I N THE R A B B I T 1 2 0 X X X I . E F F E C T OF E Q U I M O L A R I N J E C T I O N S OF GLUCAGON AND G . I . P . ON F A S T I N G BLOOD G L U C O S E L E V E L S I N THE DOG . 1 2 2 X X X I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY S E C R E T I N . 1 2 3 X X X I I I . E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H+ O U T P U T , P E P S I N O U T P U T , A N T R A L AND F U N D I C MOTOR A C T I V I T Y I N THE U N S T I M U -L A T E D A N I M A L 1 2 5 L I S T O F F I G U R E S F I G U R E P A G E 1. D I A G R A M OF C H R O N I C DOG S U R G I C A L P R E P A R A T I O N NO. 3 20 2. A C R Y L I C A R R A N G E M E N T FOR ANTRA L POUCH C ANNUL AE 25 3. (A) A B S O R B A N C E AT 275 NM OF THE PRODUCTS OF D I G E S T I O N OF H A E M O G L O B I N WITH STANDARD P E P S I N ( B ) S T A N D A R D T Y R O S I N E CURVE (c) P L O T OF JUG T Y R O S I N E A G A I N S T JUG P E P S I N . 29 4. (A) G U I N E A P I G G A L L B L A D D E R R E S P O N S E TO 4 DOSES OF STANOARO C C K - P Z P R E P A R A T I O N ( B ) L O G DOSE R E S P O N S E CURVE P L O T T E D FROM 4(A) 31 5. E X A M P L E OF AN A S S A Y FOR E N T E R O G A S T R O N E A C T I V I T Y I N THE C H R O N I C DOG 33 6 . E X A M P L E OF AN A S S A Y FOR S E C R E T I N A C T I V I T Y I N THE A C U T E CAT 35 7. G A L L B L A D D E R P R E S S U R E CHANGES PRODUCED BY 10$ AND 40$ PURE C C K - P Z 41 8. C H A N G E S I N A N T R A L MOTOR A C T I V I T Y PRODUCED BY 10$ AND 40$ PURE C C K - P Z 43 9. C H A N G E S I N P E P S I N OUTPUT FROM B I C K E L P O U C H E S PRODUCED BY 10$ AND 40$ PURE C C K - P Z . . . . . 46 10. C H A N G E S I N H + S E C R E T I O N FROM B I C K E L P O U C H E S PRODUCED BY 10$ AND 40$ PURE C C K - P Z 48 11. B I C K E L POUCH H + OUTPUT I N R E S P O N S E TO 4 DOSES OF G A S T R I N P E N T A P E P T I D E 50 12. E F F E C T OF 10$ AND 40$ PURE C C K - P Z ON B I C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 53 13. SUMMARY OF P U R I F I C A T I O N OF G A S T R I C I N H I B I -TORY P O L Y P E P T I D E . 54 XI X I I F iGURE PAGE 1 4 . F R A C T I O N A T I O N OF 1 0 $ PURE CCK-PZ ON S E P H A D E X G-50 F I N E 56 1 5 . E F F E C T OF EGI ON B I C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 5 9 1 6 . E F F E C T OF EGI ON B I C K E L POUCH P E P S I N S E C R E -T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E . . . 62 1 7 . CCK-PZ AND E N T E R O G A S T R O N E A S S A Y S OF F R A C T I O N S R E S U L T I N G FROM THE CHROMATOGRAPHY OF EGI ON S E P H A D E X G25 63 1 8 . E F F E C T OF EGI ( G 2 5 ) ON B I C K E L POUCH H+ S E C R E T I O N S T I M U L A T E D BY ENDOGENOUS G A S T R I N . 66 1 9 . E F F E C T OF EGI ( G 2 5 ) ON B I C K E L POUCH P E P S I N S E C R E T I O N S T I M U L A T E D BY ENDOGENOUS G A S T R I N . 6 8 2 0 . ( A ) E F F E C T OF EGI ( G 2 5 ) ON A N T R A L POUCH MOTOR A C T I V I T Y S T I M U L A T E D BY ENDOGENOUS G A S T R I N ( B ) S A M P L E R E C O R O I N G OF THE E F F E C T OF EGI ( G 2 5 ) ON A N T R A L MOTOR A C T I V I T Y 71 2 1 . ( A ) F R A C T I O N A T I O N OF EGI ON C M - C E L L U L O S E ( B ) CCK-PZ AND E N T E R O G A S T R O N E A S S A Y S OF F R A C T I O N S R E S U L T I N G FROM THE CHROMA-TOGR A P H Y OF EGI ON C M - C E L L U L O S E . . . . 7 2 2 2 . E F F E C T OF 0 .25* 0,5 AND 1 . 0 J U G / K G / H R OF G . I . P . ON B I C K E L POUCH H S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 77 2 3 . E F F E C T OF 0 . 2 5 , 0.5 AND 1 . 0 J U G / K G / H R OF G . I . P . ON B I C K E L POUCH P E P S I N S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 8 0 2 4 . E F F E C T OF 0.25» 0.5 AND 1 . 0 J U G / K G / H R OF G . I . P . ON A N T R A L MOTOR A C T I V I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E 8 4 2 5 . E F F E C T OF 2.0 JUG/KG/HR OF G . I . P . ON: A. B I C K E L POUCH H + S E C R E T I O N B. B I C K E L POUCH P E P S I N S E C R E T I O N C. A N T R A L POUCH MOTOR A C T I V I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I O E 8 6 2 6 . E F F E C T OF G . I . P . ON B I C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N I (SHG-1 ) 8 9 X I I I F i C U R E P A G E 2 7 . E F F E C T OF G . I . P . ON B I C K E L POUCH P E P S I N S E C R E T I ON S T I M U L A T E D BY S H G - I 91 2 8 . E F F E C T OF G . I . P . ON ANTRAL POUCH MOTOR A C T I V I T Y S T I M U L A T E D BY S H G - I . 9 4 2 9 . B I C K E L POUCH H + OUTPUT IN R E S P O N S E TO 4 DOSES OF H I S T A M I N E D I H Y D R O C H L O R I D E 9 5 3 0 . ( A ) E F F E C T OF G . I . P . ON B I C K E L POUCH H+ S E C R E T I O N S T I M U L A T E D BY 1 0 . 0 JUG/KG/HR OF H I S T A M I N E D I H Y D R O C H L O R I D E ( B ) E F F E C T OF G . I . P . ON B I C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY 5 . 0 A J G / K G / H R OF H I S T A M I N E D I H Y D R O C H L O R I D E 9 9 3 1 . ( A ) E F F E C T OF G . I . P . ON B I C K E L POUCH P E P S I N S E C R E T I O N DURING THE I N F U S I O N OF 1 0 . 0 JUG/KG/HR OF H I S T A M I N E D I HYOROCHLORI DE ( B ) E F F E C T OF G . I . P . ON B I C K E L POUCH P E P S I N S E C R E T I O N DURING THE I N F U S I O N OF 5.0 /UG/KG/HR OF H I S T A M I N E D I H Y D R O C H L O R I D E . 1 0 3 3 2 . ( A ) E F F E C T OF G . I . P . ON B I C K E L POUCH MOTOR A C T I V I T Y DURING THE I N F U S I O N OF 1 0 . 0 JUG/KG/HR OF H I S T A M I N E D I H Y D R O C H L O R I D E ( B ) E F F E C T OF G . I . P . ON B I C K E L POUCH MOTOR A C T I V I T Y DURING THE I N F U S I O N OF 5.0 /UG/KG/HR OF H I S T A M I N E D I H Y D R O C H L O R I D E . 1 0 7 3 3 » SAMPLE R E C O R D I N G OF THE E F F E C T OF G . I . P . ON B I C K E L POUCH MOTOR A C T I V I T Y ON A BACKGROUND I N F U S I O N OF H I S T A M I N E D I H Y D R O C H L O R I D E . . . . 1 0 8 3 4 . E F F E C T OF G . I . P . ON G A S T R I C REMNANT H* S E C R E T I O N S T I M U L A T E D BY I N S U L I N 1 1 1 3 5 . E F F E C T OF G . I . P . ON G A S T R I C REMNANT P E P S I N S E C R E T I O N S T I M U L A T E D BY I N S U L I N 1 1 3 3 6 . S I M I L A R I T I E S IN S T R U C T U R E OF S E C R E T I N , GLUCAGON AND G. I . P 1 1 4 3 7 . BLOOD G L U C O S E L E V E L S DURING AN E X P E R I M E N T IN WHICH G . I . P . I N H I B I T E D G A S T R I N P E N T A -P E P T I D E - S T IMULATED H+ S E C R E T I O N IN THE DOG . 1 1 8 3 8 . E F F E C T OF G . I . P . AND GLUCAGON ON BLOOD SUGAR L E V E L S IN THE R A B B I T 1 2 1 ACKNOWLEDGEMENTS I WOULD L I K E TO THANK MY S U P E R V I S O R DR. J.C. BROWN FOR H I S G U I O A N C E D U R I N G MY S T A Y I N THE D E P A R T M E N T OF P H Y S I O L O G Y , AND FOR THE L A R G E PART OF H I S P E R S O N A L L I F E THAT WAS S P E N T ON MY B E H A L F . I WOULD A L S O L I K E TO THANK DR. J.A. P E A R S O N FOR H I S A D V I C E ANO A S S I S T A N C E WITH REGARO TO MY R E S E A R C H ANO T H E S I S P R E P A R A T I O N . I AM P E R M A N E N T L Y I N D E B T E D TO MlSS JlLL D R Y B U R G H FOR HER I N V A L U A B L E T E C H N I C A L A S S I S T A N C E AND ENCOURAGEMENT AS A F R I E N D . I AM A L S O G R A T E F U L FOR THE T E C H N I C A L A S S I S T A N C E OF MRS. HEATHER G R I F F I T H S AND MR. TONY M C L I N T O C K . I WOULD L I K E TO THANK MR. KURT H E N Z E ANO MR. R A L P H A S S I N A FOR T H E I R A S S I S T A N C E THROUGHOUT THE COURSE OF MY R E S E A R C H , P A R T I C U L A R L Y I N THE P R E P A R A T I O N OF THE I L L U S T R A T I O N S FOR T H I S T H E S I S . I WOULD A L S O L I K E TO THANK MlSS B E V E R L Y WENKSTERN FOR UNDER-T A K I N G THE ARDUOUS T A S K OF T Y P I N G THE F I N A L D R A F T OF T H I S T H E S I S . I WOULD F I N A L L Y L I K E TO THANK MY W I F E MARGARET FOR T Y P I N G THE ROUGH D R A F T S OF T H I S T H E S I S , AND FOR HER P E R S E -V E R A N C E THROUGHOUT MY WORK. F I N A N C I A L A S S I S T A N C E I N THE FORM OF A S T U O E N T S H I P FROM THE M E O I C A L R E S E A R C H C O U N C I L OF CANADA I S G R A T E F U L L Y ACKNOWLEDGED. X I V INTRODUCTION MECHANISMS FOR THE INHIB IT ION OF GASTRIC S E C R E T I O N AND MOTOR A C T I V I T Y OPERAT ING FROM THE DUOOENUM HAVE BEEN SHOWN TO BE A C T I V A T E D DURING THE D I G E S T I O N OF A M E A L . THOMAS, CRIDER ANO MOGAN (1934) CONSIDERED THAT THE STOMACH PUMPED MATERIAL INTO THE DUODENUM, WITH THE RATE OF TRANSFER FROM STOMACH TO DUODENUM BEING L E S S THAN THE MAXIMAL RATE THE PUMP COULD A C H I E V E . THEY CONSIDERED THAT THE R E S T R A I N T OF THE G A S T R I C PUMP DEPENDED UPON THE A C T I V I T Y OF RECEPTORS IN THE DUODENAL WALL ST IMULATED BY CONST ITUENTS OF GASTRIC CHYME. THE IMPORTANCE OF R E S T R A I N T OF GASTRIC EMPTYING WAS I L L U S T R A T E D BY THE FACT THAT THE SMALL I N T E S T I N E WAS THE MAIN FOOD ABSORBING ORGAN, AND IF THE AMOUNTS WHICH L E F T THE STOMACH EXCEEDED THE C A P A C I T Y OF THE GUT FOR ENZYME D E G R A D A -TION AND A B S O R P T I O N , AN OSMOTIC PURGE WOULD R E S U L T . MOST I N F L U E N C E S ON G A S T R I C EMPTYING HAVE BEEN SHOWN TO BE INHIBITORY IN N A T U R E , AN E X C E P T I O N B E I N G THE F INDING BY MARBAIX ( 1 8 9 8 ) THAT D I S T E N S I O N CAUSED AN INCREASE IN GASTRIC E M P T Y I N G . THE RATE OF EMPTYING OF THE STOMACH HAS BEEN SHOWN TO BE DEPENDENT UPON THE VOLUME OF ITS CONTENTS ANO TO BE HELD IN CHECK BY INHIBITORY MECHANISMS O R I G I N A T I N G IN THE DUODENUM AND ELSEWHERE IN THE SMALL I N T E S T I N E . IN THE STUDY OF HUMORALLY MEDIATED GASTRIC INHIBITORY MECHANISMS O R I G I N A T I N G IN THE DUODENUM, THE FOLLOWING STAGES OCCURRED IN REACHING THE CURRENT L E V E L OF KNOWLEDGE OF THE MECHANISMS: 1. ACCUMULATION OF EXPERIMENTAL E V I D E N C E THAT - 2 -HUMORALLY MEDIATED G A S T R I C INHIBITORY MECHANISMS E X I S T E D , 2. COMPARISON OF P H Y S I O L O G I C A L ST IMULI ( F A T , HC L , HYPERTONIC S O L U T I O N S ) IN TERMS OF THE SPECTRUM AND POTENCY OF G A S T R I C INHIBITORY A C T I O N S , AND 3. ATTEMPTS TO ISOLATE AND P U R I F Y THE A C T I V E P R I N C I P L E S R E S P O N S I B L E FOR THE GASTRIC INHIBITORY 1 A C T I O N S . EWALO AND BOAS ( 1 8 8 6 ) F I R S T REPORTED ON WHAT WAS SUBSEQUENTLY PROVEN TO BE A DUODENAL MECHANISM FOR I N H I B I T I O N OF GASTRIC S E C R E T I O N . THEY DEMONSTRATED THAT OL IVE OIL WHEN ADDED TO A STARCH TEST MEAL WOULD DEPRESS GASTRIC S E C R E T I O N IN HUMANS. PAVLOV ( 1 9 1 0 ) FOUND THAT OL IVE OIL IN THE DUOOENUM WOULD INHIB IT M E A T - S T I M U L A T E D GASTRIC S E C R E T I O N FROM A PAVLOV POUCH. HE P O S T U L A T E D THAT THE OIL WAS R E F L E X L Y I N H I B I T I N G THE C E P H A L I C OR P S Y C H I C PHASE OF GASTRIC S E C R E T I O N . F E N G , HOU AND L IM ( 1 9 2 9 ) OBSERVED THAT OL IVE OIL IN THE DUODENUM I N H I B I T E D M E A T - S T I M U L A T E D S E C R E T I O N IN TRANSPLANTED POUCHES OF THE WHOLE STOMACH. THE SAME GROUP I N J E C T E D INTRAVENOUS FATTY CHYLE FROM ONE DOG INTO ANOTHER TO D E T E R -MINE WHETHER THE BLOOD BORNE AGENT WHICH OPERATED A F T E R FAT WAS INTRODUCED INTO THE DUODENUM CONSISTED OF A HORMONE R E L E A S E D FROM THE DUOOENUM, OR THE ABSORBED PRODUCTS OF D I G E S T I O N . THE ABSENCE OF SECRETORY INH IB IT ION PROVED THAT THE OBSERVED E F F E C T WAS NOT DUE TO ABSORPTION PRODUCTS OF THE MEAL AND THEY CONCLUDED THAT A HORMONAL PATHWAY WAS INVOLVED IN THE MECHANISM. THE F I R S T ATTEMPTS TO ISOLATE THE BLOOD BORNE AGENT R E S P O N S I B L E FOR G A S T R I C INH IB IT ION WERE MADE BY KOSAKA AND - 3 -L I M ( 1 9 3 0 A ) . THEY FOUND THAT THE CRUDE C H O L E C Y S T O K I N I N ( C C K ) OF IVY ( 1 9 2 8 ) WOULD I N H I B I T G A S T R I C S E C R E T I O N FROM H E I D E N H A I N P O U C H E S S T I M U L A T E D BY A MEAT MEAL AND H I S T A M I N E . K O S A K A ANO L I M S U G G E S T E D THAT IVY'S C C K P R E P A R A T I O N C O N T A I N E D AN I M P U R I T Y WHICH WAS R E S P O N S I B L E FOR G A S T R I C S E C R E T O R Y I N H I B I T I O N AND THEY A T T E M P T E D TO I S O L A T E I T . IN THE SAME YEAR ( 1 9 3 0 B ) , T H I S GROUP P R E P A R E D E X T R A C T S OF DUODENAL MUCOSA MADE A F T E R E X P O S U R E TO O L I V E O I L AND FOUND THAT T H E S E E X T R A C T S HAD I N H I B I T O R Y P R O P E R T I E S S I M I L A R TO THOSE OF C C K P R E P A R A T I O N S . THEY NAMED THE A C T I V E P R I N C I P L E E N T E R O G A S T R O N E . THE WORK OF FENG E_T AJL ( 1 9 2 9 ) HAS B E E N C O N F I R M E D I N S E V E R A L S P E C I E S U S I N G D I F F E R E N T S T I M U L I FOR A C I D S E C R E T I O N . FAT I N THE DUODENUM WAS SHOWN BY B I B L E R , H A R K I N S AND NYHUS ( 1 9 6 5 ) TO I N H I B I T A C I D S E C R E T I O N S T I M U L A T E D BY EXOGENOUS G A S T R I N I N THE DOG, BY H A L V O R S O N , M L D D L E T O N , B L B L E R , H A R K I N S AND NYHUS (1966) TO I N H I B I T H I S T A M I N E - S T I M U L A T E O S E C R E T I O N I N THE DOG, AND BY S H A Y , GERSHON-COHEN AND F E L S ( 1 9 3 9 ) TO I N H I B I T A C I D S E C R E T I O N S T I M U L A T E D BY BOTH MEANS IN MAN. K A S A N S K I ( 1 9 0 3 ) FOUND THAT THE P S Y C H I C OR V A G A L L Y INDUCED S E C R E T I O N OF G A S T R I C J U I C E WAS AL S O I N H I B I T E D BY FAT IN THE DOG. T H I S WAS C O N F I R M E D BY A L L E Y AND M A C K E N Z I E ( 1 9 3 4 ) , WHO FOUND THAT O L I V E O I L IN THE DUODENUM WOULD I N H I B I T G A S T R I C S E C R E T I O N FROM THE M A I N STOMACH OF THE DOG S T I M U L A T E D BY SHAM F E E D I N G . J O H N S T O N ANO DU T H I E ( 1 9 6 9 ) FOUND THAT FAT I N THE DUODENUM WOULD ONLY I N H I B I T AC ID S E C R E T I O N IN U L C E R P A T I E N T S WITH I N T A C T VAGUS N E R V E S . T H E Y FOUND THAT I N H I B I -T I O N BY FAT OF BOTH G A S T R I N - AND H I S T A M I N E - S T I M U L A T E D - 4 -S E C R E T I ON WAS A B O L I S H E D IN P A T I E N T S WHO HAD UNDERGONE VAGOTOMY. T H I S WORK SUGGESTED THAT AT L E A S T IN MAN, THE VAGUS PLAYED A ROLE IN THE INHIB IT ION OF GASTRIC S E C R E T I O N PRODUCED BY INTRADU0DENAL F A T . SLRCUS ( 1 9 5 8 ) FOUND THAT ONE OF THE CONDIT IONS OF FAT INHIB IT ION OF GASTRIC S E C R E T I ON WAS THAT THE FAT BE PRE INCUBATED WITH P A N C R E A T I C J U I C E . O L I V E OIL PLACED IN ISOLATED DUODENAL LOOPS RESULTED IN NO I N H I B I T I O N OF ACID S E C R E T I O N . S I M I L A R L Y , MENGUY ( I 9 6 0 ) FOUND THAT IN R A T S , FAT F A I L E D TO INHIB IT GASTRIC S E C R E T I O N IN THE ABSENCE OF B I L E SALTS OR L I P A S E . LOBASOV ( 1 8 9 6 ) , A P U P I L OF P A V L O V , F I R S T DEMONSTRATED THAT MIXING FAT WITH FOODSTUFFS INHIB ITED P E P T I C A C T I V I T Y OF GASTRIC J U I C E IN THE DOG. A L L E Y AND MACKENZIE ( 1 9 3 4 ) CONFIRMED THAT OL IVE OIL IN THE DUODENUM INHIB ITED THE P E P S I N OUTPUT OF THE MAIN STOMACH ST IMULATED BOTH BY H ISTAMINE AND BY SHAM F E E D I N G . FROM THE TIME OF BEAUMONT ( 1 8 3 3 ) » IT WAS KNOWN THAT THE RATE OF GASTRIC EMPTYING WAS A FUNCTION OF THE TYPE OF MEAL E A T E N . IN H IS OBSERVAT IONS ON HIS GASTRIC F I S T U L A P A T I E N T , A L E X I S S T . M A R T I N , HE NOTED THAT FATTY FOODS REMAINED IN THE STOMACH THE L O N G E S T . ONE OF THE E A R L I E S T O B S E R V A T I O N S REGARDING THE E F F E C T OF FAT ON GASTRIC EMPTYING WAS MADE 8Y WLRSCHUBSKI ( 1 9 0 0 ) . HE OBSERVED THAT FAT DELAYED THE EVACUATION OF THE STOMACH IN DOGS, A F INDING WHICH WAS CONFIRMED BY CANNON (1911 ) USING A ROENTGENOLOGICAL METHOD. UNT IL THE TURN OF THE CENTURY IT WAS THOUGHT THAT FAT E X E R T E D ITS INHIBITORY ACTION ON GASTRIC MOT IL ITY WHILE - 5 -IN THE STOMACH. HOWEVER L L N T W A R E V ( 1 9 0 3 ) O B S E R V E D I N H I B I T I O N OF G A S T R I C M O T I L I T Y UPON I N T R O D U C I N G O L I V E O I L INTO THE DUODENUM. F A R R E L L AND IVY ( 1 9 2 6 ) E S T A B L I S H E D THAT I N H I B I T I O N OF G A S T R I C M O T I L I T Y BY FAT IN THE DUODENUM O P E R A T E D AT L E A S T P A R T L Y V I A A HUMORAL M E C H A N I S M WHEN THEY SHOWED THAT THE M O T I L I T Y OF A T R A N S P L A N T E D F U N D I C POUCH WAS I N H I B I T E D BY F E E D I N G A FAT M E A L . L L M , LOO AND L L U ( 1 9 2 7 ) C O N F I R M E D THAT THE P R E S E N C E OF FAT I N THE DUODENUM OR J E J U N U M I N H I B I T E D THE MOTOR A C T I V I T Y OF A POUCH OF THE E N T I R E STOMACH AND OF A STOMACH D E P R I V E D OF A L L I T S E X T R I N S I C NERVE S U P P L Y . Q U I G L E Y » Z E T T L E M A N AND IVY ( 1 9 3 4 ) SHOWED THAT I N H I B I T I O N OF M O T I L I T Y WAS NOT DUE TO A B S O R B E D FAT I T S E L F OR TO THE PRODUCTS OF I T S D I G E S T I O N . T H I S GROUP A L S O SHOWED C O N C L U S I V E L Y THAT I N A POUCH OF THE E N T I R E STOMACH, A D E N E R V A T E D POUCH, AN AUTO-T R A N S P L A N T E D POUCH AND I N A P A V L O V POUCH, FAT P L A C E D D I R E C T L Y W I T H I N THE STOMACH WAS WITHOUT S I G N I F I C A N T E F F E C T ON G A S T R I C M O T I L I T Y , WHEREAS THE I N H I B I T O R Y E F F E C T ON MOTOR A C T I V I T Y WAS ALWAYS MARKED WHEN FAT WAS INTRODUCED D I R E C T L Y INTO THE DUODENUM. A C C O R D I N G TO P A V L O V ( 1 9 1 0 ) , A NERVOUS R E F L E X WAS R E S P O N S I B L E FOR THE I N H I B I T I O N OF G A S T R I C MOTOR A C T I V I T Y BY F A T . CANNON ( 1 9 1 1 ) A L S O A T T R I B U T E D THE I N H I B I T O R Y E F F E C T TO THE I N T E R V E N T I O N OF N E R V O U S R E F L E X E S . IT HAD B E E N SHOWN BY WADOELL AND WANG ( 1 9 5 3 ) THAT THE E F F E C T OF I N T R A D U O D E N A L FAT ON G A S T R I C M O T I L I T Y I N MAN WAS REDUCED BY VAGOTOMY, AS WAS THE I N H I B I T I O N OF G A S T R I C S E C R E T I O N BY F A T . S I M I L A R R E S U L T S WERE R E P O R T E D BY Q U I G L E Y AND MESCHAN ( 1 9 3 8 ) WORKING WITH DOGS. THE F I R S T D E M O N S T R A T I O N THAT I N T E S T I N A L A C I D I F I C A T I O N - 6 -I N H I B I T E D G A S T R I C S E C R E T I O N WAS P R O V I D E D BY SOKOLOV ( 1 9 0 4 ) . HE DEMONSTRATED THAT THE I N T R O D U C T I O N OF 0 . 5 $ HCL INTO THE DUODENUM M A R K E D L Y D I M I N I S H E D A C I D S E C R E T I O N FROM A P A V L O V POUCH S T I M U L A T E D BY A MEAT M E A L . DAY AND WEBSTER ( 1 9 3 5 ) R E I N V E S T I G A T E D T H I S P R O B L E M , U S I N G DOGS WITH E S O P H A G O T O M I E S AND METAL F I S T U L A E I N THE STOMACH AND DUODENUM. T H E Y FOUND THAT HCL OR G A S T R I C J U I C E WHEN INTRODUCED INTO THE DUODENUM I N H I B I T E D G A S T R I C S E C R E T I O N S T I M U L A T E D BY SHAM F E E D I N G . E X P E R I M E N T S WERE P E R F O R M E D ON P A V L O V POUCH DOGS WITH G A S T R I C AND DUODENAL F I S T U L A E BY P l N C U S , THOMAS AND R E H F U S S ( 1 9 4 2 ) TO D E T E R M I N E WHY I N C E R T A I N C A S E S HCL IN THE DUODENUM D I D NOT I N H I B I T G A S T R I C S E C R E T I O N . T H E Y DEMONSTRATED THAT HCL D I D NOT D E P R E S S G A S T R I C S E C R E T I O N U N T I L THE DUODENAL PH HAD F A L L E N TO 2 . 5 . G R I F F I T H S ( 1 9 3 6 ) DEMONSTRATED I N MAN THAT HCL I N THE DUODENUM I N H I B I T E D G A S T R I C S E C R E T I ON S T I M U L A T E D BY A L C O H O L . CODE AND V/ATKINSON ( 1 9 5 5 ) I M P L I C A T E D A NERVOUS M E C H A N I S M I N A C I D I N H I B I T I O N OF G A S T R I C S E C R E T I O N WHEN THEY FOUND THAT I N F U S I O N OF A C I D INTO THE DUODENUM I N H I B I T E D THE R E S P O N S E TO A MEAL FROM P A V L O V POUCHES BUT NOT FROM V A G A L L Y D E N E R V A T E D P O U C H E S . IT HAS S U B S E Q U E N T L Y B E E N E S T A B L I S H E D THAT A HUMORAL I N H I B I T O R Y M E C H A N I S M DOES E X I S T , SO THAT WHETHER A VAGAL M E C H A N I S M E X I S T S IN A D D I T I O N TO OR IN C O N J U N C T I O N WITH A HUMORAL M E C H A N I S M I S S T I L L AN OPEN Q U E S T I O N . IT HAS B E E N WELL E S T A B L I S H E D P R I N C I P A L L Y BY A N D E R S S O N ( 1 9 6 0 A , B , C ) THAT A C I D IN THE DUODENUM C A U S E S I N H I B I T I O N OF G A S T R I C S E C R E T I O N V I A A HUMORAL M E C H A N I S M . HE FOUND THAT A C I D I F I C A T I O N OF THE DUODENUM OF DOGS WITH E I T H E R VAGALLY INNERVATED OR VAGALLY OENERVATED GASTRIC POUCHES I N H I B I T E D SECRETORY RESPONSES FROM BOTH TYPES OF POUCHES DURING F A S T I N G ( 1 9 6 0 A ) » AND IN RESPONSE TO A MEAL ( 1 9 6 0 B ) . WORMSLEY AND GROSSMAN (1964) HAVE SHOWN THAT A C I D I F Y I N G THE DUODENUM I N H I B I T E D THE HEIDENHAIN POUCH RESPONSE TO EXOGENOUS G A S T R I N . S L N C E THE SECRETORY RESPONSE TO EXOGENOUS GASTRIN WAS I N H I B I T E D , ACID IN THE DUODENUM MUST HAVE R E L E A S E D A HORMONE WHICH INHIB ITED GASTRIC S E C R E T I O N AT SOME POINT A F T E R THE R E L E A S E OF G A S T R I N . ANDERSSON ( 1 9 6 0 C ) , ANDERSSON AND GROSSMAN (1965) AND JOHNSON AND GROSSMAN ( 1 9 6 8 ) CONFIRMED THAT DUOOENAL A C I D I F I C A T I O N DID NOT INHIB IT HISTAM I N E - S T I MULATED S E C R E T I O N IN THE DOG. A C I D I F I C A T I O N OF THE DUODENUM HAS BEEN SHOWN TO S T I M U -L A T E P E P S I N S E C R E T I O N BY S T E N I N G E_T AJ. (1969A ) IN CONTRAST TO THE INHIBITORY E F F E C T OF FAT IN THE DUODENUM ON THIS P A R A M E T E R . P A V L O V ( 1 9 1 0 ) E S T A B L I S H E D THAT THE PASSAGE OF CHYME FROM THE P Y L O R I C ANTRUM OF THE STOMACH INTO THE DUODENUM WAS I N T E R M I T T E N T . IT APPEARED THAT THE PASSAGE OF FOOD FROM THE STOMACH TO THE DUODENUM WAS REGULATED Q U A N T I T A T I V E L Y BY A R E F L E X FROM THE L A T T E R . T H I S WAS F I R S T DEMONSTRATED BY SERDIUKOV ( 1 9 0 3 ) , A C O L L E A G U E OF P A V L O V , WHO SHOWED THAT I N H I B I T I O N OF GASTRIC EMPTYING WAS CAUSED BY A CHEMICAL E F F E C T PRODUCED BY CONTACT OF ACID CHYME WITH THE DUODENUM. HE FOUND THAT A SOLUT ION OF SODIUM BICARBONATE PREV IOUSLY INTRODUCED INTO THE STOMACH REMAINED THERE I N D E F I N I T E L Y IF SMALL Q U A N T I T I E S OF ACID SOLUTION OR GASTRIC J U I C E WERE - 8 -CONTINUOUSLY INTRODUCED INTO THE DUODENUM. IF NO ACID WAS P R E S E N T , THE A L K A L I N E SOLUTION WAS EMPTIED FROM THE STOMACH VERY Q U I C K L Y . HENCE EACH TIME THAT THE I N T E S T I N E R E C E I V E D ACID CONTENTS FROM THE STOMACH, A MECHANISM WAS TRIGGERED WHICH TEMPORARILY BLOCKED G A S T R I C E M P T Y I N G . PAVLOV C O N -S I D E R E D T H I S TO BE A VERY L O G I C A L PROCESS AND OF GREAT A S S I S T A N C E IN THE FUNCTIONS OF THE D I G E S T I V E T R A C T . THE A C I D I F I E D FOOD ALLOWED TO PASS THROUGH THE PYLORUS WOULD CAUSE AN INCREASED FLOW OF P A N C R E A T I C J U I C E ANO B I L E WHICH WOULD RAPIDLY LEAD TO N E U T R A L I Z A T I O N OF DUOOENAL C O N T E N T S . ONLY WHEN TH IS HAD BEEN ACCOMPLISHED WOULD THE E S C A P E OF A FURTHER PORTION OF CONTENTS FROM THE STOMACH BE P E R M I T T E D . SHAY AND GERSHON-COHEN (1934) REPORTED THAT THE MECHANISM OF I N H I B I T I O N OF GASTRIC MOT IL ITY BY ACID WAS P R E S E N T IN HUMANS. THEY NOTED A DELAY IN THE EVACUATION OF THE HUMAN STOMACH WHEN HCL WAS ADDED TO A TEST M E A L . THOMAS (1947) FOUND THAT THE STOMACH WOULD CONTINUE TO EMPTY , BUT AT A D IMIN ISHING R A T E , AS THE PH OF THE DUODENAL CONTENTS DECREASED FROM PH 3.0 TO PH 2 . 0 , WITH THE STOMACH C E A S I N G TO EMPTY AT PH 2 . 0 . INVOLVEMENT OF THE VAGUS IN THE GASTRIC INHIBITORY MECHANISM TRIGGERED BY ACID WAS INDICATED BY THOMAS ( 1 9 4 7 ) AND QUIGLEY AND MESCHAN ( 1 9 3 8 ) WHEN THEY FOUND THAT THE R E F L E X MOTOR INHIBITORY RESPONSE TO ACID IN DOGS IS P R A C T I C A L L Y ABOLISHED BY VAGOTOMY. LECONTE ( 1 9 0 0 ) DEMONSTRATED THAT THE INTRODUCTION OF A 2 5 $ SOLUTION OF GLUCOSE INTO THE DUODENUM INHIB ITED BOTH THE SECRET I ON AND M O T I L I T Y OF THE STOMACH. OKADA ET AL ( 1 9 2 7 ) - 9 -B E L I E V E D THAT THE INHIBITORY MECHANISM WAS MEDIATED BY HYPERGLYCAEMI A . T H I S WAS DISPROVED AS A RESULT OF THE DEMONSTRATION BY ROHOLM (1930) THAT GASTRIC S E C R E T I O N DIO NOT CHANGE DURING ADRENAL INE—INDUCED HYPERGLYCAEM I A OR THE INTRAVENOUS INFUSION OF GLUCOSE (KALK AND MEYER, 1939). I T WAS SHOWN BY DAY AND KOMAROV (1939) THAT I N S T I L L A T I O N OF 2 0 $ OR HIGHER CONCENTRATIONS OF GLUCOSE INTO THE DUODENUM OF DOGS INHIB ITED THE RESPONSE TO H I S T A M I N E . T H I S INH IB IT ION WAS I N D I C A T I V E OF A COMMON OSMORECEPTOR MECHANISM S E N S I T I V E TO CERTAIN L E V E L S OF DUODENAL OSMOLARITY , BECAUSE OF THE FACT THAT OTHER S U G A R S , P O L Y S A C C H A R I D E S AND S A L I N E HAD S IMILAR A C T I O N S . IN A FURTHER ATTEMPT TO E L U C I D A T E THE MECHANISM OF ACTION OF G L U C O S E , S H A Y , G E R S H O N - C O H E N , F E L S AND S L P L E T ( 1 9 4 2 ) SHOWED THAT INSULIN HYPOGLYCAEMI A DID NOT COMPLETELY A B O L I S H THE E F F E C T OF DUODENAL GLUCOSE I N S T I L L -AT ION ON ACID S E C R E T I O N , ALTHOUGH IT WAS REDUCED. TH IS GROUP CONCLUDED THAT THE MAIN E F F E C T WAS DUE TO DUODENAL OSMORECEPTORS WITH A SMALL PART DUE TO HYPERGLYCAEMI A . S L R C U S ( 1 9 5 8 ) PERFORMED EXPERIMENTS IN WHICH 5 $ S A L I N E , FRUCTOSE ANO GLUCOSE IN THE DUODENUM I N H I 8 I T E D HIS T A M I N E -ST IMULATED S E C R E T I ON FROM BOTH INNERVATED AND DENERVATEO P O U C H E S . S I N C E I N H I B I T I O N WAS PRODUCED IN TRANSPLANTED P O U C H E S , IT WAS CONCLUDED THAT HYPERTONIC SOLUT IONS IN THE DUODENUM R E L E A S E D AN INHIBITORY HORMONE. SOME OF THE E A R L I E S T OBSERVAT IONS OF OSMOTIC E F F E C T S ON GASTRIC MOT IL ITY WERE MADE BY SHAY ANO GERSHON-COHEN ( 1 9 3 4 ) EMPLOYING RADIOGRAPHIC T E C H N I Q U E S . THEY N0TE0 THAT - 1 0 -HYPERTONIC SOLUTIONS OF S A L T S OR GLUCOSE SLOWEO EMPTYING OF THE STOMACH. QUIGLEY ANO H A L L A R A N ( 1 9 3 2 ) F I R S T DEMONSTRATED THAT THE INH IB IT ION OF GASTRIC MOT IL ITY WAS NOT DUE TO HYPERGLYCAEMIC E F F E C T S . THEY FOUND THAT THE INTRAVENOUS ADMINISTRAT ION OF GLUCOSE F A I L E D TO A L T E R SPONTANEOUS G A S T R O I N T E S T I N A L M O T I L I T Y IN DOGS. QUIGLEY AND P H E L P S ( 1 9 3 4 ) FOUND THAT SUGARS IN THE I N T E S T I N E I N H I B I T E D THE MOT IL ITY OF TRANSPLANTED AND THEREFORE DENERVATED GASTRIC P O U C H E S , INDICAT ING THAT A HUMORAL MECHANISM WAS INVOLVED IN THE INH IB IT ION OF GASTRIC MOT IL ITY BY CARBOHYDRATES IN THE DUODENUM. QUIGLEY AND MESCHAN ( 1 9 3 8 ) FOUND THAT INHIB IT ION OF GASTRIC M O T I L I T Y AND S E C R E T I O N IN DOGS, PRODUCED BY P L A C I N G HYPERTONIC SOLUT IONS IN THE DUODENUM, WAS ABOL ISHED BY VAGOTOMY. AS S T A T E D E A R L I E R , P A V L O V J S GROUP ASSUMED THAT MECHAN-ISMS OF I N H I B I T I O N OF GASTRIC S E C R E T I O N AND MOT IL ITY WERE MEDIATED BY NERVOUS R E F L E X E S . EVEN THOUGH HUMORAL FACTORS HAD L A T E R BEEN I M P L I C A T E D IN THE ACTION OF F A T , ACID AND HYPERTONIC SOLUT IONS ON GASTRIC S E C R E T I O N AND M O T I L I T Y , E V I D E N C E E X I S T E D FOR THE I M P L I C A T I O N OF NERVOUS MECHANISMS AS WELL . THOMAS AND MOGAN ( 1 9 3 1 ) PROPOSED AN " E N T E R O G A S T R I C R E F L E X " THROUGH WHICH INHIB IT ION OF GASTRIC P E R I S T A L S I S COULD BE BROUGHT ABOUT BY A P P R O P R I A T E CHEMICAL OR MECHANICAL S T I M U L A T I O N OF THE MUCOSA OF THE UPPER I N T E S T I N E . T H I S R E F L E X WAS I M P L I C A T E D IN S I T U A T I O N S MENTIONED E A R L I E R WHERE I N H I B I T I O N OF ACID S E C R E T I O N AND M O T I L I T Y FROM THE DUODENUM WAS MARKEDLY REDUCED BY S E C T I O N I N G THE VAGUS N E R V E S . A - 11 -N E R V O U S M E C H A N I S M HAS THUS B E E N I M P L I C A T E D IN THE I N H I B I T I O N OF G A S T R I C S E C R E T I ON BY FAT AND A C I D I N THE DUODENUM, AND I N THE I N H I B I T I O N OF G A S T R I C M O T I L I T Y BY F A T , A C I D AND H Y P E R T O N I C S O L U T I O N S I N THE DUODENUM. NO E X P E R I M E N T A L D E S I G N , HOWEVER, HAS B E E N P R O P O S E D TO I S O L A T E A NERVOUS M E C H A N I S M FROM THE HUMORAL I N H I B I T O R Y M E C H A N I S M S THAT ARE KNOWN TO E X I S T . A F T E R THE I N I T I A L D I S C O V E R Y , A T T E M P T S BY WORKERS TO I S O L A T E THE E N T E R O G A S T R O N E OF KOSAKA AND L l M ( 1 9 3 0 B ) MET WITH L I T T L E S U C C E S S . WALAWSKI ( 1 9 2 8 ) PRODUCED A " B I O D I A L Y -SATE 1' BY S O A K I N G S M A L L ANO L A R G E I N T E S T I N E S OF DOGS I N R I N G E R - L O C K E ' S S O L U T I O N AT 3 7 ° C FOR ONE HOUR. THE B I O -D I A L Y S A T E PRODUCED I N H I B I T I O N OF H I S T A M I N E - S T I M U L A T E D S E C R E -T I O N I N G A S T R I C F I S T U L A DOGS. K O S A K A , L L M , L L N G ANO L L U ( 1 9 3 2 ) R E P E A T E D WALAWSKL'S E X P E R I M E N T ANO FOUND THAT THE M A T E R I A L E X T R A C T E D WOULD I N H I B I T THE R E S P O N S E OF A H E I D E N H A I N POUCH S E C R E T I N G I N R E S P O N S E TO A M E A L . F U R T H E R A T T E M P T S WERE MADE BY GRAY, B R A D L E Y AND IVY ( 1 9 3 7 ) AND GREENGARD, A T K I N S O N , GROSSMAN AND IVY ( 1 9 4 6 ) TO I S O L A T E E N T E R O G A S T R O N E , BUT EFFORTS TO C O N C E N T R A T E THE A C T I V E P R I N C I P L E MET WITH L I T T L E S U C C E S S . AT THE END OF T H E S E P U R I F I C A T I O N P R O C E D U R E S , S E C R E T I N AND CCK A C T I V I T Y WERE S T I L L R E T A I N E D , M A K I N G I T I M P O S S I B L E TO D E T E R M I N E WHETHER OR NOT THE I N H I B I T O R Y E F F E C T OF FAT I N THE DUODENUM WAS DUE TO S E C R E T I N , C C K , A C O M B I N A T I O N OF T H E S E TWO, OR DUE TO SOME OTHER HUMORAL A G E N T . AS A R E S U L T OF WORK DONE S U B S E Q U E N T L Y ON G A S T R I C I N H I B I T I O N , THE C L A S S I C A L D E F I N I T I O N OF E N T E R O G A S T R O N E AS N A N I N H I B I T O R Y HORMONE L I B E R A T E D FROM THE DUODENUM WHEN FAT IS INTRODUCEO THERE 1 1 WAS EXPANDED BY GREGORY ( 1 9 6 7 ) TO "A HORMONE OF THE UPPER I N T E S T I N A L MUCOSA WHICH IS LI BERATED BY FAT OR ITS D I G E S T I O N P R O D U C T S , HYPERTONIC S O L U T I O N S , OR A C I D , AND WHICH I N H I B I T S G A S T R I C S E C R E T I O N ANO M O T I L I T Y . " WORK ON ISOLAT ION OF A DUODENAL INHIBITORY HORMONE WANED UNTIL THE 1950'S WHEN G R E E N L E E , L O N G H I , GUERRERO, NE L S O N , E L -B E D R I AND DRAGSTEDT (1957), USING A CRUDE COMMER-C I A L S E C R E T I N P R E P A R A T I O N , OBSERVED MARKED INHIB IT ION OF ACID S E C R E T I O N FROM A HE IDENHAIN POUCH ST IMULATED TO S E C R E T E BY IRRIGAT ION OF A S E P A R A T E ANTRAL POUCH WITH L I V E R EXTRACT TO R E L E A S E ENDOGENOUS G A S T R I N . THE WORK OF G R E E N L E E WAS CONFIRMED BY KENNEDY AND H A L L E N B E C K ( 1 9 6 3 ) WHO ALSO DEMON-STRATED THAT THE GASTRIC SECRETORY INHIB IT ION BY S E C R E T I N P E R S I S T E D AFTER PANCREATECTOMY. T H I S E L I M I N A T E D THE P O S S I B I L I T Y THAT THE INH IB IT ION WAS SECONDARY TO THE P A S S A G E OF A L K A L I N E P A N C R E A T I C S E C R E T I O N INTO THE DUODENUM. FURTHER WORK ON G A S T R I C SECRETORY INHIB IT ION WAS CARRIED OUT BY WORMSLEY AND GROSSMAN ( 1 9 6 4 ) . TH E Y FOUND THAT AN E S S E N T I A L L Y PURE S E C R E T I N PREPARAT ION ( J O R P E S ANO MUTT , 1 9 6 2 ) INH IB ITED ACID S E C R E T I O N S T I M U L A T E D BY EXOGENOUS G A S T R I N . THEY CONCLUDED FROM THESE S T U D I E S THAT S E C R E T I N WAS BLOCKING THE ACTION OF GASTRIN AT THE L E V E L OF THE P A R I E T A L C E L L . T H E S E F INDINGS WERE CONFIRMED BY G I L L E S P I E AND GROSSMAN ( 1 9 6 4 ) WHO ALSO FOUND THAT THE CCK PREPARATION OF J O R P E S AND MUTT (1964) WOULD INHIB IT SECRET ION OF A HE IDENHAIN POUCH S T I M U L A T E D BY EXOGENOUS GASTRIN BUT WOULD - 1 3 -INH IB IT ONLY LOW DOSES OF H I S T A M I N E . AT THAT T I M E , THE INHIBITORY ACT IONS OF CCK AND S E C R E T I N WERE INCOMPLETELY D E F I N E D , MAINLY BECAUSE PURE P R E P A R A T I O N S WERE NOT THEN A V A I L A B L E . ALTHOUGH INHIB IT ION OF GASTRIC S E C R E T I O N AND MOT IL ITY BY THE R E L E A S E OF ENDOGENOUS HORMONES WAS WELL DOCUMENTED, IT WAS S T I L L UNDECIDED WHETHER THE INHIB IT ION PRODUCED BY THE P R E S E N C E OF A C I D , FAT AND HYPERTONIC SOLUT IONS IN THE DUODENUM WERE MEDIATED BY THE SAME DUODENAL HORMONE, OR THROUGH S E P A R A T E MECHANISMS. THE F I R S T OF THE DUODENAL INHIBITORY HORMONES TO HAVE ITS STRUCTURE E L U C I D A T E D WAS S E C R E T I N , THE AMINO ACID SEQUENCE BEING P U B L I S H E D BY MUTT AND JORPES ( 1 9 ^ 6 ) . V A G N E , S T E N I N G , BROOKS AND GROSSMAN ( 1 9 6 8 ) COMPARED THE P H Y S I O -LOGICAL ACT IONS OF NATURAL S E C R E T I N AND S Y N T H E T I C MATERIAL PRODUCED BY BODANSKY, ONDETTI AND LE V I N E ( 1 9 6 6 ) . THEY FOUND THE INHIBITORY ACT IONS OF THE S Y N T H E T I C MATERIAL TO BE THE SAME AS NATURAL S E C R E T I N , E S T A B L I S H I N G THAT THE I N H I B I T I O N OF THE HEIDENHALN POUCH RESPONSE TO GASTRIN IN FACT WAS DUE TO S E C R E T I N AND NOT AN IMPURITY . T H I S O B S E R -VATION HAS BEEN CONFIRMED BY JOHNSON AND GROSSMAN ( 1 9 6 9 ) USING PURE S E C R E T I N P R E P A R A T I O N S . WAY ( 1 9 7 0 ) ADMINISTERED S E C R E T I N TO PAVLOV POUCH DOGS IN WHICH ACID S E C R E T I O N WAS ST IMULATED BY INSUL IN AND A SUBMAXIMAL DOSE OF H I S T A M I N E , THE R E S U L T S INDICATED THAT S E C R E T I N DID NOT INHIB IT VAGALLY S T I M U L A T E D ACID S E C R E T I O N IN DOGS THAT HAD BEEN ANTRECTOM I ZED. THE E V I D E N C E REGARDING THE E F F E C T OF S E C R E T I N ON GASTRIC MOT IL ITY IS NOT AS D E C I S I V E AS THAT P E R T A I N I N G TO ITS ACTION ON G A S T R I C S E C R E T I O N . JOHNSON ANO M A G E E ( 1 9 6 5 ) FOUND THAT S E C R E T I N PRODUCED SOME INH IB IT ION OF GASTRIC M O T I L I T Y , BUT NOT AS C O N S I S T E N T L Y AS DID C C K - P Z . V A G N E £1 AL ( 1 9 6 8 ) COMPARED THE E F F E C T S OF NATURAL AND S Y N T H E T I C S E C R E T I N ON G A S T R I C MOTOR A C T I V I T Y AND FOUND THAT THEY BOTH I N H I B I T E D ANTRAL AND F U N D l C POUCH MOTOR A C T I V I T Y IN THE DOG TO AN EQUAL E X T E N T . IN THE ABSENCE OF A BLOOD ASSAY CAPABLE OF D E T E C T I N G A L T E R E D BLOOD L E V E L S OF A PART ICULAR HORMONE OR HORMONES DURING DUODENAL A C I D I F I C A T I O N , THE ONLY MEANS OF E L U C I D A T I N G THE P R I N C I P L E INVOLVED WOULD BE TO COMPARE THE E F F E C T S OF KNOWN G A S T R O I N T E S T I N A L HORMONES WITH THOSE OF DUODENAL A C I D -I F I C A T I O N . THE R E S U L T S OF A LARGE NUMBER OF INDEPENDENT S T U D I E S REPORTED E A R L I E R INDICATED THAT S E C R E T I N AND DUODENAL A C I D I F I C A T I O N BOTH I NHIB IT GASTRIC S E C R E T I O N AND M O T I L I T Y UNDER S IMILAR C I R C U M S T A N C E S . PRESHAW, COOK AND GROSSMAN ( 1 9 6 6 ) OBSERVED THAT WHEN THE DUODENUM WAS PERFUSED WITH A C I D , P A N C R E A T I C ENZYME OUTPUT I N C R E A S E D . THEY CONCLUDED THAT C C K - P Z MAY HAVE BEEN R E L E A S E D UNDER THESE C I R C U M S T A N C E S . NAKAJIMA AND MAGEE ( 1 9 7 0 ) FOUND THAT ACID AT PH 1 . 0 IN DUODENAL POUCHES I N H I B I T E D P E P S I N S E C R E T I O N AS WELL AS ACID S E C R E T I O N FROM HEIDENHAIN P O U C H E S , SUGGEST ING THAT C C K PLAYS A MORE IMPORTANT ROLE IN THIS MECHANISM. THE FACT THAT S E C R E T I N S T I M U L A T E D P E P S I N S E C R E T I O N AND C C K I N H I B I T E D IT (NAKAJ IMA AND M A G E E , 1 9 7 0 ) , PLUS THE OBSERVATION BY HONG, MAGEE AND CREWDSON ( 1 9 5 6 ) THAT ACID IN THE DUODENUM CAUSED GALL BLADDER C O N T R A C T I O N , IMPL ICATED THE R E L E A S E OF - 15 -C C K - P Z AS WELL AS S E C R E T I N . JOHNSON AND GROSSMAN ( 1 9 6 8 ) COMPARED THE INHIBITORY E F F E C T S OF PURE S E C R E T I N AT DOSES SUBMAXIMAL FOR P A N C R E A T I C S E C R E T I O N AND HYDROCHLORIC ACID IN THE DUODENUM, ON G A S T R I N - AND HISTAM I N E - S T I M U L A T E D ACID S E C R E T I O N . THE CLOSE S I M I L A R I T Y BETWEEN THE INHIBITORY E F F E C T S OF THESE TWO PROCEDURES LED THEM TO CONCLUDE THAT S E C R E T I N WAS PROBABLY THE ONLY ENTEROGASTRONE R E L E A S E D BY ACID IN THE DUODENUM. IN SUPPORT OF TH IS CONCLUSION WERE THE F INDINGS OF S T E N I N G , JOHNSON AND GROSSMAN ( 1 9 6 9 A ) THAT BOTH S E C R E T I N AND DUODENAL A C I D I F I C A T I O N ST IMULATED P E P S I N S E C R E T I O N IN THE DOG AND CAT TO A S IMILAR D E G R E E . AS MENTIONED E A R L I E R , IT WAS E S T A B L I S H E D BY G I L L E S P I E AND GROSSMAN ( 1 9 6 4 ) THAT AN IMPURE C C K - P Z PREPARAT ION WOULD INHIB IT G A S T R I N - S T I M U L A T E D ACID S E C R E T I O N . THE WORK OF JO R P E S AND MUTT ( 1 9 6 6 ) SUGGESTED THAT C H O L E C Y S T O K I N I N AND P A N C R E O Z Y M I N , THE POSTULATED P A N C R E A T I C E N Z Y M E - S T I M U L A T I N G HORMONE OF HARPER AND RAPER ( 1 9 4 3 ) » MAY BE ONE ANO THE SAME HORMONE. THE ORIGINAL OBSERVAT IONS ON THE GASTRIC E F F E C T S OF C C K - P Z WERE EXTENDED BY BROWN AND MAGEE ( 1 9 6 7 ) WHO DEMONSTRATED THAT AN IMPURE C C K - P Z PREPARAT ION WOULD INHIB IT ACID S E C R E T I O N FROM HEIDENHAIN POUCHES WHICH HAD BEEN S T I M U L A T E D BY ANTRAL PERFUSION WITH A C E T Y L C H O L I N E OR PEPTONE S O L U T I O N S . THE C C K - P Z P R E P A R A T I O N S EMPLOYED IN THESE S T U D I E S CONTAINED APPROXIMATELY 2 5 0 IVY DOG UNITS ( l . D . U . ) PER M G . , AND WERE ONLY 1 0 $ P U R E . To QUAL IFY AS E N T E R O G A S T R O N E , C C K - P Z MUST BE SHOWN TO INHIBIT GASTRIC MOTOR A C T I V I T Y AS WELL AS GASTRIC S E C R E T I O N . JOHNSON AND - 16 -MAGEE ( 1 9 6 5 ) DEMONSTRATED THAT A PREPARATION OF C C K - P Z I N H I B I T E D GASTRIC MOT IL ITY OF DENERVATED GASTRIC POUCHES AS DID FAT AND H C L . T H I S WAS SUPPORTED BY JOHNSON, BROWN AND MAGEE ( 1 9 6 6 ) WHO FOUND THAT C C K - P Z WAS A POTENT INHIBITOR OF M O T I L I T Y IN MAN. WHILE STUDYING P A N C R E A T I C ENZYME S E C R E T I O N , PRESHAW AND GROSSMAN ( 1 9 6 5 ) FOUND THAT SMALL DOSES OF C C K - P Z WHEN GIVEN ALONE S T I M U L A T E D ACID S E C R E T I O N . TH IS OBSERVATION WAS CONFIRMED BY TWO GROUPS, MURAT AND WHITE ( 1 9 6 6 ) AND M A G E E AND NAKAMURA ( 1 9 6 6 ) WHO SUGGESTED THAT C C K - P Z BEHAVED L I K E G A S T R I N , A C T I N G IN SMALL DOSES AS A ST IMULANT FOR ACID S E C R E T I O N AND IN LARGE DOSES AS AN I N H I B I T O R . NAKAMURA, NAKADLMA AND MAGEE ( 1 9 6 8 ) AGAIN STUDIED C C K - P Z AND A T T R I B U T E D THE ST IMULATORY ACTION OF THIS MATERIAL TO THE FACT THAT BOTH MOLECULES P O S S E S S E D IOENT ICAL AMINO ACID SEQUENCES OF THE C - T E R M I N A L P E N T A P E P T I D E . S I N C E A S Y N T H E T I C PREPARATION OF C C K - P Z WAS NOT A V A I L A B L E , IT COULD NOT BE STATED WITH ASSURANCE THAT ALL A C T I O N S OF C C K - P Z P R E P A R A T I O N S WERE P R O P E R T I E S OF THE HORMONE I T S E L F . BY METHODS ANALAGOUS TO THOSE EMPLOYED IN A T T E M P T I N G TO SHOW THAT S E C R E T I N WAS R E L E A S E O DURING DUODENAL A C I D I F I -C A T I O N , E X P E R I M E N T A L E V I D E N C E HAS BEEN REPORTED IN SUPPORT OF THE H Y P O T H E S I S THAT C C K - P Z WAS R E L E A S E D WHEN FAT WAS P L A C E D IN THE DUODENUM. THE PRESENCE OF FAT IN THE DUODENUM HAS BEEN SHOWN BY IVY ( 1 9 3 4 ) TO BE A POTENT ST IMULUS FOR GALL BLADDER CONTRACTION AND BY WANG AND GROSSMAN ( L 9 5 1 ) TO R E L E A S E P A N C R E A T I C E N Z Y M E S . THE FACT THAT THE GALL BLADDER - 1 7 -AND P A N C R E A T I C E F F E C T S OF I NTRADUODENAL FAT WERE MIMICKED BY C C K - P Z AND THAT G A S T R I C INH IB IT ION BY THIS HORMONE HAD BEEN WELL DOCUMENTED LED TO THE SUGGESTION THAT C C K - P Z MIGHT BE IN P A R T , IF NOT E N T I R E L Y , R E S P O N S I B L E FOR THE I N H I B I T I O N OF GASTRIC SECRET I ON AND M O T I L I T Y CAUSED BY FAT IN THE SMALL I N T E S T I N E . A S MENTIONED A B O V E , IN THE ABSENCE OF D E F I N I T I V E ASSAYS FOR THESE P O L Y P E P T I D E S IT IS IMPOSSIBLE TO MAKE A STATEMENT AS TO WHICH INHIBITORY HORMONE IS R E L E A S E D FROM THE DUOOENUM UPON A D M I N I S T E R I N G SECRETOGOGUES SUCH AS FAT OR A C I D . THUS THE C IRCUMSTANT IAL E V I D E N C E CONCERNING THE ROLE OF S E C R E T I N AND C C K - P Z IN GASTRIC SECRETORY AND MOTOR I N H I B I T I O N DOES NOT RULE OUT A S E P A R A T E AND D I S T I N C T ENTEROGASTRONE OR ENTEROGASTRONES WHOSE ROLE MAY BE S E P A R A T E FROM OR S U P P L E -MENTARY TO THE E S T A B L I S H E D DUODENAL HORMONES. TH I S INTRODUCTION HAS POINTED OUT THAT THE DUODENAL HORMONES C C K - P Z AND S E C R E T I N DO NOT COMPLETELY S A T I S F Y THE REQUIREMENTS PROPOSED FOR THE D E F I N I T I O N OF E N T E R O G A S T R O N E . NE ITHER HORMONE E F F E C T I V E L Y INH IB ITS H I S T A M I N E - OR V A G A L L Y -S T I M U L A T E D ACID S E C R E T I O N , A MECHANISM WHICH O P E R A T E S WHEN FAT IS P L A C E D IN THE DUODENUM. T H I S , TOGETHER WITH THE I N A B I L I T Y OF MANY WORKERS TO ISOLATE AND C H A R A C T E R I Z E AN ENTEROGASTRONE D I S T I N C T FROM OTHER DUODENAL HORMONES, HAS PROVIDED THE J U S T I F I C A T I O N FOR THE PRESENT WORK. M E T H O D S O P E R A T I V E P R O C E D U R E S I CHRONIC DOGS DOGS WEIGHING 2 0 - 3 0 KG WERE U S E D . THE ANIMALS WERE F A S T E D 1 8 HOURS PRIOR TO SURGERY. A N A E S T H E S I A WAS INDUCED WITH 5 $ SODIUM PENTOTHAL TO E F F E C T ( 7 - 1 0 M L ) , AND M A I N -TAINED WITH 0 . 5 $ FLUOTHANE U T I L I Z I N G AN 0 2 FLOW RATE OF 2 . 5 - 3 . 0 L / M I N . A . PR E P A R A T I O N NO. 1 : USED IN THE MULTIPARAMETER STUDY OF THE ACT IONS OF 2 P R E P A R A T I O N S CONTAINING C C K - P Z A) B I C K E L POUCH B I C K E L POUCHES WERE PREPARED WHICH WERE VAGALLY AND S Y M P A T H E T I C A L L Y D E N E R V A T E D . A POUCH OF THE FUNDIC GLAND AREA WAS CONSTRUCTED FROM THE GREATER CURVATURE AND ALLOWED TO DRAIN TO THE EXTERIOR BY MEANS OF A METAL CANNULA ( F L G . 1 ) , I N CONSTRUCTING THE POUCH THE VAGAL F I B R E S WERE SECT IONED AND THE S Y M P A T H E T I C F I B R E S WERE REMOVED BY S T R I P P I N G THE NERVE P L E X U S FROM THE S P L E N I C ARTERY AND VE IN AND S E V E R I N G ALL M E S E N T E R I C CONNECTIONS TO THE POUCH. THE S P L E E N WAS REMOVED. B) ANTRAL POUCH AL L DOGS PREPARED WITH B I C K E L POUCHES WERE ALSO PREPARED WITH VAGALLY DENERVATED POUCHES OF THE ANTRUM OF THE STOMACH ( F L G . 1 ) . THE L A T T E R OPERATION WAS CARRIED OUT APPROXIMATELY 3 - 4 WEEKS A F T E R THE B L C K E L POUCH WAS PREPARED, THE STOMACH WAS F I R S T EXAMINED FOR THE SUBTLE CHANGE IN - 1 8 -- 19 -T E X T U R E WHICH MAY BE USED AS AN I N D I C A T I O N OF THE J U N C T I O N BETWEEN THE ANTRUM AND THE FUNDUS. THE BLOOD V E S S E L S TO THE L E S S E R C U R V A T U R E , FROM THE P Y L O R U S TO THE A N G U L A R I S , WERE S E C T I O N E D . T H I S A L S O REMOVED THE VAGAL F I B R E S WHICH RUN TO THE ANTRUM A L O N G S I D E THE R I G H T G A S T R I C A R T E R Y . T H E ANTRUM WAS I S O L A T E D BY S E C T I O N I N G BELOW THE P Y L O R U S AND AT THE O B S E R V E D J U N C T I O N WITH THE FUNDUS. BEF O R E C O N S T R U C T I N G THE P O U C H , THE MUCOSA WAS E V E R T E D AND T E S T E D WITH U N I V E R S A L PH P A P E R TO E N S U R E THAT NO A C I D - S E C R E T I N G T I S S U E WAS B E I N G I N C O R P O R A T E D INTO THE A N T R A L POUCH. As ADDED I N S U R A N C E A G A I N S T T H I S , A C U F F OF 2 — 3 CM OF ANTRAL T I S S U E WAS R E S E C T E D . THE CUT E D G E S OF THE ANTRUM WERE S T I T C H E D TOGETHER AND THE POUCH BROUGHT TO THE E X T E R I O R THROUGH A BUTTON WOUND I N THE A N I M A L ' S F L A N K . BY I N C O R P O R A T I N G THE P Y L O R U S INTO THE POUCH, THE S P H I N C T E R A C T E D AS A N A T U R A L V A L V E TO P R E V E N T THE L E A K A G E OF F L U I D D U R I N G P E R F U S I O N . THE POUCH R E C E I V E D AN AOEQUATE BLOOD S U P P L Y V I A THE R I G H T G A S T R O -E P I P L O I C BRANCH OF THE GASTRODUODENAL ARTERY WHICH S U P P L I E D THE G R E A T E R C U R V A T U R E . A L T H O U G H THE POUCH WAS V A G A L L Y D E N E R V A T E D , NO A T T E M P T WAS MADE TO REMOVE THE S Y M P A T H E T I C I N N E R V A T I O N . G A S T R O I N T E S T I N A L C O N T I N U I T Y WAS R E S T O R E D BY AN E N D - T O - S I D E G A S T R O - J E J U N O S T O M Y 30 CM D I S T A L TO THE L I G A M E N T OF T R E I T Z ( F l G . 1). c) GALL B L A D D E R C A N N U L A DOGS USED I N E X P E R I M E N T S IN WHICH G A L L B L A D D E R P R E S S U R E WAS MONITORED WERE P R E P A R E D WITH C A N N U L A E OF P E 260 P O L Y E T H Y L E N E T U B I N G I N S E R T E D INTO THE FUNDUS OF THE G A L L - 2 0 -F I GURE 1 . DIAGRAM OF SURGICAL USEO IN ALL S T U O I E S P O L Y P E P T I 0 E . PREPARATION NO. 3 (CHRONIC OOG) INVOLVING GASTRIC INHIBITORY B L A D D E R . THE CANNULA WAS SECURED BY MEANS OF A PURSE S T R I N G SUTURE WHICH DID NOT P E N E T R A T E THE L U M E N , AND WAS E X T E R I O R -ISED LOW ON THE A N I M A L ' S F L A N K . B. PR E P A R A T I O N NO. 2: USED IN THE I N V E S T I G A T I O N OF THE COMPARISON OF TWO P R E P A R A T I O N S CONTAINING CCK-PZ IN TERMS OF GASTRIC SECRETORY INH IB IT ION AND GASTRIC SECRETORY S T U D I E S INVOLVING E G STAGE I DOGS USED IN TH IS STUDY WERE PREPARED WITH B I C K E L POUCHES AND ANTRAL POUCHES ONLY. C. PR E P A R A T I O N NO. 3S USED IN ALL S T U D I E S INVOLVING THE P U R I F I E D GASTRIC INHIBITORY P O L Y -P E P T I D E DESIGNATED E G I I I DOGS USED IN THESE S T U D I E S WERE PREPARED WITH B I C K E L AND ANTRAL P O U C H E S . DURING THE SURGICAL PROCEDURE INVOLVING CONSTRUCTION OF AN ANTRAL POUCH, A THOMAS CANNULA F I T T E D WITH A NYLON CAP WAS INSERTED INTO THE GASTRIC REMNANT BEFORE THE GASTRO—JEJUNAL ANASTOMOSIS WAS C O M P L E T E D . T H I S PROVIDED A MEANS OF DRAINING THE GASTRIC REMNANT TO THE E X T E R I O R . I I ACUTE CATS AN A E S T H E S I A WAS INDUCED WITH FLUOTHANE AND MAINTAINED BY INTRAVENOUS I N J E C T I O N OF 2 $ CHLORALOSE ( 8 0 MG/KG) I N J E C T E D VIA A CANNULA IN THE SAPHENOUS VE IN OF THE A N I M A L . S A T I S -FACTORY A N A E S T H E S I A COULD BE MAINTAINED FOR 9 - 1 0 HOURS BY TH IS METHOD. THE TRACHEA WAS I N T U B A T E D . THE STANDARD PROCEDURE IN ACUTE CAT P R E P A R A T I O N S INVOLVED INTUBATION OF - 22 -THE STOMACH AND CANNULATI ON OF THE P A N C R E A T I C DUCT. THE GREATER AND L E S S E R S P L A C H N I C NERVES WERE CUT E X T R A -PERI TONEALLY THROUGH I N C I S I O N S IN THE F L A N K S . THE ESOPHAGUS WAS EXPOSED IN THE NECK AND INTUBATED WITH A F L E X I B L E RUBBER T U B E , WHICH WAS PASSED INTO THE STOMACH. A M I D L I N E INCIS ION WAS MADE IN THE ABDOMEN AND A TAPE L IGATURE T I E D T IGHTLY AROUND THE P Y L O R U S , CARE BEING TAKEN NOT TO OCCLUDE THE GASTRODUODENAL BLOOD V E S S E L S . T H I S PROCEDURE ENSURED THAT NONE OF THE STOMACH CONTENTS COULD BE E X P E L L E D INTO THE SMALL I N T E S T I N E . THE P O S I T I O N OF THE STOMACH TUBE WAS THEN A D J U S T E D SO THAT THE T I P WAS IN THE MOST DEPENDENT PART OF THE STOMACH. THE TUBE WAS T IED IN P O S I T I O N WITH A THREAD L I G A T U R E AT ITS ENTRANCE INTO THE ESOPHAGUS. THE P A N C R E A T I C DUCT WAS CANNULATED AT A POINT BEFORE IT P I E R C E D THE DUODENAL WALL . A BRISK FLOW OF P A N C R E A T I C J U I C E WAS S T I M U L A T E D BY AN INTRAVENOUS I N J E C T I O N OF S E C R E T I N TO AID CANNULATI ON OF THE DUCT . IN ALL EXPERIMENTS THE VAGI WERE SECT IONED IN THE N E C K . I F TWO ROUTES OF INTRAVENOUS I N J E C T I O N WERE REQUIRED A RADIAL V E I N WAS ALSO C A N N U L A T E D . THROUGHOUT THE COURSE OF EXPERIMENTS BODY TEMPERATURE WAS MAINTAINED AT 3 6 . 5 ° C USING A HEATING PAD CONTROLLED THROUGH A T E L E - T H E R M O M E T E R (YELLOW S P R I N G S INSTRUMENT C O . , MODEL 7 3 ) WHICH MONITORED BODY TEMPERATURE VIA A RECTAL P R O B E . I I I ACUTE GUINEA P I G S GUINEA P I G S WERE A N A E S T H E T I Z E D WITH 3 0 $ URETHANE ( 3 0 0 M G / 1 0 0 G) ADMINISTERED S U B C U T A N E O U S L Y . WHEN SURGICAL A N A E S T H E S I A WAS A C H I E V E D (|N APPROXIMATELY 4 5 MINUTES) THE - 2 3 -TRACHEA WAS INTUBATED WITH PE 2 6 0 T U B I N G . THE EXTERNAL JUGULAR VE IN WAS CANNULATED TO F A C I L I T A T E I N J E C T I O N S DURING THE COURSE OF THE E X P E R I M E N T . A M IDL INE INCIS ION 3 - 4 CM L O N G , WHICH JUST R E V E A L E D THE T I P OF THE X IPHISTERNUM , EXPOSED THE GALL B L A D D E R . A L IGATURE WAS T IED AROUND THE APEX OF THE FUNDUS OF THE GALL BLADDER FOR SUBSEQUENT ATTACHMENT TO A S T R A I N GAUGE TO RECORD FORCE OF GALL BLADDER C O N T R A C T I O N . BODY TEMPERATURE WAS MAINTAINED BY THE SAME METHOD AS THAT USED FOR C A T S . IV ACUTE RA B B I T S AN A E S T H E S I A WAS INDUCED WITH NEMBUTAL ( 3 5 MG/KG BODY W E I G H T ) , ADMINISTERED INTRAVENOUSLY VIA THE MARGINAL EAR VE IN AND MAINTAINED WITH 3 0 $ URETHANE GIVEN TO E F F E C T AS R E Q U I R E D . A M I D L I N E INCIS ION IN THE NECK WAS MADE AND A GLASS CANNULA INSERTED IN A TRACHEAL I N C I S I O N . AN EXTERNAL JUGULAR V E I N WAS CANNULATED WITH P O L Y E T H Y L E N E TUBING PE 6 0 FOR TAKING BLOOD SAMPLES AND G I V I N G I N J E C T I O N S . A PE 2 4 0 P O L Y E T H Y L E N E CANNULA WAS PLACEO IN THE CAROTID ARTERY AND CONNECTED TO A S A L I N E - F I L L E D STATHAM HIGH PRESSURE T R A N S -DUCER ( P 2 3 AA) WITH BLOOD PRESSURE RECORDED ON A GlLSON PEN RECORDER WHEN THE EXPERIMENTS INVOLVED A R T E R I A L BLOOD PRESSURE MONITORING. C O L L E C T I O N AND A N A L Y S I S OF SAMPLES I CO L L E C T I O N OF GA S T R I C SE C R E T I O N A. B I C K E L POUCH CO L L E C T I O N - DOG CO L L E C T I O N S WERE MADE AT E I T H E R 1 0 OR 1 5 MINUTE I N T E R V A L S . - 24 -T W E N T Y - F I V E ML OF WATER WERE INTRODUCED INTO THE F U N D I C POUCH AND ALLOWED TO R E M A I N THERE FOR THE D U R A T I O N OF THE P E R I O D . AT THE END OF THE P E R I O D THE F L U I D FROM THE POUCH WAS D R A I N E D AND THE POUCH WASHED OUT WITH A FURTHER 2 5 ML OF WATER WHICH WAS POOLED WITH THE O R I G I N A L S A M P L E . A L I Q U O T S OF T H I S C OMBINED S A M P L E WERE USED FOR H + AND P E P S I N E S T I M A T I O N . B. G A S T R I C REMNANT C O L L E C T I O N - DOG IN THE S T U D I E S I N V O L V I N G S E C R E T I O N OF THE V A G A L L Y I N N E R -V A T E D G A S T R I C REMNANT, G A S T R I C S E C R E T I O N WAS C O L L E C T E D D I R E C T L Y BY G R A V I T Y THROUGH THE THOMAS CANNULA INTO A 2 5 0 ML P O L Y E T H Y L E N E B O T T L E . G A S T R I C S A M P L E S WERE D I L U T E D 1 : 1 0 AND S A M P L E S WERE T A K E N FOR H + AND P E P S I N E S T I M A T I O N . C. WHOLE STOMACH C O L L E C T I O N S - CAT G A S T R I C C O L L E C T I O N S WERE MADE FROM THE WHOLE STOMACH OF THE A N A E S T H E T I Z E D CAT I N THE SAME MANNER AS D E S C R I B E D FOR F U N D I C POUCH DOGS. D. P E R F U S I O N OF A N T R A L POUCH AND MEASUREMENT OF A N T R A L M O T I L I T Y I N THE DOG IN ORDER TO P E R F U S E THE A N T R A L POUCH WITH T E S T S O L U T I O N S AND TO MEASURE THE A N T R A L POUCH M O T I L I T Y , A S E R I E S OF P O L Y -E T H Y L E N E C A N N U L A E WERE INTRODUCED INTO THE POUCH BY WAY OF THE P Y L O R I C S P H I N C T E R . AN A C R Y L I C S U PPORT WAS MOULDED AROUND THE T U B I N G ( F L G . 2 ) AND S H A P E D TO CONFORM TO THE A N I M A L ' S BODY TO HOLD THE C A N N U L A E S E C U R E L Y IN P L A C E . THE S U P P O R T WAS HELD IN P O S I T I O N BY B I N D I N G S T I E D AROUND THE ABDOMEN. ONE TUBE I N S E R T E D WELL INTO THE LUMEN OF THE POUCH AND A T T A C H E D E X T E R N A L L Y TO A S Y R I N G E WAS USED TO P E R F U S E THE - 2 5 -F I G U R E 2. A C R Y L I C ARRANGEMENT FOR CANNULAE FOR S I M U L T A N E O U S P E R F U S I O N , D R A I N A G E AND MOTOR A C T I V I T Y R E C O R D I N G OF A N T R A L P O U C H E S . A-D P E R F U S I O N CANNULA B-C D R A I N A G E CANNULA E MOTOR A C T I V I T Y R E C O R D I N G CANNULA F T I E S G A C R Y L I C S U PPORT - 2 6 -A N T R A L POUCH WITH F L U I D . A SECOND S A L I N E - F I L L E D TUBE P O S I T I O N E D S L I G H T L Y B E H I N D THE F I R S T WAS USED TO T R A N S M I T P R E S S U R E C H A N G E S I N THE POUCH TO A STATHAM H I G H P R E S S U R E T R A N S D U C E R ( P 2 3 AA) ANO G l L S O N P E N RECORDER. P E R F U S I O N F L U I D WAS ALLOWED TO D R A I N C O N T I N U O U S L Y FROM AROUND THE A C R Y L I C S U P P O R T . WHEN ANTRA L M O T I L I T Y WAS B E I N G RECORDED THE R E C O R D I N G CANNULA WAS P E R F U S E D WITH S A L I N E AT A RATE OF 0 . 2 7 5 M L / M I N WITH 0 . 9 $ S A L I N E TO P R E V E N T I T S B L O C K A G E WITH M U C I N . AN I N D E X OF MOTOR A C T I V I T Y HAS B E E N E M P L O Y E D TO A N A L Y Z E THE MOTOR A C T I V I T Y OF A N T R A L AND F U N D I C P O U C H E S . T H E I N D E X OF MOTOR A C T I V I T Y WAS C A L C U L A T E D AS FOLLOWS: SUM OF ( A M P L I T U D E I N MM HG X D U R A T I O N IN S E C S ) OF E A C H WAVE T I M E OF P E R I O D I N M I N S X 1 0 E . M E A S U R E M E N T OF F U N D I C POUCH MOTOR A C T I V I T Y IN THE DOG A W A T E R - F I L L E D P O L Y E T H Y L E N E TUBE IN C O N T I N U I T Y WITH THE F U N D I C POUCH CONTENTS WAS P O S I T I O N E D BETWEEN THE METAL F U N D I C POUCH CANNULA AND A STATHAM LOW P R E S S U R E T R A N S D U C E R ( P 2 3 BB) CONNECTED TO A G l L S O N P E N RECORDER. F U N D I C POUCH MOTOR A C T I V I T Y WAS RECORDED AS P R E S S U R E WAVES FROM WHICH AN I N D E X OF MOTOR A C T I V I T Y WAS D E R I V E D U S I N G THE FORMULA D E S C R I B E D FOR A N T R A L M O T I L I T Y . F. M E A S U R E M E N T OF GALL BLADDER A C T I V I T Y I N THE DOG CHANGES I N G A L L B L A D D E R P R E S S U R E IN THE DOG WERE MONITORED U S I N G A P E R M A N E N T I N D W E L L I N G P O L Y E T H Y L E N E C A N N U L A . AT THE B E G I N N I N G OF E X P E R I M E N T S IN WHICH G A L L B L A D D E R P R E S S U R E WAS M O N I T O R E D , B I L E WAS ALLOWED TO FLOW OUT OF THE CANNULA AND THE P R E S S U R E IN THE G A L L B L A D D E R A D J U S T E D TO A P P R O X I M A T E L Y - 2 7 -5 MM HG. THE CANNULA WAS THEN A T T A C H E D TO A STATHAM LOW P R E S S U R E T R A N S D U C E R ( P 2 3 BB) AND P R E S S U R E CHANGES MONITORED ON THE G l L S O N P E N RECORDER. II A N A L Y S I S OF S A M P L E S A. G A S T R I C S E C R E T I O N A ) E S T I M A T I O N OF H + C O N C E N T R A T I O N H + C O N C E N T R A T I O N OF G A S T R I C S A M P L E S WAS D E T E R M I N E D BY T I T R A T I O N TO PH 7.0 WITH 0.01 M NAOH U S I N G A R A D I O M E T E R T I T R A T O R A S S E M B L Y ( T l T R A T O R 1 1 ) AND A M A G N E T I C V A L V E . H + WAS E X P R E S S E D A S / J E Q / 1 0 OR 1 5 M I N P E R I O D . B ) E S T I M A T I O N OF P E P S I N P E P S I N OUTPUT WAS D E T E R M I N E D BY A M O D I F I C A T I O N OF THE METHOD OF ANSON AND M L R S K Y ( 1 9 3 2 ) . IN T H I S T E C H N I Q U E THE G A S T R I C S A M P L E WAS ALLOWED TO D I G E S T A H A E M O G L O B I N S U B S T R A T E AND THE AMOUNT OF T Y R O S I N E L I B E R A T E D WAS MEASURED S P E C T R O -P H O T O M E T R Y AL L Y AT 2 7 5 NM. V A L U E S FOR T Y R O S I N E WERE READ FROM A STANDARD CURVE FOR T Y R O S I N E C O N C E N T R A T I O N . IN THE METHOD OF ANSON AND M l R S K Y ( 1 9 3 2 ) THE P E P S I N D I G E S T I O N OF THE H A E M O G L O B I N S U B S T R A T E WAS S T O P P E D BY THE A D D I T I O N OF T R I C H L O R A C E T I C A C I D AND THE R E S U L T A N T M I X T U R E F I L T E R E D . F O L I N - C I O C A L T E A U R E A G E N T WAS THEN ADDED TO THE F I L T R A T E AND THE L I G H T A B S O R B A N C E OF THE PRODUCT OF THE COLOR R E A C T I O N WAS RE A 0 AT 6 4 0 NM. THE M O D I F I C A T I O N OF T H I S METHOD I N V O L V E D M E A S U R I N G THE L I G H T A B S O R B A N C E OF THE F I L T R A T E OF THE H A E M O G L O B I N D I G E S T I O N M I X T U R E D I R E C T L Y , E L I M I N A T I N G THE COLOR R E A C T I O N . WHEN P E P S I N E S T I M A T I O N S U S I N G THE M O D I F I E D METHOD WERE COMPARED WITH THE O R I G I N A L T E C H N I Q U E , NO - 28 -D I F F E R E N C E IN R E S U L T S WAS O B T A I N E D . THE H A E M O G L O B I N S U B -S T R A T E HAD B E E N D I G E S T E D WITH D I F F E R E N T C O N C E N T R A T I O N S OF A STANDARD P E P S I N P R E P A R A T I O N (WORTHINGTON B I 0 C HE M I C A L S ) , ( F I G . 3A). E M P L O Y I N G T H I S CURVE AND THE STANDARD T Y R O S I N E CURVE ( F I G . 3B), P E P S I N V A L U E S WERE P L O T T E D A G A I N S T JJQ OF T Y R O S I N E ( F I G . 3C) SO THAT P E P S I N OUTPUT COULD BE E X P R E S S E D E I T H E R AS AMOUNT OF T Y R O S I N E L I B E R A T E D OR AS pQ P E P S I N . B. P A N C R E A T I C S E C R E T I O N A ) VOLUME WAS MEASURED D I R E C T L Y BY C O L L E C T I O N I N GRADUATED T U B E S . B ) P R O T E I N OUTPUT WAS MEASURED AS FOLLOWS: THE A S S U M P T I O N WAS MADE THAT AT A WAVELENGTH OF 2 8 0 NM A S O L U T I O N OF M I X E D P A N C R E A T I C P R O T E I N C O N T A I N I N G 1 MG/ML HAD AN O P T I C A L D E N S I T Y OF 1.8. T H I S P R O V I D E D AN INDEX FOR D E T E R M I N I N G P R O T E I N C O N C E N T R A T I O N OF S A M P L E S OF P A N C R E A T I C J U I C E . OD OF P J / - — £ X O I L U T I O N FACTOR = MG/ML P R O T E I N I N P A N C R E A T I C J U I C E C. E S T I M A T I O N OF BLOOD GLUCOSE BLOOD G L U C O S E L E V E L S WERE D E T E R M I N E D BY THE 0 - T O L U I D I N E METHOD OF DUBOWSKI ( 1 9 6 2 ) . T H I S WAS A C O L O R I M E T R I C METHOD B A S E D ON THE F A C T THAT 0 - T O L U I D I N E , A P R I M A R Y A R O M A T I C A M I N E , R E A C T E D R E L A T I V E L Y S E L E C T I V E L Y WITH G L U C O S E , Y I E L D I N G A S T A B L E G R E E N COLOUR WHICH ADHERED TO THE B E E R - L A M B E R T LAW OVER A WIDE RANGE OF C O N C E N T R A T I O N S . ASSAY METHODS I A S S A Y OF C H O L E C Y S T O K I N I N A C T I V I T Y OF G A S T R I C I N H I B I T O R Y P R E P A R A T I ONS - 29 -/Jfl. Pepsin F I G U R E 3. (A) THE A B S O R B A N C E AT 275 NM OF THE PRODUCTS OF D I G E S T I O N OF H A E M O G L O B I N S U B S T R A T E WITH D I F F E R E N T C O N C E N T R A T I O N S OF A STANDARD P E P S I N P R E P A R A T I O N . ( B ) STANDARD T Y R O S I N E C U R V E , A D H E R I N G TO B E E R ' S LAW OVER THE RANGE OF C O N C E N T R A T I O N S U S E D . (c) P L O T OF UG T Y R O S I N E A G A I N S T JUG P E P S I N FROM THE DATA OF F l G U R E 3 ( A ) AND ( B ) . - 3 0 -C H O L E C Y S T O K I N I N A S S A Y S WERE C A R R I E D OUT ON THE G U I N E A P I G G A L L B L A D D E R P R E P A R A T I O N O E S C R I B E O ON P A G E S 21 AND 2 2 . THE A S S A Y USED WAS A M O D I F I C A T I O N OF THE METHOD OF L J U N G B E R G (1964) . THE S I L K L I G A T U R E T I E D TO THE A P E X OF THE G A L L B L A D D E R WAS A T T A C H E D TO A STATHAM 3 02 S T R A I N GAUGE (G 1 0B - 3 - 3 5 0 ± ) . THE S T R A I N GAUGE WAS CONNECTED TO A G I L S O N P E N RECORDER AND C A L I B R A T E D SO THAT A WEIGHT OF 2 . 0 GRAMS PRODUCED A P E N D E F L E C T I O N OF 3 CM. THE C C K-PZ P R E P A R A T I O N USED AS A STANDARD I N A L L C C K - P Z A S S A Y S WAS O B T A I N E D FROM THE G . I . H . R E S E A R C H L A B O R A T O R Y , STOCKHOLM (BATCH NO. 2 6 8 4 1 ) . THE M A T E R I A L C O N T A I N E O A P P R O X I -M A T E L Y 2 5 0 I . D . U . C C K - P Z/MG AND i s R E F E R R E D TO THROUGHOUT T H I S T H E S I S AS 1 0 $ PURE C C K - P Z . IN C A R R Y I N G OUT AN A S S A Y , A LOG D O S E - R E S P O N S E CURVE WAS F I R S T O B T A I N E D U S I N G THE STANDAR 0 C C K - P Z P R E P A R A T I O N . F L G . 4A SHOWS R E C O R D I N G S OF THE G A L L B L A O D E R R E S P O N S E TO 4 DOSES OF STANDARD C C K - P Z P R E P A R A T I O N . FORCE OF G A L L B L A D D E R C O N T R A C T I O N I N GRAMS WAS P L O T T E D A G A I N S T LOG DOSE OF C C K - P Z I N I . D . U . ( F I G . 4 B ) . T H I S R E L A T I O N S H I P WAS SHOWN TO BE L I N E A R I N A RANGE OF ABOUT 0 . 0 5 I . D . U . - 1 . 0 I . D . U . OF C C K - P Z I N THE G U I N E A P I G . WEIGHED S A M P L E S OF UNKNOWN WERE THEN I N J E C T E D AND THE C C K - P Z A C T I V I T Y / M G D E T E R M I N E D BY M E A S U R I N G THE G A L L B L A D D E R R E S P O N S E I N GRAMS AND C O N V E R T I N G THE R E S P O N S E TO I . D . U . OF C C K - P Z U S I N G THE D O S E - R E S P O N S E C U R V E . A F T E R FORCE OF C O N T R A C T I O N HAD R E T U R N E D TO P R E I N J E C T I O N L E V E L S ( A P P R O X I M A T E L Y 5 M I N U T E S ) , AN I N J E C T I O N OF STANDARD WAS G I V E N TO ENSURE THAT THE DOSE R E S P O N S E R E L A T I O N S H I P TO THE STANDARD C C K - P Z P R E P A R -A T I O N S T I L L CONFORMED TO THE STANDARD C U R V E . WHEN THE R E S P O N S E - 31 -F I G U R E 4. ( A ) R E S P O N S E O F T H E G U I N E A - P I G G A L L B L A D D E R IN G R A M S F O R C E T O I N T R A V E N O U S I N J E C T I O N S O F F O U R D O S E S O F T H E S T A N D A R D C C K P R E P A R A T I O N ('10$', 2 5 0 I.D.U./M G B A T C H NO* 2 6 8 4 1 ) . ( B ) L O G D O S E R E S P O N S E C U R V E P R E P A R E D F R O M T H E D A T A R E P R E S E N T E D IN FlGURE 4 ( A ) . - 32 -OF THE ANIMAL PREPARATION BEGAN TO DECREASE ( 3 - 4 HOURS) , THE EXPERIMENT WAS TERMINATED. I I ASSAY OF ENTEROGASTRONE AC T I V I T Y ASSAYS FOR ENTEROGASTRONE A C T I V I T Y WERE CARRIED OUT ON DOGS PREPARED AS DESCRIBED IN PREPARATIONS 2 AND 3 , PAGE 2 0 . INHIB ITORY MATERIAL F R O M .EG S TAGE I I TO PURE GASTR IC I N H I B I -TORY P O L Y P E P T I D E ( E G I I I ) WAS ASSAYED FOR ENTEROGASTRONE A C T I V I T Y IN DOGS WITH A THOMAS CANNULA IN THE GASTR IC REMNANT (PREPARATION 3 ) • INHIB ITORY MATERIAL WAS GIVEN AS A ONE HOUR INTRAVENOUS INFUSION AGAINST A PLATEAU OF BLCKEL POUCH H + SECRET ION ST IMULATED BY 1 . 5 J UG/KG/HR OF GASTRIN P E N T A P E P T I D E . E N T E R O -GASTRONE A C T I V I T Y WAS EXPRESSED AS " $ INH IB IT ION 1 1 , WHICH WAS CALCULATED BY COMPARING H + OUTPUT DURING THE PERIODS OF GREATEST ACID INH IB IT ION WITH THE MEAN OUTPUT OF THE 3 PLATEAU PERIOOS OF H + SECRET ION PRIOR TO THE START OF THE INFUSION OF THE INH IB ITOR. AN EXAMPLE OF AN ASSAY FOR ENTEROGASTRONE A C T I V I T Y OF A FRACTION RESULT ING FROM THE FRACT IONAT ION OF E G STAGE I ON C M - C E L L U L O S E IS SHOWN IN F I G . 5 . T HIS FRACTION PRODUCED ONLY 3 9 $ INH IB IT ION OF ACID SECRET ION BY THE ABOVE C A L C U L A T I O N . I I I ASSAY OF S E C R E T I N AC T I V I T Y S E C R E T I N A C T I V I T Y WAS ASSAYED FOR IN THE ACUTE C A T , PREPARED AS DESCRIBED ON PAGES 2 0 AND 2 1 . A CONTINUOUS INTRAVENOUS INFUSION OF SECRET IN WAS G IVEN AT A DOSE WHICH WOULD Y IELD AT L E A S T 1 . 0 ML OF PANCREAT IC J U I C E PER 15 MINUTE - 33 -Gastrin Pentapeptide I.O/jg./kg./hr. I i I i i i i 1 1 1 1 1 1 1 0 2 4 6 8 10 12 14 15 min. periods FIGURE 5. EXAMPLE OF AN ASSAY FOR ENTEROGASTRONE ACTIVITY IN THE CHRONIC DOG. AN INFUSION OF 1.0/)G/KG/HR OF THE FRACTION TO BE ASSAYED WAS INFUSED FOR ONE HOUR ON A PLATEAU OF B l C K E L POUCH H+ SECRETION STIMULATED BY 1.5 /JG/KG/HR OF GASTRIN PENTAPEPTIDE. - 3 4 -P E R I O D . A F T E R AT L E A S T THREE P E R I O D S D U R I N G WHICH THE VOLUME WAS CONSTANT ( ± 1 0 $ ) AND THE P R O T E I N OUTPUT LOW (<2.0 MG P R O T E I N / 1 5 M I N ) , R A P I D I N T R A V E N O U S I N J E C T I O N S OF S A M P L E S OF M A T E R I A L TO BE A S S A Y E D WERE G I V E N . T H E S E I N J E C T I O N S WERE FOLLOWED BY I N J E C T I O N S OF S E C R E T I N . A L L P R E P A R A T I O N S USED WERE R E S P O N S I V E TO AN I N J E C T I O N OF 0.5 U N I T S OF S E C R E T I N OR L E S S . T H I S R E P R E S E N T E D THE S E N S I T I V I T Y I N D E T E R M I N I N G S E C R E T I N A C T I V I T Y OF A G I V E N F R A C T I O N . F I G . 6 SHOWS THE R E S U L T S OF ONE SUCH A S S A Y E X P E R I M E N T . S I N C E S E C R E T I N A C T I V I T Y WAS REMOVED AT AN E A R L Y S T A G E I N THE P U R I F I C A T I O N OF G . I . P . ( F I G . 1 3 ) , THE S E C R E T I N A S S A Y WAS P R I N C I P A L L Y D E S I G N E D TO Q U A L I T A T I V E L Y C O N F I R M THE A B S E N C E OF S E C R E T I N A C T I V I T Y IN THE PRODUCTS OF THE L A T E R P U R I F I C A T I O N S T A G E S . IV A S S A Y FOR BLOOD P R E S S U R E CHANGES AND P Y R O G E N I C E F F E C T S A. BLOOD P R E S S U R E A R T E R I A L BLOOD P R E S S U R E WAS RECORDED ON A G I L S O N P E N RECORDER D U R I N G THE I N J E C T I O N OF WEIGHED Q U A N T I T I E S OF M A T E R I A L S TO BE A S S A Y E D . T H E P R E P A R A T I O N USED WAS THE ACUTE R A B B I T P R E P A R E O AS D E S C R I B E D ON P A G E 2 2 . B. P Y R O G E N I C E F F E C T S P Y R O G E N I C E F F E C T S OF S A M P L E S WERE A S S A Y E D FOR IN DOGS BY M O N I T O R I N G R E C T A L T E M P E R A T U R E B E F O R E , D U R I N G AND A F T E R I N F U S I O N OF THE M A T E R I A L B E I N G T E S T E D . SOURCE OF HORMONE PR E P A R A T I O N S G A S T R I N P E N T A P E P T I D E : A Y E R S T L A B O R A T O R I E S ( M O N T R E A L , C A N A D A ) - 35 -6.0 units /hr Secretin ID O 3.0r 2.0 c o CL *- 1.0 o <u E 0.0 0.5 U Secretin 10.0 jag G.I.P 0.5 U Secretin 25.0/jg G.I.R 0.5 U Secretin 1 I I I _L 8 10 15 min. periods 12 14 16 18 F I G U R E 6. E X A M P L E O F A N A S S A Y F O R S E C R E T I N A C T I V I T Y I N T H E A C U T E C A T . S I N G L E I ' . V . I N J E C T I O N S O F 0.5 u S E C R E T I N A N D 10 A N D 25 JUG O F G.I.P. W E R E G I V E N O N A B A C K G R O U N D O F P A N C R E A T I C J U I C E S T I M U L A T E D B Y A C O N S T A N T I N F U S I O N O F 6 u/HR O F S E C R E T I N . - 36 -S Y N T H E T I C HUMAN G A S T R I N It I M P E R I A L C H E M I C A L I N D U S T R I E S ( M A C C L E S F I E L D , E N G L A N D ) I N S U L I N : CONNAUGHT L A B O R A T O R I E S (TORONTO, C A N A D A ) G L U C A G O N t E L I L I L L Y AND COMPANY (TORONTO, C A N A D A ) CCK-PZ ( 2 5 0 I.D.U./MG ) BATCH NO. 26841 : G . I . H . R E S E A R C H L A B O R A T O R I E S ( S T O C K H O L M , SWEDEN) CCK-PZ ( 1 5 0 0 I.D.U./MG ) BATCH N o . 2 6 7 5 1 : G . I . H . R E S E A R C H L A B O R A T O R I E S ( S T O C K H O L M , SWEDEN) S E C R E T I N BATCH N o . 1 7 0 4 2 : G . I . H . R E S E A R C H L A B O R A T O R I E S ( S T O C K H O L M , SWEDEN) A N A L Y S I S OF DATA IN A L L S T U D I E S I N V O L V I N G I N F U S I O N OF A G A S T R I C I N H I B I T O R A G A I N S T A CONSTANT I N F U S I O N OF A S T I M U L A N T , THE V A L U E S OF H + S E C R E T I O N AND MOTOR A C T I V I T Y I N D E X WERE E X P R E S S E D AS R A T I O S OF THE MEAN OF THREE P L A T E A U P E R I O D S . IN ANY ONE E X P E R I M E N T THE R A T I O S C O N S I S T E D OF E A C H O B S E R V A T I O N / M E A N OF 3 P L A T E A U P E R I O D S . THE C R I T E R I O N FOR A P L A T E A U WAS 3 C O N S E C U T I V E P E R I O D S WITH L E V E L S OF H + S E C R E T I O N ± 1 0 $ OF ONE ANOTHER. T H I S METHOD WAS E M P L O Y E D B E C A U S E OF V A R Y I N G S E C R E T O R Y C A P A -C I T I E S OF 0 I F F E R E N T B l C K E L POUCHES TO THE SAME DOSE OF S T I M U L A N T . T H I S P O I N T I S I L L U S T R A T E D BY R E F E R E N C E TO THE RAW DATA WHICH I S I N C L U D E D IN T A B U L A R FORM. P E P S I N L E V E L S WERE NOT E X P R E S S E D AS R A T I O S B E C A U S E IN MANY C A S E S , I N F U S I O N OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E REDUCED P E P S I N L E V E L S TO Z E R O . THE R A T I O S OF V A L U E S .OF H + S E C R E T I O N AND MOTOR A C T I V I T Y WERE TRANSFORMED INTO L O G A R I T H M S IN OROER TO A P P L Y T E S T S OF - 37 -S I G N I F I C A N C E . L O G A R I T H M S O F R A T I O S O F H + A N D M O T O R A C T I V I T Y V A L U E S F O R T H E T H I R D P L A T E A U P E R I O D W E R E C O M P A R E D W I T H T H E V A L U E S O F T H E P E R I O D O F M A X I M U M I N H I B I T I O N U S I N G T H E S T U D E N T T T E S T F O R P A I R E D D A T A . W H E R E T E S T S O F S I G N I F I C A N C E W E R E C A R R I E D O U T ON P E P S I N D A T A , C O M P A R I S O N S W E R E M A D E O F P E P S I N V A L U E S ( M G T Y R O S I N E / 1 0 OR 15 M I N ) O F T H E P E R I O D O F M A X I M U M I N H I B I T I O N W I T H T H E C O R R E S P O N D I N G V A L U E S F O R T H A T P E R I O D IN C O N T R O L S T U D I E S , U S I N G T H E S T U D E N T T T E S T F O R U N P A I R E D D A T A . R E S U L T S I M U L T I P A R A M E T E R S T U D Y ON THE E F F E C T S OF THE I N T R A V E N O U S I N F U S I O N OF 2 P R E P A R A T I O N S C O N T A I N I N G C H O L E C Y S T O K I N I N -P A N C R E O Z Y M I N ( C C K - P Z ) A N I M A L S USED IN T H I S STUDY WERE P R E P A R E D AS D E S C R I B E D ON P. 1 8 OF THE METHODS S E C T I O N , P R E P A R A T I O N NO. 1. IN T H E S E A N I M A L S I T WAS P O S S I B L E TO RECORD S I M U L T A N E O U S L Y H + S E C R E T I O N , P E P S I N S E C R E T I O N ANO MOTOR A C T I V I T Y I N B l C K E L P O U C H E S , G A L L B L A D D E R P R E S S U R E AND MOTOR A C T I V I T Y IN A N T R A L P O U C H E S . T H E P A R A M E T E R S WERE MEASURED AND THE DATA A N A L Y Z E D AS D E S C R I B E D I N THE METHODS S E C T I O N , P. 2 3 • AT THE B E G I N N I N G OF THE E X P E R I M E N T S , CONTROL DATA WERE O B T A I N E D FOR AT L E A S T THREE 1 O - M I N P E R I O D S . C O N D I T I O N S WERE C O N S I D E R E D TO BE B A S A L I F THE L E V E L S OF H + S E C R E T I O N FROM THE B I C K E L P OUCHES WERE < 1 0 0 /JE Q / 1 0 M I N AND I N T R A - G A L L B L A D D E R P R E S S U R E WAS < 6 . 0 MM HG. A F T E R THE E S T A B L I S H M E N T OF B A S A L C O N D I T I O N S , THE A N I M A L S R E C E I V E D AN I N T R A V E N O U S I N F U S I O N OF E I T H E R 1 0 $ C C K - P Z ( 2 5 0 I . D . U . / M G ) OR 4 0 $ C C K - P Z ( 1 , 5 0 0 I . D . U . / M G ) FOR A 1 0 - M I N P E R I O D . T H E C C K - P Z P R E P A R A -T I O N S WERE A S S A Y E D P R I O R TO T H E I R USE I N T H I S S T U D Y , U S I N G THE G U I N E A P I G G A L L B L A D D E R P R E P A R A T I O N , D E S C R I B E D ON P. 22 OF THE METHODS S E C T I O N AND THE A S S A Y T E C H N I Q U E D E S C R I B E D ON P. 2 8 . IN T H I S A S S A Y , THE 1 0 $ PURE C C K - P Z WAS C O N S I D E R E D TO P O S S E S S THE P O T E N C Y A S C R I B E D TO I T ANO THE 4 0 $ PURE M A T E R I A L WAS A S S A Y E D A G A I N S T T H I S S T A N D A R D . T H I S I N I T I A L A S S A Y OF G A L L B L A D D E R A C T I V I T Y WAS E S S E N T I A L - 3 8 -- 39 -I N C A L C U L A T I N G C O M P A R A B L E D O S E S O F B O T H P R E P A R A T I O N S . W H E R E L E V E L S O F S I G N I F I C A N C E A R E R E P O R T E D , C O M P A R I S O N S W E R E M A D E B E T W E E N D A T A O B T A I N E D F R O M T H E P E R I O D S I M M E D I A T E L Y P R I O R TO T H E I N F U S I O N O F T H E C C K - P Z A N D T H O S E I M M E D I A T E L Y A F T E R T H E C E S S A T I O N O F T H E I N F U S I O N . A ) T H E E F F E C T O F C C K - P Z O N I N T R A - G A L L B L A D D E R P R E S S U R E C O M P A R A B L E D O S E S O F B O T H P R E P A R A T I O N S ( 0 . 2 I . D . U . / K G / M I N ) W E R E I N F U S E D A N D T H E R E S U L T S P R E S E N T E D I N F I G . 7 ( T A B L E 1 ) . E A C H P O I N T I N T H E F I G U R E R E P R E S E N T S T H E M E A N i S.E. O F 1 3 O B S E R V A T I O N S I N 3 A N I M A L S . T H E R E W A S N O S I G N I F I C A N T D I F F E R E N C E ( P y 0 . 5 0 ) I N T H E G A L L B L A D D E R R E S P O N S E S B E T W E E N T H E 2 P R E P A R A T I O N S . T H I S I N D I C A T E D T H A T B O T H P R E P A R A T I O N S W E R E E Q U A L L Y P O T E N T A S S T I M U L A N T S O F G A L L B L A D D E R C O N T R A C T I O N . T H E S E R E S P O N S E S R E P R E S E N T E D A P P R O X I M A T E L Y 5 0 - 6 0 $ O F M A X I M U M G A L L B L A D D E R P R E S S U R E I N T H E S E A N I M A L S . A G A L L B L A D D E R P R E S S U R E L E S S T H A N C O N T R O L L E V E L S W A S F O U N D T O O C C U R F O L L O W I N G T H E C E S S A T I O N O F T H E C C K - P Z I N F U S I O N . B ) T H E E F F E C T O F C C K - P Z O N A N T R A L M O T O R A C T I V I T Y B O T H C C K - P Z P R E P A R A T I O N S W E R E F O U N D T O H A V E E F F E C T S O N T H E I N D E X O F A N T R A L M O T O R A C T I V I T Y W H I C H W E R E N O T S I G N I F I C A N T L Y D I F F E R E N T ( P > 0 . 3 0 ) . T H E R E S U L T S A R E S H O W N I N F I G . 8 A N D S U M M A R I Z E D I N T A B L E I I . E A C H P O I N T I N T H E F I G U R E R E P R E S E N T S T H E M E A N jt S.E. O F 1 3 O B S E R V A T I O N S I N 3 A N I M A L S . c ) T H E E F F E C T O F C C K - P Z O N P E P S I N O U T P U T F R O M B l C K E L P O U C H E S T H E P E P S I N L E V E L S O F T H E P E R I O D P R I O R T O C C K - P Z T A B L E I E F F E C T OF INTRAVENOUS I N F U S I O N OF CCK-PZ 1 ON I N T R A - G A L L BLADDER P R E S S U R E (MM HG) CONTROL P E R I O D S CCK-PZ POST- i N F U S I O N P E R I O D S ' DOG EXP NO. K 61 K 109 K 33 K 30 C 38 J 37 J 36 J 35 J 34 1 3.0 6.0 0.0 4.8 6.0 1.8 2.4 1.8 4.8 3.0 6.0 1.4 0.0 4.4 2.0 3.6 1.8 5.2 5.0 6.0 0.4 0.0 4.8 2.0 4.4 2.0 6.4 9.0 14.0 3.7 10.4 17.2 10.0 10.4 14.0 10.8 2.0 8.0 0.0 2.0 4.8 2.0 4.0 7.0 3.0 1.0 2.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 2.0 4.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 o o o 7^  I D INI i S . E . 3.4 0.7 3.0 0.6 3.4 0.8 11.1 1.3 3.6 0.9 0.3 0.2 0.7 0.5 CONTROL PERIOOS CCK-PZ P O S T - I N F U S I O N P E R I O O S K K K K K K K K J J J J C 29 32 39 46 53 63 61 108 44 48 51 52 43 4.0 3.6 8.8 7.2 6.0 2.0 5.0 6.0 2.4 1.6 5.2 4.8 4.8 5.2 4.7 8.0 7.6 4.8 2.4 4.0 6.0 3.6 3.2 4.8 3.2 3.6 5.2 4.0 6.4 9.2 4.8 2.4 5.0 6.0 3.6 3.6 5.6 4.0 4.8 10.4 9.3 12.8 11.6 13.6 6.8 8.0 10.0 12.8 10.0 15.6 12.0 13.6 2.0 1.8 3.6 1.2 3.6 6.4 0.0 6.0 1.6 0.0 4.4 0.0 4.8 0.0 0.0 0.0 0.0 0.0 0.0 0.0 6.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 5.0 0.0 0.0 0.0 0.0 0.0 C D o o o 7K I T3 rsi t S . E . 4.7 0.6 4.7 0.5 5.0 0.5 11.0 0.8 2.7 0.6 1 0.2 I .D.U./KG/MIN 2 1 0 MIN DURAT iON - 41 -0.2 u / k g / min. CCK-PZ I I 10 min. periods F I G U R E 7. G A L L B L A D D E R P R E S S U R E CHANGES PRODUCED BY THE I N T R A V E N O U S I N F U S I O N OF M 0 $ ' AND ' 4 0 $ ' PURE C C K - P Z ( 0 . 2 I . D . U . / K G / M I N FOR 1 0 M I N ) . E A C H P O I N T R E P R E S E N T S THE MEAN OF 1 3 O B S E R V A T I O N S ON 3 DOGS. IN T H I S AND S U B S E Q U E N T F I G U R E S THE V E R T I C A L BARS ARE THE STANDARD ERRORS OF THE MEAN. D A T A R E P R E S E N T E D I N T H I S GRAPH I S T A K E N FROM T A B L E I . T H E S E P E R C E N T A G E P U R I T I E S WERE G I V E N BY THE S U P P L I E R AND ARE A R B I T R A R Y . A C T U A L I V Y DOG U N I T NUMBERS USED I N THE T H E S I S ARE C O R R E C T . T A B L E I I 1 2 EFFECT OF INTRAVENOUS INFUSION OF CCK-PZ ON ANTRAL M O T I L I T Y DOG EXP NO. J J J J J J K K K H H H C 8 12 34 35 36 37 3 0 3 3 61 1 0 5 106 1 0 8 38 I S.E. J J J J J K K K K K K C 3 9 44 4 8 51 52 2 9 32 46 5 3 6 3 61 1 0 8 t S.E. CONTROL PERIODS' 1 7.3 7.4 63.2 39.6 7 0 . 3 30.4 1 3 7 . 3 2 6 . 8 0.0 26.5 56.3 1 2 . 9 1 9 . 0 38.8 8.9 7.3 18.6 6 8 . 8 22.1 7.7 31.8 0.0 1 5 3 . 9 0.0 38.5 4 7 . 6 15.8 25.JL 7.3 26. 6 6 1 . 9 3 1 . 8 32.7 1 7 . 3 0.0 2.8 0.0 56.8 34.0 23-4 18.1 31.5 9-9 22. 6 4.9 CONTROL PERIOPS' 6 0 . 0 7 4 . 8 1 3 5 . 0 79-2 145.1 8.3 0.0 12.3 18.5 14.0 7.3 20.4 59-0 1 1 8 . 8 103.1 1 0 9 - 3 1 2 1 . 0 0.0 11.4 41.6 2 3 - 2 14.4 0.0 1 6 . 3 2 8 . 9 4 2 . 3 8 1 . 6 1 4 3 . 9 98.1 1 2 . 3 18.8 2 6 . 0 8.3 17.7 5.2 9.6 4 7 . 9 14.7 51.0 12.9 4 3 . 2 11.8 CCK-PZ 9 1 . 7 1 2 5 . 2 1 1 5 . 3 1 3 1 . 0 1 4 6 . 5 6 1 . 6 6 4 . 0 1 1 2 . 8 2 5 . 8 1 5 5 . 8 151 .2 4 5 . 0 1 4 2 . 2 1 0 2 . 6 1 0 . 6 CCK-PZ 6 4 . 0 1 1 6 . 0 1 0 2 . 3 183.1 3 9 . 4 5 1 . 5 5 3 . 4 1 7 4 . 0 177.1 1 8 . 5 3 5 . 9 5 2 . 5 9 0 . 9 16.1 P O S T — I N F U S I O N PERIOOS' 11.7 97.7 7 0 . 5 7 2 . 4 6 3 . 3 2 9 . 9 45.1 1 0 4 . 0 16.0 1 0 0 . 0 2 0 0 . 0 2 6 . 6 9 7 . 9 11.2 18.1 4 2 . 2 6.4 15 . 3 4.8 8.6 12.2 4.0 53.6 6 4 . 8 2 5 . 5 4 5 . 4 10.1 6.4 2 4 . 6 0.0 2.0 0.0 20.1 3.7 0.0 2 5 . 0 4 0 . 7 6 8 . 6 6 7 . 0 12.6 2 3 . 2 5.2 2 2 . 2 6.6 POST- iNFUS iON PERIOOS' 12. 5 59.7 3 8 . 8 5 3 . 8 8.4 70.4 2 5 . 9 1 2 4 . 2 9 5 . 7 14.6 1 1 . 5 4 7 . 3 25.2 41.7 1 0 3 . 0 40.1 4 4 . 6 2 0 . 5 14.2 38.1 10.0 0.0 0.0 34.6 4 3 . 6 7 2 . 0 171.1 8 7 . 2 7 3 . 8 5.5 1 2 . 9 10.8 8.7 18.5 2.8 8.9 53.7 11.8 3 6 . 3 9.0 4 9 . 9 15.1 o •A o o -v CD o o o 7Z I T3 M 4» 1 0.2 I .O.U./KG/MIN 2 MOTOR A C T I V I T Y INOEX 3 1 0 MIN 0URAT I ON - 43 -0 2 u / kg /min CCK - PZ 4 0 % C C K - P Z 10 % C C K - P Z 0 I 2 3 4 5 6 7 1 0 min. periods F I G U R E 8. CHANGES I N A N T R A L MOTOR A C T I V I T Y A F T E R THE INTRA VENOUS I N F U S I O N OF ' 1 0 $ ' AND ' 4 0 $ ' PURE C C K - P Z ( 0 . 2 I . D . U . / K G / M I N FOR 1 0 M I N ) . T H I R T E E N O B S E R -V A T I O N S ON 3 DOGS WITH E A C H HORMONE P R E P A R A T I O N . DATA I S T A K E N FROM T A B L E I I . - 4 4 -I N F U S I O N WERE S I G N I F I C A N T L Y D I F F E R E N T ( P < 0 . 0 5 ) IN THE TWO S E T S OF E X P E R I M E N T S I N V O L V I N G THE 2 P U R I T I E S OF CCK-PZ ( F I G . 9 ; T A B L E I I I ) . T H I S D I F F I C U L T Y AROSE IN PART B E C A U S E I T WAS NOT P O S S I B L E TO D E T E R M I N E P E P S I N OUTPUTS U N T I L THE END OF THE E X P E R I M E N T S AND THUS F L U C T U A T I N G P E P S I N L E V E L S COULD NOT BE D E T E C T E D B E F O R E CCK-PZ I N F U S I O N . ALTHOUGH THE ABOVE P R E C L U D E D M A K I N G A D E F I N I T I V E S T A T E M E N T ABOUT P E P S I N R E S P O N S E , IT A P P E A R E D THAT THE 4 0 $ PURE M A T E R I A L MAY HAVE S T I M U L A T E D P E P S I N OUTPUT TO A G R E A T E R DEGREE THAN THE 1 0 $ M A T E R I A L . E A C H P O I N T IN THE F I G U R E R E P R E S E N T S THE MEAN jt S . E . OF 1 3 O B S E R V A T I O N S I N 3 DOGS. o) THE E F F E C T OF CCK-PZ ON H + S E C R E T I O N FROM THE B I C K E L P OUCHES A D M I N I S T R A T I O N OF BOTH THE 1 0 $ AND THE 4 0 $ PURE CCK-PZ I N C R E A S E D H + OUTPUT FROM THE B l C K E L P O U C H E S . THE PURER M A T E R I A L WAS MUCH MORE P O T E N T THAN THE 1 0 $ PURE M A T E R I A L I N S T I M U L A T I N G H + O U T P U T , THE P E A K OUTPUTS B E I N G S I G N I F I -C A N T L Y D I F F E R E N T ( P < 0 . 0 0 5 ) ( F | G . 1 0 ; T A B L E I V ) . THE 4 0 $ CCK-PZ P R E P A R A T I O N PRODUCED A MEAN P E A K A C I D OUTPUT OF 1 5 5 . 5 /JEQ rT*"/1 0 M I N AS COMPARED TO 1 1 1 . 9 JUEQ H+/"l 0 M I N A F T E R I N F U S I O N OF 1 0 $ CCK-PZ. E A C H P O I N T IN THE F I G U R E R E P R E S E N T S THE MEAN - S . E . OF 1 3 O B S E R V A T I O N S I N 3 DOGS. THE H + R E S P O N S E TO THE P U R E R M A T E R I A L WAS A L S O OF MUCH LONGER D U R A T I O N . I I C O M P A R I S O N OF TWO P R E P A R A T I O N S C O N T A I N I N G CCK-PZ I N TERMS OF G A S T R I C S E C R E T O R Y I N H I B I T I O N T H I S STUDY WAS U N D E R T A K E N AS A R E S U L T OF THE F I N D I N G THAT E F F E C T O F -T A B L E I I I 1 2 N T R A V E N O U S I N F U S I O N O F C C K - P Z ON P E P S I N O U T P U T C O N T R O L P E R I O D S ' C C K - P Z P O S T - i N F U S i ON P E R I O O S ' Doc E X P NO. 1 J J J J J K K K K K H H H J 3 12 35 36 37 30 33 61 109 107 105 106 108 34 t S . E . 0.825 0.356 1.122 0.257 0.780 1.716 0.312 0.202 0.400 2.236 0.663 0.0 0.500 0.867 0.350 0.300 0.850 0.202 0. 300 0.936 0.350 0.202 0.312 1 .224 0.480 0.053 0.300 0.850 0.475 0.375 0.624 0.153 0.100 0.416 0.450 0.300 0.324 0.936 0.832 0.106 0.530 0.714 1.026 0.503 0.618 0.212 0.714 0.468 0.756 0.364 0.432 1 .288 0.833 0.159 0.0 0.459 0.600 0.250 0.400 0.102 0.306 0.312 0.408 0.536 0.309 0.927 0.404 0.052 0.0 0.306 0.325 0.100 0.200 0.0 0.1 56 0.153 0.300 0.312 0.104 0.600 0.400 0.104 0.0 0.306 0.225 0.075 0.250 T 0.102 0.300 -0.153 £ 0.364 0 0.306 o 0.052 ? 1.377 £ 0.108 0.0 0.208 0.770 0.160 0.520 0.090 0.500 0.080 0.610 0.100 0.380 0.060 0.260 0.050 0.280 0.090 C O N T R O L P E R I O O S ' C C K - P Z P O S T - I N F U S I O N P E R I O D S K 29 0.500 • K 32 1.050 K 46 0.0 K 53 0.104 K 63 1.122 K 61 0.210 K 108 0.416 J 39 0.159 J 44 0.0 J 48 0.330 J 51 0.200 J 52 0.0 C 43 0.357 0.663 0.0 0.106 0.900 0.103 0.306 0.105 0.561 0.100 0.312 0.0 0.500 0.300 0.350 0.0 0.051 0.714 0.0 0.361 0.208 0.196 0.150 1.530 0.052 0.350 0.572 0.770 0.153 0.378 1.484 0.156 0.416 0.468 1.070 0.350 2.080 0.520 1.352 0.702 0.702 0.094 0.265 1 .007 0.327 0.780 0.204 1 .240 0.250 0.561 0.350 0.720 0.312 0.306 0.0 0.104 0.594 0.104 0.578 0.106 0.900 0.102 0.300 0.0 0.364 0.156 0.102 0.153 0.0 0.200 0.156 0.550 0.102 0.800 0.102 0.364 1 .224 0.364 I S . E . 0.340 0.110 0.310 0.080 0.330 0.110 0.750 0.160 0.550 0.090 0.290 0.070 0.330 0.100 CD o o o I ~v K l 1 0.2 I . D . U . / K G / M I N 2 MG T Y R O S I N E/10 M I N 3 10 M I N D U R A T I O N - 4 6 -F I G U R E 9. CHANGES IN P E P S I N OUTPUT FROM B I C K E L P OUCHES A F T E R THE I N T R A V E N O U S I N F U S I O N OF ' 1 0 $ ' AND ' 4 0 $ ' C C K - P Z ( 0 . 2 I.D.U./KG/MIN FOR 1 0 M I N ) . T H I R T E E N O B S E R -V A T I O N S ON 3 DOGS WITH E A C H HORMONE P R E P A R A T I O N . DATA I S T A K E N FROM T A B L E I I I . T A B L E IV E F F E C T O F I N T R A V E N O U S I N F U S I O N O F C C K - P Z ^ ON H + O U T P U T C O N T R O L P E R I O D S ^ C C K - P Z P O S T - i N F U S i O N 3 P E R I O D S DOG E X P NO . 1 2 3 4 5 6 7 J 8 33 33 25 67 58 35 25 J 12 100 106 75 121 70 60 52 J - 34 43 45 45 152 117 71 57 > J 35 117 112 109 146 135 70 63 ' J 36 110 106 102 217 132 63 63 J 37 71 75 65 163 135 119 120 K 30 104 83 46 67 78 56 46 K 33 33 37 35 102 102 62 52 o K 61 95 95 90 119 164 114 89 ? K 109 45 42 41 60 72 62 57 . 1 K 107 114 64 36 46 54 35 41 ^ C 38 107 112 110 183 130 100 105 H 106 37- 48 58 70 36 52 60 H 105 43 43 52 108 35 49 H 108 15 15 14 57 • 16 26 40 71.1 67.3 60.2 111.9 88.9 64.9 61.4 + S . E . 9.4 8.3 7.9 13.4 11.6 7.0 7.0 C O N T R O L P E R I O O S ' C C K - P Z P O S T - i N F U S i O N 3 " E R I O D S K 29 50 43 45 78 162 96 42 K 32 45 38 35 107 129 92 61 CD K- 46 119 110 115 198 263 224 183 * K 53 68 64 51 119 180 177 1 6 1 K 63 43 35 33 90 148 105 70 o K 61 89 84 76 135 237 187 163 >P> K 108 57 54 46 68 114 74 45 o J 39 103 99 187 202 175 100 102 9. J 44 180 82 44 122 78 80 80 -L, J 48 39 25 30 100 70 41 46 M J 52 52 56 47 109 105 78 173 H 43 100 105 338 280 275 145 x 74.2 54.0 65.5 136.2 155.5 122.6 104.1 + S . E . 12.2 7.8 12.6 20.2 21.4 19.5 14.7 1 0.2 I . O . U . / K G / M I N 2 pEo H + / 1 0 M I N 3 10 M I N C U R A T I ON F I G U R E 1 0 . CHANGES IN H S E C R E T I O N FROM THE B I C K E L P O U C H E S A F T E R THE I N T R A V E N O U S I N F U S I O N OF ' 1 0 $ ' AND ' 4 0 $ ' CCK-PZ ( 0 . 2 t.D.U./KG/M iN FOR 1 0 M I N ) . T H I R T E E N O B S E R V A T I O N S ON 3 DOGS WITH E A C H HORMONE P R E P A R -A T I O N . DATA I S T A K E N FROM T A B L E IV. - 4 9 -THE 4 0 $ PURE C C K - P Z P R E P A R A T I O N HAD A G R E A T E R A C I D S T I M U -L A T O R Y E F F E C T ON B L C K E L POUCHES THAN THE 1 0 $ PURE C C K - P Z P R E P A R A T I O N . A P O S S I B L E E X P L A N A T I O N FOR T H I S D I F F E R E N C E WAS THAT AN I N H I B I T O R Y M A T E R I A L WAS P R O P O R T I O N A T E L Y REMOVED D U R I N G THE F U R T H E R P U R I F I C A T I O N . A C O M P A R I S O N OF THE I N H I B I T O R Y A C T I V I T Y OF THE TWO C C K - P Z P R E P A R A T I O N S AGA I N S T G A S T R I N P E N T A P E P T I D E - S T I M U L A T E D B L C K E L POUCH H+ S E C R E T I O N WAS U N D E R T A K E N TO T E S T T H I S H Y P O T H E S I S . T H I S DOSE WAS C A L C U L A T E D FROM THE DATA P R E S E N T E D I N F | G . 1 1 , O B T A I N E D FROM THE I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E I N DOSES OF 0.75» 1.5, 3.0 AND 6.0 JUG/KG/HR ON 2 O C C A S I O N S TO E A C H OF 2 DOGS. D O S E S OF 3.0 J UG/KG/HR AND ABOVE INDUCED V O M I T I N G I N OVER H A L F OF THE E X P E R I M E N T S AT THOSE L E V E L S . A DOSE OF 1.5 AJG/KG/HR WAS S E L E C T E D AS Y I E L D I N G 6 5 - 7 0 $ OF MAXIMUM H + S E C R E T I O N . A F T E R AT L E A S T 3 P E R I O D S OF B A S A L H + S E C R E T I O N , ( < 1 0 0 / J E Q H + / 1 0 M I N ) A C O N T I N U O U S I N T R A V E N O U S I N F U S I O N OF 1.5 UG/KG/HR OF G A S T R I N P E N T A P E P T I D E WAS S T A R T E D AND M A I N -T A I N E D THROUGHOUT THE COURSE OF THE E X P E R I M E N T . UPON A C H I E V I N G A P L A T E A U OF H + S E C R E T I O N ( l . E . , H + V A L U E S OF 3 P E R I O D S t 1 0 $ OF ONE A N O T H E R ) , A 1 0 M I N U T E I N F U S I O N OF C C K - P Z ( E I T H E R 1 0 $ OR 4 0 $ ) AT A DOSE L E V E L OF 0.2 I.D.U./ K G / M I N WAS G I V E N . FOUR TO S I X F I F T E E N MINUTE P E R I O D S OF I N F U S I O N OF G A S T R I N P E N T A P E P T I D E WERE R E Q U I R E D TO E S T A B L I S H A P L A T E A U OF H + S E C R E T I O N . T H E C C K - P Z P R E P A R A T I O N S WERE A S S A Y E D I N THE G U I N E A P I G G A L L B L A O D E R P R E P A R A T I O N TO CHECK THE U N I T A G E P R I O R TO E X P E R I M E N T A T I O N . BOTH P R E P A R A T I O N S - 50 -F I G U R E 11. THE H OUTPUT FROM B I C K E L POUCHES OF 2 DOGS, L AND P , I N R E S P O N S E TO THE I . V . I N F U S I O N OF G A S T R I N P E N T A P E P T I D E IN DOSES OF 0.75» 1»5» 3.0 AND 6.0 /JG/KG/HR. EACH P O I N T R E P R E S E N T S THE MEAN OF 6 O B S E R V A T I O N S IN EACH A N I M A L MADE A F T E R A P L A T E A U OF H + S E C R E T I O N HAD B E E N E S T A B L I S H E D . - 51 -S I G N I F I C A N T L Y I N H I B I T E D CONTROL L E V E L S OF H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E ( 1 0 $ C C K - P Z - P < 0 . 0 0 0 5 , 4 0 $ C C K - P Z - P < 0 . 0 0 0 5 ) . THE PURER M A T E R I A L WAS L E S S P O T E N T IN I N H I B I T I N G G A S T R I N S T I M U L A T E D H + S E C R E T I O N ( 4 8 $ ) THAN THE 1 0 $ PURE P R E P A R A T I O N ( 6 4 $ ) ( F | G . 1 2 ; T A B L E V ) . THE L E V E L S OF H + S E C R E T I O N AT THE P E R I O D OF P E A K I N H I B I T I O N WERE S I G N I F I C A N T L Y D I F F E R E N T ( P < 0 . 0 2 5 ) . L E V E L S OF H + WERE REDUCED FROM A MEAN OF 613.1 JUEQ H + / 1 0 M I N TO 2 4 0 . 0 JUEQ H + / 1 0 M I N BY 1 0 $ C C K - P Z , WHEREAS 4 0 $ C C K - P Z ONLY REDUCED H + S E C R E T I O N FROM 6 0 0 . 4 AIEQ H +/1 0 M I N TO 3 7 2 . 8 JUEQ H + / 1 0 M I N . EACH P O I N T I N THE F I G U R E R E P R E S E N T S THE MEAN ± S . E . OF 9 O B S E R V A T I O N S IN 3 DOGS. IN T H I S AND S U B S E Q U E N T S T U D I E S , P E R C E N T A G E I N H I B I T I O N WAS C A L C U L A T E D BY C O M P A R I N G THE V A L U E OF THE P A R A M E T E R UNDER STUDY I N THE P E R I O D OF G R E A T E S T I N H I B I T I O N WITH THE C O R R E S P O N D I N G MEAN V A L U E I N CONTROL S T U D I E S . P E R C E N T A G E I N H I B I T I O N WAS C A L -C U L A T E D FROM R A T I O S WHERE R E S U L T S WERE E X P R E S S E D AS R A T I O S . I l l P R E P A R A T I O N , A S S A Y , AND G A S T R I C I N H I B I T O R Y A C T I O N S OF EG S T A G E 1 R E S U L T S OF THE ABOVE S T U D I E S L E D TO A T T E M P T S TO S E P A R A T E A G A S T R I C I N H I B I T O R D I S T I N C T FROM C C K - P Z U S I N G THE CRUDER 1 0 $ C C K - P Z P R E P A R A T I O N S . THE S T A R T I N G M A T E R I A L FOR T H I S P U R I F I C A T I O N WAS THE C C K - P Z P R E P A R E O BY THE METHOD OF J O R P E S AND MUTT ( 1 9 6 1 ) . A FLOW CHART OF THE P U R I F I C A T I O N OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E I S SHOWN I N F I G . 1 3 . IN A T Y P I C A L E X P E R I M E N T , 1.0 G OF S T A R T I N G M A T E R I A L WAS S U B J E C T E D TO GEL F I L T R A T I O N U S I N G S E P H A D E X G-50 F I N E . THE COLUMN S I Z E WAS 5 X 9 0 CM AND THE M A T E R I A L WAS E L U T E D WITH T A B L E V E F F E C T OF I N T R A V E N O U S I N F U S I O N OF C C K - P Z ON \V OUTPUT 1-S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E " ' P L A T E A U P E R I O D S C C K - P Z P O S T - I N F U S I O N P E R I O D S DOG EXP NO. 1 2 3 4 5 6 7 M 134 481 4 6 2 4 1 6 342 1 8 2 2 5 9 • 3 2 3 M 1 5 0 532 5 9 9 6 1 5 572 3 8 9 2 7 5 2 7 5 M 1 1 0 5 8 3 6 6 6 6 6 0 4 3 2 2 2 4 2 7 0 3 7 0 K 145 3 3 5 2 9 7 354 2 5 4 1 9 6 2 3 8 331 K 1 4 8 4 0 6 3 7 0 3 8 0 2 7 0 1 6 7 1 9 8 2 9 2 K 149 3 0 2 3 1 3 342 2 8 6 1 2 7 181 231 H 151 661 6 4 4 6 3 3 4 4 3 194 3 0 8 5 0 4 H 147 8 4 3 8 6 9 9 0 0 5 3 4 4 7 0 291 4 5 6 H 146 1 1 6 5 1336 1 2 1 8 6 4 6 211 3 2 9 6 0 8 X 5 8 9 . 7 6 1 7 . 3 6 1 3 . 1 4 1 9 . 8 2 4 0 . 0 261 . 0 3 7 6 . 6 + S . E . 9 1 . 1 1 0 9 . 5 9 7 . 5 4 7 . 2 3 7 . 6 1 6 . 2 4 0 . 8 o o o 7^ I ~0 M P L A T E A U P E R I O D S C C K - P Z P O S T - I N F U S I O N P E R I O O S M 1 3 8 . 5 5 8 5 7 7 M 137 6 6 6 585 M 136 1 0 3 5 1 0 3 8 K 139 4 3 4 3 7 4 K 140 4 0 3 4 0 5 K 141 4 4 5 4 6 8 H 142 6 1 4 6 8 2 H 143 7 4 8 7 6 7 H 144 6 0 4 7 0 0 543 7 0 0 9 8 6 4 1 0 3 5 3 4 5 0 6 1 6 671 6 7 5 4 6 2 5 2 8 7 8 7 3 6 4 2 6 7 3 2 9 551 4 7 5 5 3 5 3 6 4 3 3 0 5 6 4 2 8 0 195 2 0 8 4 9 6 3 7 8 5 4 0 4 1 3 4 8 7 5 6 0 2 9 0 2 0 2 3 H 6 0 9 4 4 8 5 0 2 431 6 0 9 6 0 0 3 3 0 2 0 0 3 6 4 696 4 9 4 6 0 0 00 o o o I + S . E . 6 1 1 . 8 6 5 . 2 6 2 1 . 7 6 9 . 6 6 0 0 . 4 6 3 . 7 4 7 7 . 5 5 0 . 9 3 7 2 . 8 4 5 . 4 4 2 5 . 0 4 4 . 5 4 8 0 . 4 5 3 . 8 1 0 . 2 I . D . U;/KG/MIN 2 JJEQ H + / 1 0 MIN 3 1 . 5 JUG/KG/HR - 5 3 -•o o 0. c o O tO o c o 0> 4> . C o o o CO o CL 4— O + X 1.2 0.8 0.4 -l.5/jg./kg./hr. Gastrin Pentapeptide 1096 or 4 0 % C C K - P z 0.2 I.D.U./kg./min. T 1 O.O © © Control data A - - A 1 0 % C C K - P z ( 2 5 0 I.D.U./mg.) 4 0 % « ( 1 5 0 0 . .. ) -i r 2 ~i 1 1 r~ 6 8 10 min. periods F I G U R E 1 2 . E F F E C T OF 1 0 M I N U T E I . V . I N F U S I O N S OF 0 . 2 I.D.U./ M I N OF ' 1 0 $ ' CCK-PZ ( 2 5 0 I.D.U./MG) AND ' 4 0 $ ' CCK-PZ ( 1 5 0 0 I.D.U./MG) ON B I C K E L POUCH H + S E C R E -T I O N S T I M U L A T E D BY 1 . 5 J U G / K G / H R OF G A S T R I N P E N T A -P E P T I D E . DUE TO V A R I A B I L I T Y IN A B S O L U T E AMOUNTS OF H + PRODUCED BY D I F F E R E N T DOGS TO THE SAME DOSE OF S T I M U L I , H + I S E X P R E S S E D AS A R A T I O OF THE MEAN OF 3 P L A T E A U P E R I O D S . CONTROLS R E C E I V E D ONLY G A S T R I N P E N T A P E P T I D E THROUGHOUT THE E X P E R I M E N T . E A C H P L O T ON THE G R A P H R E P R E S E N T S THE MEAN OF 9 O B S E R V A T I O N S I N 3 DOGS. E X P E R I M E N T A L DATA FROM WHICH R A T I O S WERE C A L C U L A T E D I S P R E S E N T E D I N T A B L E V. - 54 -F I G U R E 1 3 SUMMARY OF P U R I F I C A T I O N OF G A S T R I C INHIB ITORY P O L Y P E P T I D E PROCEDURE HEAT C O A C U L A T E O H O C O U O O E N Q - J E J U N A L M U C O S A A C E T I C A C I D A C E T I C A C I D E X T R A C T J ^ ^ A L G I N I C A C I D A D S O R P T I O N N A C L P R E C I P I T A T E C O N T A I N I N G  S N , C C K - P Z A N D E G A C T I V I T Y METHANOL S Q L U B L E F R A C T I O N ( S N ) M E T H A N O L M E T H A N O L I N S O L U B L E F R A C T I O N C M - C E L L U L O S E P H 6 . 5 i C R U O E " C C K - P Z " T E A E - C E L L U L O S E P H 9 . 1 — • S E P H A D E X G 5 0 ( P H O S P H A T E ) P H 8 . 0 C M - C E L L U L O S E 1 0 # P U R E C C K - P Z > AMMONIUM B I C A R B O N A T E >M) I ,2M) ( 0 . 0 2 M ) pH 7 . 8 (& o.; 4 0 4 P U R E C C K - P Z E G S T A G E I F R A C T I O N A F R A C T I O N C E G S T A G E I I ( F R A C T I O N B ) S E P H A D E X G25 F I N E ( A C E T I C A C I D ) E G S T A G E I I I G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E C C K - P Z A C T I V I T Y I .D.U . / M O 2 2 - 2 5 2 5 0 - 2 7 5 1 , 5 0 0 1 0 6 1 2 0 7 . 5 2 . 0 H I N H I • I tI 0 * O F O U t P U * ' 3 0 0 7 0 7 5 1 I N H I B I T O R Y A C T I V I T Y A S S A Y E D A S D E S C R I B E D O N P . 3 2 0.25 M P H O S P H A T E B U F F E R , PH 8.0. F R A C T I O N S OF 50 ML WERE C O L L E C T E D . A B S O R B A N C E WAS MEASURED AT 280 NM THROUGH A 1.0 CM L I G H T P A T H . F l G . 14 SHOWS THE CHROMATOGRAM O B T A I N E D . E A C H F R A C T I O N WAS A S S A Y E D FOR C C K A C T I V I T Y U S I N G THE G U I N E A P I G G A L L B L A D D E R T E C H N I Q U E AND E M P L O Y I N G THE A S S A Y PROCEDURE D E S C R I B E D ON P. 28 OF THE METHODS S E C T I O N . A L L F R A C T I O N S NOT D E M O N S T R A T I N G C C K A C T I V I T Y WERE P 0 0 L E 0 , D E S A L T E D AND C O N C E N T R A T E D U S I N G A L G I N I C A C I D ANO D E A E - S E P H A D E X . THE F R A C T I O N S FROM THE S E P H A D E X G-50 COLUMN WHICH P O S S E S S E D L I T T L E C C K A C T I V I T Y WERE POOLED AND D I L U T E D 10X WITH D I S T I L L E D WATER. THE P H OF THE S O L U T I O N WAS LOWERED TO 2.5 WITH 2.0 M H C L AND THE A B S O R B A N C E AT 215 NM, THROUGH A 1.0 CM L I G H T P A T H WAS M E A S U R E D . IN A T Y P I C A L PROCEDURE T H I S WAS FOUND TO BE ABOUT 2.0. A L G I N I C A C I D (7.0 - 10.0 G WET W E I G H T ) WHICH HAD B E E N P R E V I O U S L Y WASHED WITH A C I D -E T H A N O L , FOLLOWED BY D I L U T E AQUEOUS H C L AND WATER, WAS ADDED TO THE O I L U T E D S O L U T I O N AND S T I R R E D FOR 15 M I N . THE A B S O R B A N C E AT 215 NM WAS READ AND A D S O R P T I O N C O N S I D E R E D C O M P L E T E WHEN T H I S WAS <. 0.10. THE A L G I N I C A C I D WITH ADSORBED P O L Y P E P T I D E S WAS C O L L E C T E D BY VACUUM F I L T R A T I O N ON 2 L A Y E R S OF WHATMAN 541 F I L T E R P A P E R AND WASHED S E V E R A L T I M E S WITH I C E COLD 0.005 M H C L . THE ADSORBED P O L Y P E P T I D E S WERE E L U T E D FROM THE A L G I N I C A C I D WITH A P P R O X I M A T E L Y 20 - 30 ML I C E COLD 0.2 M H C L , A P P L I E D IN S M A L L A L I Q U O T S . T H E E L U A T E WAS P A S S E D THROUGH A 1.5 X 10 CM COLUMN OF D E A E - S E P H A D E X WHICH HAD B E E N E Q U I L I B R A T E D WITH 0.2 M A C E T I C A C I D . THE E F F L U E N T , ABOUT 40 ML ANO C L - F R E E , WAS L Y O P H I L I Z E D FOR 24 - 56 -0 . 2 5 M Phosphate Buffer pH 8.0 t 10 12 14 16 18 20 22 24 26 26 30 Sample Number F I G U R E 1 4 . ' F R A C T I O N A T I O N OF S T A R T I N G M A T E R I A L ON S E P H A D E X G-50 F I N E . 1.0 G OF S T A R T I N G M A T E R I A L A P P L I E D TO A COLUMN 5 X 9 0 CM AND E L U T E D WITH 0.25 M P H O S P H A T E B U F F E R , P H 8.0. F R A C T I O N S I Z E 5 0 ML. A B S O R B A N C E M E A S U R E D AT 2 8 0 NM THROUGH A 1.0 CM L I G H T P A T H . SHADED AREA DEMONSTRATED E N T E R O -GASTRONE A C T I V I T Y . - 57 -HOURS. Y I E L D S AT T H I S S T A G E RANGED FROM 1 5 0 - 2 5 0 MG OF M A T E R I A L . T H I S P R E P A R A T I O N WAS R E F E R R E D TO AS EG S T A G E I (EG I ) . EG I P O S S E S S E D ^ 1 0 I.D.U. CCK-PZ/MG AND WAS FOUND TO HAVE NO S E C R E T I N A C T I V I T Y , E M P L O Y I N G THE S E C R E T I N A S S A Y P ROCEDURE O U T L I N E D ON P. 3 2 OF THE METHODS S E C T I O N . A. E F F E C T S OF E G I ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y DOGS USED I N T H I S STUDY WERE P R E P A R E D AS D E S C R I B E D ON P. 21 OF THE METHODS S E C T I O N . G A S T R I C J U I C E WAS C O L L E C T E D AND A N A L Y Z E D FOR H AND P E P S I N AS O U T L I N E D IN THE METHODS S E C T I O N . THE E X P E R I M E N T A L D E S I G N WAS THE SAME AS IN THE P R E V I O U S S T U D Y , WITH E G I B E I N G G I V E N AS A 1 0 M I N U T E I N T R A -VENOUS I N F U S I O N ( 1 . 0 J U G/KG/M IN) A G A I N S T A P L A T E A U OF H + S E C R E T I ON S T I M U L A T E D BY 1.5> IG/KG/HR OF G A S T R I N P E N T A P E P T I D E . A; B I C K E L POUCH H S E C R E T I O N H + OUTPUT I S E X P R E S S E D AS A R A T I O OF THE MEAN OF 3 CONTROL P E R I O D S AS I N T H E „ P R E V I O U S S T U D Y . I N F U S I ON OF 1.0 J UG/KG/M I N OF EG I PRODUCED 7 0 $ ( P < 0 . 0 5 ) I N H I B I T I O N OF CONTROL L E V E L S OF H + S E C R E T I O N ( F | G . 1 5 , T A B L E V I ) . As WITH THE 1 0 $ C C K - P Z , MAXIMUM I N H I B I T I O N DID NOT OCCUR U N T I L THE P E R I O D A F T E R THE I N F U S I O N OF THE I N H I B I T O R . EG I REDUCED L E V E L S OF H + S E C R E T I O N FROM A MEAN OF 6 1 8 . 2 /JEQ H +/ 1 0 M I N IN CONTROL S T U D I E S TO A LOW OF 168.1 /jEQ H / 1 0 M I N IN THE F I R S T P 0 S T - I N F U S I 0N P E R I O D . E A C H CONTROL P O I N T IN THE F I G U R E R E P R E S E N T S THE MEAN 1 S . E . OF 9 O B S E R V A T I O N S IN 3 DOGS. E A C H EG I P O I N T R E P R E S E N T S THE MEAN i S . E . OF 7 O B S E R V A T I O N S IN 3 DOGS. T A B L E VI E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EG I ON H + O U T P U T 1 S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E P L A T E A U P E R I O O S ' DOG EXP No. 1 2 3 4 5 6 7 8 9 K 1 5 6 2 8 6 2 7 0 281 2 9 2 281 2 9 7 3 1 3 2 9 7 2 6 0 K 1 5 5 2 4 9 2 5 4 262 2 7 5 2 7 6 2 7 5 2 7 3 2 7 5 3 0 0 K 1 5 4 2 0 8 167 2 1 4 232 2 7 8 2 5 7 2 1 0 2 1 2 2 1 2 M 1 5 3 6 7 2 6 3 6 627 6 9 5 6 1 0 5 7 7 545 5 8 8 554 M 1 5 2 481 4 9 3 4 8 8 4 8 6 4 7 0 4 8 7 4 5 2 4 7 5 4 8 7 M 151 6 0 5 5 5 3 594 554 5 5 5 5 5 0 554 5 7 5 4 9 7 H 1 5 9 7 4 8 8 0 3 8 1 7 8 2 3 8 7 2 8 3 9 7 7 3 7 3 8 7 8 5 H 1 6 0 1 0 4 3 1386 1183 1 4 0 7 1 3 3 4 1 2 6 6 1 2 6 9 1 1 6 8 1 2 0 0 H 1 5 0 7 8 8 9 0 0 1 0 5 0 1 0 3 5 8 8 8 8 8 8 851 9 0 0 8 7 0 + X S . E . 5 6 4 . 0 9 4 . 1 6 0 6 . 8 127 .9 6 1 2 . 8 1 1 5 . 8 6 4 4 . 3 1 3 0 . 8 6 1 8 . 2 1 1 9 . 1 6 0 4 . 0 1 1 2 . 7 5 7 5 . 5 1 0 7 . 1 5 8 0 . 8 1 0 4 . 9 5 7 3 . 8 1 0 8 . 2 P L A T E A U P E R I O D S ' EG I P O S T - i N F U S i O N P E R I O D S K 1 7 3 1 8 7 2 0 0 2 0 5 H 1 8 5 5 4 5 6 3 5 651 H 1 7 0 1 3 6 3 1081 1 1 9 2 M 1 8 7 4 6 5 519 521 M 1 8 8 594 591 6 1 0 H 7 2 2 2 6 0 3 0 0 302 K 1 7 2 2 9 7 2 6 0 2 2 8 2 0 0 7 3 0 8 2 6 3 0 2 4 3 2 2 6 5 2 1 2 1 0 0 1 1 4 1 2 0 1 5 3 1 7 9 3 5 4 1 5 0 180 2 8 6 3 5 2 1 6 6 2 6 0 3 4 8 4 0 4 5 0 6 1 5 7 1 7 8 2 4 8 2 9 7 3 7 5 1 9 0 2 2 8 3 2 3 3 9 8 4 3 7 7 7 182 2 8 3 4 0 2 3 5 0 1 3 3 161 1 8 3 1 7 2 191 X ± S . E . 5 3 0 . 1 1 5 0 . 2 512.3 114.5 5 2 9 . 8 1 2 9 . 8 4 2 3 . 8 96 .4 1 6 8 . 1 34.3 1 8 1 . 8 1 8 . 5 2 4 0 . 7 3 1 . 5 3 0 1 . 7 4 0 . 5 3 4 1 . 4 4 5 . 4 1 >>EQ H + / 1 0 M I N 2 1 . 5 UG/KG/HR 3 G A S T R I N P E N T A P E P T I 4 1 0 M I N I N F U S I O N (1 DE ONLY . 0 JJG/K G/M I N ) - 59 -CO "CT O k_ <D 0-2 1.2 —^ c o o rO o o s: n o o o or ro o 3 Q. O + I l.5/jg./kg./hr. Gostrin Pentapeptide • E.GI. 0.8 0.4 0.0 Control data A — A 1.0 /jg./kg./min. - i ' r 1 T r— 2 -1 r 4 T 1 1 1 8 10 15 min. periods F I G U R E 1 5 . E F F E C T OF A 1 0 M I N U T E I N T R A V E N O U S I N F U S I O N OF 1.0 JUG/KG/MIN OF E G S T A G E I ON B I C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY 1.5 J U G / K G / H R OF G A S T R I N P E N T A P E P T I D E . E A C H P O I N T ON THE CONTROL CURVE R E P R E S E N T S 9 E X P E R I M E N T S I N 3 DOGS. E A C H P O I N T ON THE E G I CURVE R E P R E S E N T S 7 E X P E R I M E N T S IN 3 DOGS. THE R A T I O S ARE C A L C U L A T E D FROM DATA IN T A B L E V I . - 60 -B ) B I C K E L POUCH P E P S I N S E C R E T I O N TEN M I N U T E I N F U S I O N OF E G 1 PRODUCED 7 0 $ ( P < 0 . 0 0 5 ) I N H I B I T I O N OF CONTROL L E V E L S OF P E P S I N S E C R E T I O N ( F | G . 1 6 ; T A B L E V I I ) . P E P S I N L E V E L S DROPPED FROM A CONTROL V A L U E OF 0 . 5 0 1 MG T Y R O S I N E / 1 0 M I N TO 0 . 0 9 1 MG T Y R O S I N E / 1 0 MIN IN THE F I RST P O S T - I N F U S I ON P E R I O D . E A C H CONTROL P O I N T I N THE F I G U R E R E P R E S E N T S THE MEAN — S . E . OF 7 O B S E R V A T I O N S IN 3 DOGS. EACH E G 1 P O I N T R E P R E S E N T S THE MEAN i S . E . OF 5 O B S E R V A T I O N S IN 3 DOGS. A s M E N T I O N E D E A R L I E R , MEAN P E P S I N V A L U E S WERE P L O T T E D AS MG T Y R O S I N E / 1 5 M I N RATHER THAN R A T I O S . E G S T A G E 1 BECAME THE S T A R T I N G P O I N T FOR S E V E R A L P U R I F I C A T I O N P R O C E D U R E S IN AN A T T E M P T TO A C H I E V E A H I G H L Y P U R I F I E D AND P O T E N T G A S T R I C I N H I B I T O R D I S T I N C T FROM THE G A S T R O I N T E S T I N A L HORMONES S E C R E T I N AND C C K - P Z . ONE SUCH PROCEDURE I N V O L V E D THE RECHROMAT 0GRAPHY OF E G 1 ON S E P H A D E X G 2 5 F I N E , E L U T I N G WITH 0 . 2 M A C E T I C A C I D ( F L G . 1 3 ) . T H R E E F R A C T I O N S WERE O B T A I N E D AND L Y O P H I L I Z E D . T H E S E F R A C T I O N S WERE A S S A Y E D FOR C C K - P Z AND E N T E R O G A S T R O N E ACT I V I TY ( F | G . 1 7 ) . I N F U S I O N OF F R A C T I O N 2 Y I E L D E D 7 3 $ I N H I B I T I O N OF G A S T R I N P E N T A P E P T I D E S T I M U L A T E D S E C R E T I O N AND P O S S E S S E D 1 1 I . D . U . CCK-PZ/MG. T H I S WAS THE P U R E S T P R E P A R A T I O N OF THE I N H I B I T O R . T H I S F R A C T I O N I S R E F E R R E D TO AS E G 1 ( G 2 5 ) . THE FACT THAT E G 1 PRODUCED 7 0 $ I N H I B I T I O N OF G A S T R I N P E N T A P E P T I D E S T I M U L A T E D H + S E C R E T I O N ( F l G . 1 5 ) I N D I C A T E D THAT NO S I G N I F I -CANT I N C R E A S E I N PO T E N C Y OF THE I N H I B I T O R Y M A T E R I A L WAS A C H I E V E D AS A R E S U L T OF F R A C T I O N A T I O N OF E G 1 ON S E P H A D E X G 2 5 . FOR T H I S R E A S O N THE TWO P R E P A R A T I O N S WERE LOOKED UPON T A B L E VI I E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ON P E P S I N OUTPUT S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E P L A T E A U P E R I O D S ,3 DOG EX P NO. 1 2 3 4 5 6 7 8 9 K 1 56 0.572 0.424 0.429 0.385 0 . 5 3 0 0.371 0 . 3 1 8 0.371 0 . 4 3 2 K 1 5 5 0 . 2 1 2 0 . 2 1 2 0.159 0. 2 1 6 0 . 2 1 2 0 . 1 0 8 0 . 1 5 9 0 . 1 6 2 0.162 H 1 5 0 2.451 1.458 0.840 0.901 1 .092 0 . 8 4 0 0 . 4 4 8 0 . 3 3 6 M 1 1 2 1.450 0.689 0.741 0.605 0 . 6 1 6 0 . 5 3 5 0 . 6 0 6 0 . 7 0 7 0 . 6 5 0 K 7 9 0 . 336 0 . 2 6 5 0 . 3 1 8 0.300 0 . 8 4 0 0 . 2 1 2 0 . 3 0 0 0 . 2 2 6 0 . 3 5 0 K 7 8 0 . 1 1 0 0 . 1 0 8 1.020 0.054 0 . 1 0 8 0.106 0 . 1 0 6 0 . 1 5 9 0 . 3 7 8 M 1 1 0 0.159 0.106 0 . 0 5 3 0.161 0 . 1 0 8 0 . 1 1 0 0 . 1 6 2 0 . 3 9 9 0 . 2 3 0 X 0.755 0.466 0.466 0.374 0.501 0.326 0 . 2 9 9 0 . 3 3 5 0.367 S.E. 0.332 0 . 1 8 2 0.182 0 . 1 1 0 0.144 0.104 0 . 0 6 0 0 . 0 7 0 0 . 0 6 3 3 P L A T E A U P E R I O D S 4 EGI 3 P O S T - i N F U S i O N P E R I O D S K 1 7 3 0.364 0.364 0.312 0.364 0 . 3 0 0 0 . 2 1 2 0 . 2 0 8 0 . 3 1 2 0 . 2 0 8 H 18 5 0.550 0.580 0.360 0.351 0 . 1 5 6 0 . 1 1 6 0 . 1 0 7 0 . 1 6 2 0 . 1 1 0 M 18 7 0.165 0.171 0.056 0 . 0 5 4 0.0 0.0 0.0 0.0 0.0 M 1 8 8 0.162 0 . 1 0 8 0 . 1 0 8 0.0 0.0 0 . 0 5 0 0.0 0 . 2 1 2 0 . 1 9 5 H 1 7 2 1.762 1.166 1.040 0.0 0.0 0.0 0.0 0.0 0.0 0.600 0 .477 0.477 0.154 0.091 0 . 0 8 0 0 . 0 6 3 0.137 0 . 1 0 3 + S.E. 0.298 0 . 1 9 0 0 . 1 9 0 0.080 0 . 0 6 0 0.031 0.041 0 . 0 6 0 0 . 0 4 5 1 MG T Y R O S I N E / 1 0 M I N 2 1.5 P G / K G / H R 3 G A S T R I N P E N T A P E P T I D E ONLY 4 1 0 M I N I N F U S I O N ( 1 . 0 JUG/KG/MIN) - 62 -F I G U R E 1 6 . E F F E C T OF A 1 0 M I N U T E I . V . I N F U S I O N OF 1.0 JJG/KG/ M I N OF E G I ON P E P S I N OUTPUT FROM B L C K E L POUCHES S T I M U L A T E D B Y 1.5 ^UG/KG/HR OF G A S T R I N P E N T A P E P T I D E . E A C H P L O T ON THE CONTROL CURVE R E P R E S E N T S THE MEAN OF 7 E X P E R I M E N T S IN 3 DOGS. EA C H P L O T ON THE CURVE WITH E G I R E P R E S E N T S 5 E X P E R I M E N T S IN 3 DOGS. P E P S I N V A L U E S T A K E N FROM T A B L E V I I . - 63 -% Inhibition I.D.U. CCK/mg. 8O-1 60 •D • CL -•— o •J-X 40 o •£ 20 c E.G.I. ( G - 2 5 ) E.G.I. ( G - 2 5 ) 3 E.G.I. ( G - 2 5 ) M20 r 160 h 80 o> E N O O ci h 40 ^ 0 F r a c t i o n I F r a c t i o n 2 F rac t ion 3 F I G U R E 1 7 . R E S U L T S OF CCK-PZ AND E N T E R O G A S T R O N E A S S A Y S OF F R A C T I O N S R E S U L T I N G FROM THE CHROMATOGRAPHY OF EG I ON S E P H A D E X G25. - 64 -AS B E I N G EQUAL IN I N H I B I T O R Y S T U O I E S . B. E F F E C T S OF EG I ( G 2 5 ) ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y S T I M U L A T E D BY ENDOGENOUS G A S T R I N A N I M A L S USED IN THESE E X P E R I M E N T S WERE AS O E S C R I B E O IN P R E P A R A T I O N NO. 2, P. 21 . ENDOGENOUS G A S T R I N WAS R E L E A S E D BY P E R F U S I N G I S O L A T E D ANTRAL POUCHES WITH 0 . 1 $ A C E T Y L C H O L I N E I N 0 . 9 $ NACL S O L U T I O N AT A RATE OF 0.5 M L / M I N . A F T E R 3 C O N S E C U T I V E 1 0 M I N U T E P E R I O D S OF P L A T E A U L E V E L S OF H + / S E C R E T I ON FROM THE B l C K E L P O U C H E S , EG I ( G 2 5 ) WAS G I V E N AS A 1 0 M I N U T E I N T R A V E N O U S I N F U S I O N ( 1 . 0 J UG/KG/M IN). A ) B l C K E L POUCH H + S E C R E T I ON EG I ( G 2 5 ) PRODUCED 6 6 $ ( P < 0 . 0 0 2 5 ) I N H I B I T I O N OF CONTROL L E V E L S OF H S E C R E T I O N ( F l G . 1 8 ; T A B L E V I I I ) . L E V E L S OF H S E C R E T I O N F E L L FROM A MEAN OF 4 3 3 . 9 JJEQ H / 1 0 MIN IN THE CONTROL S T U D I E S TO 1 2 1 . 6 JUEQ H +/1 0 M I N IN THE SECOND POST I N F U S I O N P E R I O D . E A C H P O I N T IN THE F I G U R E R E P R E S E N T S THE MEAN i S.E. OF 8 O B S E R V A T I O N S IN 3 DOGS. B ) B l C K E L POUCH P E P S I N S E C R E T I O N EG I ( G 2 5 ) PRODUCED 6 5 $ ( P < 0 . 0 1 ) I N H I B I T I O N OF CONTROL L E V E L S OF P E P S I N S E C R E T I O N S T I M U L A T E D BY ENDOGENOUS G A S T R I N ( F I G . 1 9 ; T A B L E I X ) . P E P S I N L E V E L S DROPPED FROM A CONTROL V A L U E OF 0.511 MG T Y R O S I N E / 1 0 M I N TO 0 . 1 7 9 MG T Y R O S I N E / 1 0 M I N IN THE SECOND POST I N F U S I O N P E R I O D . c ) ANTRAL MOTOR A C T I V I T Y EG I ( G 2 5 ) PRODUCED 7 0 $ ( P < 0 . 0 5 ) I N H I B I T I O N OF CONTROL V A L U E S OF THE INDEX OF ANTRAL MOTOR A C T I V I T Y T A B L E VI I I E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ( G 2 5 ) ON H + OUTPUT S T I M U L A T E D BY P E R F U S I O N OF ANTRAL P O U C H E S WITH 0 . 1 $ ACH 1 P L A T E A U P E R I O D S DOG EXP NO. ,1 2 3 4 5 6 7 8 9 J 1 0 6 4 4 0 473 386 417 386 3 4 0 545 465 5 2 5 H ' 120 6 4 2 562 778 773 703 738 710 719 7 2 0 H 1 2 7 290 310 365 446 477 6 0 4 691 455 486 H 1 2 6 519 4 7 0 7 0 4 629 676 559 551 718 637 J 97 4 4 4 435 336 2 9 4 309 319 2 4 4 2 4 4 363 M 75 3 5 0 341 329 315 316 371 4 1 6 351 337 K 74 237 1 9 4 270 212 1 56 1 4 6 151 1 4 8 165 K 73 2 8 6 355 290 308 354 396 379 4 2 4 465 + X S . E . 4 0 0 . 6 48.2 392.5 4 0 . 8 4 3 2 . 2 68.9 4 2 4 . 2 67.1 4 2 2 . 1 6 6 . 4 433.9 6 6 . 5 4 6 0 . 9 71.0 4 4 0 . 5 7 1 . 7 4 6 2 . 3 6 2 . 1 P L A T E A U P E R I O D S 3 EGI ( G 2 5 ) P O S T - i N F U S i O N P E R I OPS M 1 0 4 549 6 2 0 562 K 9 6 2 6 5 3 0 0 3 1 9 M 9 5 2 2 4 2 6 5 2 8 0 K 9 4 2 1 5 2 3 5 2 1 6 K 9 3 571 5 7 7 6 0 5 M 91 8 6 2 7 0 291 3 4 0 K 201 2 3 9 2 6 0 K 7 2 6 2 0 5 6 7 541 453 2 3 0 197 190 4 0 5 2 6 0 193 306 1 1 3 1 2 5 1 8 8 196 2 6 5 1 2 0 9 7 186 2 6 5 3 4 0 1 3 5 82 1 6 3 221 2 4 5 1 6 4 2 2 5 2 5 9 2 6 7 2 5 0 2 3 3 1 5 8 2 3 5 2 6 0 3 1 3 1 1 0 1 2 0 175 2 0 9 2 1 3 135 1 3 0 196 2 2 7 3 1 7 7 8 36 9 8 181 2 2 2 1 3 6 . 0 1 2 1 . 6 1 8 7 . 5 2 2 8 . 3 2 7 0 . 6 1 6 . 3 1 9 . 6 17.1 1 1 . 6 1 6 . 6 + S . E . 3 2 7 . 8 6 0 . 7 3 8 6 . 8 5 9 . 7 3 9 0 . 3 5 4 . 3 2 7 6 . 8 3 4 . 1 1 JJEQ H + / 1 0 M I N 2 ANTRAL P E R F U S I O N WITH ACH ONLY 3 1 0 M I N I N F U S I O N ( 1 . 0 / J G / K G / M I N ) - 66 -0.1% Ach (Antral Perfusion) F I G U R E 1 8 . E F F E C T OF A 1 0 M I N U T E I . V . I N F U S I O N OF 1.0 JUG/KG/ M I N OF E G I ( G 2 5 ) ON B L C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY ENDOGENOUS G A S T R I N R E L E A S E D BY P E R F U S I O N OF A N T R A L P O U C H E S WITH 0 . 1 $ A C E T Y L -C H O L I N E . EACH P L O T ON THE GRAPH R E P R E S E N T S THE MEAN OF 8 O B S E R V A T I O N S I N 3 DOGS. R A T I O S C A L -C U L A T E D FROM E X P E R I M E N T A L DATA IN T A B L E V I I I . T A B L E IX E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ( G 2 5 ) ON P E P S I N OUTPUT S T I M U L A T E D BY P E R F U S I O N OF ANTRAL P O U C H E S WITH 0 . 1 $ ACH P L A T E A U P E R I O D S 2 DOG EXP NO. 1 2 3 4 5 6 7 8 9 J J M K K K M 1 0 6 9 7 7 5 7 4 7 3 41 7 6 0.594 3 . 2 1 6 0 . 5 4 0 0 . 3 6 8 0 . 6 4 3 0 . 8 8 4 0 . 6 9 6 0 . 2 0 6 0 . 6 8 9 0 . 4 1 6 0 . 2 1 2 0 . 6 3 6 0 . 6 6 3 0 . 8 1 0 0 . 3 0 9 0 . 3 9 2 0 . 3 3 6 0 . 1 0 6 0 . 5 2 0 0 . 5 3 0 0 . 4 1 2 0 . 2 0 6 0 . 3 6 8 0 . 3 7 1 0 . 1 5 6 0 . 8 1 0 0 . 6 9 5 0 . 2 0 8 0 . 5 6 7 0 . 4 1 6 0 . 3 9 9 0 . 2 0 8 0 . 6 4 8 1 . 6 9 6 0 . 1 5 9 0 . 8 6 4 0 . 3 6 4 0 . 3 2 4 0 . 1 0 6 0 . 8 5 6 0 . 7 5 4 0 . 3 1 5 0 . 8 0 3 0 . 2 0 8 0 . 3 1 8 0 . 1 5 3 0 . 8 1 7 0 . 5 4 0 0 . 2 1 2 2 . 2 7 9 0 . 4 1 6 0 . 3 7 8 0 . 1 5 5 0 . 8 2 5 0 . 6 3 8 0 . 1 0 8 2 . 3 6 0 0 . 5 3 0 0 . 3 7 8 0 . 1 5 6 1 . 3 7 5 0 . 6 3 8 0 . 2 0 4 + X S . E . 1 . 2 7 7 0 . 3 7 9 0 . 5 1 8 0 . 0 8 9 0 . 3 7 2 0 . 0 4 4 0 . 4 0 2 0 . 0 9 4 0 . 5 8 4 0 . 1 9 4 0 . 5 1 1 0 . 1 1 4 0 . 4 3 5 0 . 1 0 4 0 . 6 8 5 0 . 2 8 0 0 . 8 0 5 0 . 3 0 0 2 P L A T E A U P E R I O D S 3 EGI ( G 2 5 ) 2 POST-1NFUS1 ON P E R I O D S M K M K K M K K 1 0 4 9 6 9 5 94 9 3 91 8 6 72 0 . 1 0 6 0 . 7 4 2 0 . 8 3 2 0 . 1 0 4 1 . 9 0 4 0 . 6 6 3 0 . 9 9 0 1 . 1 6 6 0 . 1 0 5 0 . 4 5 9 0 . 4 2 4 0 . 1 0 8 1 . 3 2 0 0 . 4 0 8 0 . 7 8 0 1 . 0 2 6 0 . 0 5 5 0 . 5 5 0 0 . 2 1 6 0 . 1 0 0 1 . 0 2 6 0 . 3 5 0 1 . 1 4 4 1 . 1 4 0 0 . 1 0 3 0 . 3 0 6 0 . 1 4 1 0 . 0 5 1 0 . 5 9 4 0 . 1 0 0 0 . 7 9 5 0 . 4 5 9 -0 . 0 0 . 4 0 8 0 . 0 0 . 0 5 0 0 . 3 1 8 0 . 1 5 0 0 . 5 2 0 0 . 5 2 0 0 . 0 0 . 4 0 8 0 . 1 0 2 0 . 0 5 3 ' 0 . 1 5 3 0 . 0 0 . 3 0 0 0 . 4 1 6 0 . 0 0 . 5 3 0 0 . 0 5 0 0 . 1 0 5 0 . 8 1 0 0 . 3 0 6 0 . 5 3 0 0 . 4 1 6 0 . 0 0 . 5 1 0 0 . 0 0 . 2 1 4 0 . 7 7 1 0 . 1 0 2 0 . 6 4 8 0 . 2 7 5 0 . 0 0 . 6 4 8 0 . 0 0 . 2 0 0 0 . 8 1 0 0 . 0 5 2 1 . 6 6 4 0 . 3 1 8 + X S . E . 0 . 8 1 3 0 . 2 0 4 0 . 5 7 8 0 . 1 5 1 0 . 5 7 2 0 . 1 6 4 0 . 3 1 8 0 . 0 9 4 0 . 2 4 5 0 . 0 7 7 0 . 1 7 9 0 . 0 5 4 0.343 0 . 0 9 4 0 . 3 1 5 0 . 1 0 0 0 . 4 6 1 0 . 2 0 0 1 MG TYROS I N E / 1 0 M I N 2 ANTRAL P E R F U S I O N WITH ACH ONLY 3 1 0 M I N I N F U S I O N ( 1 . 0 JUG/KG/HIN) - 68 -E g \ CD c 'co o E CL o to CL CD 0_ 0 . 1 % Ach (Antral Perfusion) 1.6 1.4-1.2 -l .O-0 . 8 -0 .6 0.4 0.2 H 0.0 ( G 2 5 - F r 2 ) o—o control data 1.0 jug./kg./min I —r-4 n 1 8 9 10 min. periods F I G U R E 19. E F F E C T OF A 10 M I N U T E I . V . I N F U S I O N OF 1.0 JUG/KG/ HR OF E G I (G25) ON B I C K E L POUCH P E P S I N S E C R E T I O N S T I M U L A T E D BY ENDOGENOUS G A S T R I N . E A C H P L O T ON THE GRAPH R E P R E S E N T S THE MEAN OF 8 O B S E R V A T I O N S I N 3 DOGS. P E P S I N V A L U E S T A K E N FROM T A B L E I X . - 69 -( F I G . 2 0 A J T A B L E X ) . THE DATA R E P R E S E N T THE MEAN t S.E. OF 7 O B S E R V A T I O N S I N 3 DOGS. F I G . 2 0 B SHOWS A S A M P L E R E C O R D I N G OF A N T R A L MOTOR A C T I V I T Y FROM AN E X P E R I M E N T I N WHICH A 1 0 M I N U T E I N F U S I O N OF 1.0 JUG/KG/MIN OF EG I ( G 2 5 ) WAS G I V E N A L O N G WITH A N T R A L P E R F U S I O N OF 0 . 1 $ A C H . IV P R E P A R A T I O N AND A S S A Y OF EG S T A G E II IN A T Y P I C A L E X P E R I M E N T 6 0 MG EG S T A G E I WAS D I S S O L V E D I N 5.0 ML 0.01 M AMMONIUM B I C A R B O N A T E AND THE PH A D J U S T E D TO 7.8 WITH 0.01 M NH3 I N WATER. A S L I G H T P R E C I P I T A T E FORMED, WHICH WAS REMOVEO BY C E N T R I F U G A T I ON ANO D I S C A R D E D . THE C L E A R S O L U T I O N WAS ALLOWED TO S I N K INTO A COLUMN ( 1 . 5 X 1 9 CM) OF C M - C E L L U L O S E (WHATMAN C M 1 1 ) , E Q U I L I B R A T E D AND D E V E L O P E D WITH 0.01 M NH4HCO3 B U F F E R , P H 7.8, T H E N WITH 0.2 M NH4HCO3 B U F F E R PH 8.0. THE E L U A T E WAS C O L L E C T E D I N F R A C T I O N S OF 5.0 ML AT A FLOW R A T E OF 1 3 0 ML/HR. THE A B S O R B A N C E OF THE F R A C T I O N S WAS M E A S URED AT 2 8 0 NM THROUGH A 1.0 CM L I G H T P A T H . THE R E S U L T S ARE SHOWN I N F I G . 2 1 A . THE S A M P L E S M A K I N G UP E A C H OF THE 3 F R A C T I O N S WERE P O O L E D , L Y O P H I L I Z E D AND A S S A Y E D FOR C C K ANO E N T E R O -G A S T R O N E A C T I V I T Y . THE R E S U L T S OF THE A S S A Y S ( F I G . 2 1 B ) I NO I CATEO THAT F R A C T I O N B ( S A M P L E S ' 1 0 - 4 8 ) P O S S E S S E D THE MOST S I G N I F I C A N T E N T E R O G A S T R O N E A C T I V I T Y . T H E Y I E L D S OF F R A C T I O N S A , B AND C WERE 6.05* 2 0 . 6 AND 2 4 . 3 MG R E S P E C T -I V E L Y . F R A C T I O N B WAS R E F E R R E D TO AS EG S T A G E II ( E G I I ) . T A B L E X E F F E C T OF I N T R A V E N O U S I N F U S I O N OF EGI ( G 2 5 ) ON A N T R A L M O T I L I T Y S T I M U L A T E D BY P E R F U S I O N OF ANTRAL P O U C H E S WITH 0 . 1 $ ACH 1 DOG E X P NO. P L A T E A U P E R I O D S 1 8 J H H J M K K 1 0 6 1 2 0 1 2 6 9 7 7 5 7 4 7 3 ± S . E . 2 1 4 . 9 2 2 . 1 6 9 . 1 9 7 . 5 4 8 . 5 1 3 . 1 1 6 . 3 3 3 0 . 1 5 2 . 6 8 1 . 7 1 8 8 . 3 8 1 . 2 1 8 2 . 1 1 3 5 . 7 6 8 . 7 2 7 . 0 1 5 0 . 2 3 5 . 9 2 6 6 . 0 5 7 . 6 8 5 . 6 1 7 6 . 7 5 7 . 1 199 .7 1 4 2 . 0 1 4 0 . 6 2 9 . 8 2 8 9 . 0 3 8 . 2 1 1 5 . 6 1 5 3 . 3 5 2 . 3 2 0 4 . 4 1 2 0 . 4 3 1 6 . 0 4 8 . 8 9 8 . 9 1 8 7 . 2 5 5 . 2 1 4 6 . 4 1 2 9 . 3 2 4 3 . 4 6 0 . 8 9 0 . 4 1 3 8 . 2 5 0 . 0 1 0 3 . 7 1 3 8 . 4 1 9 5 . 8 4 2 . 9 5 0 . 4 1 7 6 . 0 7 1 . 5 8 7 . 4 1 0 6 . 8 1 9 0 . 1 4 0 . 3 7 9 . 6 1 7 7 . 5 5 0 . 4 1 0 3 . 7 9 8 . 0 139.0 32.9 1 4 0 . 3 3 4 . 7 1 1 7 . 8 2 4 . 6 1 0 4 . 4 2 2 . 7 1 0 5 . 7 2 2 . 0 1 7 2 . 0 5 0 . 4 9 6 . 4 1 2 0 . 6 4 7 . 6 9 5 . 6 1 0 0 . 4 9 7 . 6 1 6 . 1 o P L A T E A U P E R I O D S 3 EGI ( G 2 5 ) P O S T - i N F U S i O N P E R I O D S M 1 0 4 1 9 7 . 3 K 96 1 7 1 . 4 M 9 5 5 7 . 6 K 9 4 1 5 1 . 6 K 9 3 3 2 0 . 7 M 91 5 7 . 2 K 7 2 3 0 5 . 2 x 1 8 0 . 1 + S . E . 4 0 . 1 1 0 6 . 5 9 0 . 0 5 9 . 4 1 3 2 . 8 3 9 4 . 9 4 5 . 0 1 5 8 . 1 1 0 2 . 4 8 7 . 1 7 8 . 5 1 4 2 . 2 2 0 6 . 6 5 7 . 6 1 3 0 . 4 4 7 . 5 1 1 2 . 3 2 3 . 7 1 5 8 . 4 1 9 6 . 2 5 0 . 1 2 2 0 . 7 4.3 46.8 26.3 1 1 8 . 1 170.3 44.6 69 . 2 1 0 . 0 7 1 . 6 1 5 . 8 8 2 . 8 8 5 . 3 9 . 4 4 4 . 3 2 2 . 7 3 0 . 6 1 3 . 7 8 2 . 4 4 1 . 4 1 5 . 5 4 2 . 8 3 2 . 7 3 6 . 0 2 7 . 9 8 2 . 4 5 4 . 4 6 0 . 8 4 8 . 2 1 4 0 . 9 4 4 . 9 1 1 4 . 9 1 8 . 8 1 1 5 . 5 2 9 . 6 6 8 . 5 2 1 . 7 4 4 . 2 1 3 . 7 3 5 . 6 4 8 . 9 7 . 1 29.5 50.4 8 0 . 6 83.1 51.1 45 . 2 2 6 . 6 5 2 . 2 8 . 4 1 MOTOR A C T I V I T Y INDEX/10 MIN 2 A N T R A L PERFUSION WITH A C H ONLY 3 1 0 MI,', INFUSION ( 1 . 0 /JG/KG/MIN) - 7 1 -B f 0 E E. : 200 r i L_J k_XJ 2 0 0 r n l — > -Time in Minutes F I G U R E 2 0 . ( A ) E F F E C T OF A 1 0 MI N U T E I . V . I N F U S I O N OF 1 . 0 JJG/KG/HR OF E G I ( G 2 5 ) ON A N T R A L POUCH MOTOR A C T I V I T Y S T I M U L A T E D BY ENDOGENOUS G A S T R I N . E A C H P L O T ON THE GRAPH R E P R E S E N T S THE MEAN OF 7 O B S E R V A T I O N S IN 3 DOGS. R A T I O S C A L C U L A T E D FROM THE E X P E R I M E N T A L DATA IN T A B L E X. ( B ) S A M P L E R E C O R D I N G OF A N T R A L MOTOR A C T I V I T Y B E F O R E , D U R I N G AND A F T E R THE I N F U S I O N OF E G I ( G 2 5 ) ON A BACKGROUND OF MOTOR A C T I V I T Y S T I M U L A T E D BY ENDOGENOUS G A S T R I N . B | I.D.U CCK/mg •$ 60 -o E.G.I. (CM- II) Froctien A I E.GJ. (CM-II) 80 o E.O.I (CM-II) Froction C F I G U R E 2 1 . (A) F R A C T I O N A T I O N OF EG STAG E I ON C M - C E L L U L O S E . F I F T Y MG EGI WAS A P P L I E D TO A COLUMN 1.5 x 1 9 CM AND E L U T E D WITH 0.01 M NH4HCO3 B U F F E R P H 7.8 AND 0.2 M N H 4 H C O 3 B U F F E R PH 8.0. F R A C T I O N S I Z E WAS 5.0 ML. AB S O R B A N C E MEASURED AT 2 8 0 NM THROUGH A 1.0 CM L I G H T P A T H . SHADED AREA DEMONSTRATED THE MOST P O T E N T E N T E R O G A S T R O N E A C T I V I T Y . ( B ) R E S U L T S OF CCK AND E N T E R O G A S T R O N E A S S A Y S OF 3 F R A C T I O N S R E S U L T I N G FROM F R A C T I O N A T I O N OF EG ST A G E I ON C M - C E L L U L O S E ( F l G U R E 21 ( A ) ) . - 73 -V P U R I F I C A T I O N OF EG S T A G E I I TO EG STAGE I I I THE F I N A L S T A G E OF P U R I F I C A T I O N I N V O L V E D THE USE OF S E P H A D E X G25 F I N E . IN A T Y P I C A L E X P E R I M E N T 1 2 . 0 MG OF EG S T A G E I I WERE D I S S O L V E D I N 1.0 ML OF 0.2 M A C E T I C A C I D , A P P L I E D TO A COLUMN OF S E P H A D E X G25 F I N E ( 0 . 6 X 1 2 0 CM) AND E L U T E D WITH 0.2 M A C E T I C A C I O . THE E L U A T E WAS C O L L E C T E D I N 2.0 ML F R A C T I O N S AT A FLOW RATE OF 8.0 ML/HR. THE A B S O R -BANCE OF THE F R A C T I O N S WAS MEASURED AT 2 8 0 NM ANO F R A C T I O N S FROM THE S I N G L E R E S U L T A N T P E A K WERE POOLED AND L Y O P H I L I Z E D . T H I S F R A C T I O N A T I O N Y I E L D E D 4.1 MG OF L Y O P H I L I Z E D M A T E R I A L WHICH WAS R E F E R R E D TO AS EG S T A G E I I I . T H I S WAS PURE P O L Y -P E P T I D E AND WAS S U B S E Q U E N T L Y R E F E R R E D TO AS " G A S T R I C I N H I B I -TORY P O L Y P E P T I D E " ( G . I . P . ) . A S S A Y FOR CCK-PZ A C T I V I T Y R E V E A L E D THERE TO BE 2.0 I.D.U./MG. TWO E X P E R I M E N T S WERE C A R R I E D OUT I N THE ACUTE R A B B I T TO D E T E R M I N E I F G . I . P . HAD ANY V A S O D E P R E S S O R A C T I V I T Y , U S I N G THE P R E P A R A T I O N D E S C R I B E D ON P. 2 3 OF THE METHODS S E C T I O N . I N J E C T I O N S OF UP TO 2 0 JUG/KG PRODUCED NO CHANGE I N A R T E R I A L BLOOD P R E S S U R E . VI E F F E C T OF PURE G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON B I C K E L POUCH A C I D AND P E P S I N S E C R E T I O N AND ANTRAL M O T I L I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E A N I M A L S USED I N THE STUDY WERE P R E P A R E D AS D E S C R I B E D ON P. 21 OF THE METHODS S E C T I O N ( P R E P A R A T I O N NO. 3 ) . E X P E R I -MENTS WERE CONDUCTED WITH THE THOMAS CANNULA O P E N . D U R I N G T H E S E E X P E R I M E N T S , R E C T A L T E M P E R A T U R E S WERE MONITORED I N 3 DOGS B E F O R E , D U R I N G AND A F T E R THE I N T R A V E N O U S I N F U S I O N OF - 74 -G . I . P . THE A B S E N C E OF ANY T E M P E R A T U R E I N C R E A S E WAS T A K E N TO I N D I C A T E AN A B S E N C E OF P Y R O G E N I C E F F E C T S . A ) B I C K E L POUCH H S E C R E T I O N THE E F F E C T OF THRE E DOSES OF G . I . P . ( 0 . 2 5 * 0.5, AND 1.0 JJG / K G / H R ) ON A P L A T E A U OF H + S E C R E T I O N S T I M U L A T E D BY 1.5 J U G/KG/HR OF G A S T R I N P E N T A P E P T I D E I S SHOWN IN F l G . 2 2 ; T A B L E S XI AND XI I . THE DOSES OF 0.25» 0.5» AND 1.0 JUG/KG/HR PRODUCED 2 5 $ ( P < 0 . 0 1 ) , 55$ ( P < 0 . 0 0 0 5 ) , AND 75$ ( P < 0 . 0 0 0 5 ) I N H I B I T I O N OF CONTROL L E V E L S OF H + OUTPUT. THE CONTROL V A L U E OF 8 8 8 ^JEQ H / 1 5 M I N WAS REDUCED TOt 856.0 I N THE FOURTH P E R I O D OF G . I . P . I N F U S I O N AT 0.25 JUG/KG/HRJ 453.8 pEQ H / 1 5 M I N AT 0.5 JUG/KG/HR, AND 270.7 /UEQ H / 1 5 M I N AT 1.0 JUG/KG/HR. I N C R E A S I N G THE DOSE OF G . I . P . TO 2.0 /JG/KG/HR PRODUCEO 8 3 $ ( P < 0 . 0 0 0 5 ) I N H I B I T I O N OF H S E C R E T I O N S T I M U L A T E D BY 1.5 U G / K G / HR OF G A S T R I N P E N T A P E P T I D E ( F | G . 25A; T A B L E X V I I I ) . G . I . P . AT A DOSE OF 2 . 0 J U G / K G / H R REDUCED L E V E L S OF H + FROM A CONTROL V A L U E OF 8 8 8 JUEQ H +/1 5 M I N TO 1 5 9 . 8 pEo H / 1 5 M I N . E A C H P O I N T I N THE F I G U R E R E P R E S E N T S THE MEAN OF 6 E X P E R I M E N T S I N 3 DOGS. CONTROL V A L U E S FOR F I G S . 2 2 AND 2 5 A WERE C A L C U L A T E D FROM DATA I N T A B L E X I . B ) B I C K E L POUCH P E P S I N S E C R E T I O N THE E F F E C T S OF THRE E DOSES OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E ARE SHOWN IN F | G . 23? T A B L E X I V . I N F U S I O N OF 0.5 AND 1.0 JUG/KG/HR OF G . I . P . PRODUCED 5 0 $ ( P < 0 . 0 5 ) AND 7 8 $ ( P < 0 . 0 1 2 5 ) I N H I B I T I O N OF CONTROL L E V E L S OF P E P S I N . AT THE 0.25 J U G/KG/HR L E V E L , P E P S I N O U T P U T S WERE NOT REDUCED FROM CONTROL L E V E L S . I N C R E A S I N G T A B L E XI 1 2 H OUTPUT IN R E S P O N S E TO THE I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E DOG K K K M M M H H H P P P L L L EXP NO 1 56 155 1 54 155 152 151 159 1 6 0 1 5 0 4 0 6 4 0 7 4 0 4 3 9 0 391 3 9 2 + S . E . P L A T E A U P E R I O D S 1 7 8 4 2 9 3 7 4 31 2 1 0 0 8 7 2 2 9 0 8 1 1 2 2 1 5 6 5 1 1 8 2 7 1 7 3 9 6 6 3 0 1 5 0 5 1 2 7 4 9 6 0 4 0 5 381 2 5 1 9 5 4 7 4 0 8 3 0 1 2 0 5 2 0 7 9 1 3 5 0 8 1 4 4 1 9 6 8 0 1 4 9 3 1 2 6 0 9 0 3 4 2 3 3 9 3 321 1 1 1 1 7 3 2 8 9 1 1 2 2 6 1 7 7 5 . 1 5 7 5 8 0 6 4 5 0 6 9 0 1 2 1 1 1 0 4 4 1 1 0 9 4 2 8 4 1 3 3 5 0 1 0 4 3 739 831 1235 2110 1553 667 4 9 0 7 0 0 1525 1157 11 0 9 4 3 7 4 U 4 1 7 91 5 7 0 5 8 3 3 1 3 0 8 2 0 0 1 1 3 3 2 719 581 6 7 0 1 5 3 4 1 1 6 8 1 31 6 8 7 4 1 0 5 9 1 8 1 2 8 9 1 7 1 1 2 9 5 6 1 3 0 957 121 1 H + OUTPUT MEASURED IN J J E Q / 1 5 MIN 2 INTRAVENOUS I N F U S I O N OF 1 . 5 J U G / K G / H R 3 P E R I O D S OF 1 5 MIN D U R A T I O N 4 4 6 4 1 3 3 6 6 8 6 6 731 8 2 5 1 2 5 9 1 8 9 9 1 3 3 2 7 2 5 5 9 0 6 8 0 1 4 5 0 1 2 2 0 1 0 5 0 9 2 4 1 1 3 4 7 0 410 31 5 8 1 8 6 7 8 8 3 1 11 6 0 1 9 0 4 1 2 7 7 7 9 7 4 1 2 6 7 5 1 2 7 6 1 2 0 0 1 1 0 0 8 8 8 1 1 2 446 413 31 8 8 8 2 71 3 8 6 3 1 1 0 7 1 7 5 2 1 3 5 0 7 9 7 41 2 6 7 5 1 2 7 6 1 2 0 0 1 1 0 0 8 8 7 1 0 6 390 450 31 8 831 731 746 11 76 1 8 0 0 I 3 0 5 8 0 4 386 6 6 0 1375 1220 I I 50 8 8 9 11 2 v_n T A B L E XI I T O F I N T R A V E N O U S I N F U S I O N O F G . I . P . ON H* S E C R E T I O N S T I M U L . A T E O B Y G A S T R I N P E N T A P E P T I O E P L A T E A U P E R I O D S G. I . P . (1 .0 ;UG/KG P O S T - I N F U S I O N ' DOG E X P NO. 1 __2 . — i t . - 5 6 7 9 H 191 904 871 823 941 609 505 420 465 8 3 8 H 190 866 990 1050 764 373 305 312 388 4 1 0 M 194 466 468 483 388 207 173 172 275 355 M 193 624 575 671 554 341 281 247 366 448 M 204 514 504 462 . 418 250 188 194 246 335 M 183 342 407 375 329 241 175 143 135 135 P 507 515 435 542 533 232 235 181 228 375 L_ _ _ _ 5 4 J - 1 6 4 3 _ 1659 J 2 8 7 _ _ _5J1 572 497 794 1015 X 73~3.8 71 5*. 6 758.1 651 ."7 361 . ¥ 304.2 270.7 362.1 488.8 + S.E . . . 1 32JLP_ _J.5P_.J_ IJ 5__8 61.1 ... 5-4-2. 45.5 71.7 102.3 P L A T E A U P E R I O D S ^ J3.J. • P . (0.5 J U G / K G / H R ) P O S T - I N F U S 1 0 N ^ H 192 575 622 605 550 386 307 289 286 350 M 196 739 725 683 577 392 316 292 423 500 M 195 470 407 420 442 260 206 195 275 335 L 800 1490 1525 1543 1501 1172 1144 1139 1506 1 506 P 801 480 . 466 585 506 316 246 332 471 501 P 802 528 698 723 632 424 416 489 518 536 P 803 643 907 941 858 518 413 406 432 484 P 804 528 699 724 633 424 416 489 518 536 X 681.6 756.0 778.0 712.4 468.0 433.0 453.8 553.6 593.5 + S . E . 119.6 122.8 121.6 120.7 101.6 105.4 104.3 139.9 133.2 3 P L A T E A U P E R I O D S _ _ _ _ G . J _ . P . ( 0 . 2 5 J J G / K G / H R ) P O S T - I N F U S I O N M 197 393 400 394 ~371 286 286 297 41 0 4 5 9 M 198 638 710 714 608 476 437 406 432 4 9 8 P 011 611 621 594 580 406 382 380 486 529 L 009 1142 1281 1687 1765 1151 1288 1350 1425 1500 L 0 1 0 1469 1646 1386 1409 1309 1288 1134 1327 1497 L__ 0 1 2 1575 1596 1752 1653 1652 1698 1 566 1663 1440 X 971.3 1 0 4 2 . 3 1082.8 1064.3 880.0 896.0 856.0 957.0 987.1 + S . E . 201.4 218.2 239.3 2 5 0 . 3 230.4 245.2 229.0 221.6 2 2 0 . 3 1 pEa H +/15 M I N 2 1.5 J U C / K G / H R 3 15 M I N D U R A T I ON - 77 -F I G U R E 2 2 . E F F E C T OF ONE HOUR I N F U S I O N OF 0 . 2 5 , 0.5 AND 1.0 JUG/KG/HR OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ( G . I . P . ) ON B I C K E L POUCH H + S E C R E T I O N S T I M -U L A T E D BY 1.5 JUG/KG/HR OF G A S T R I N P E N T A P E P T I D E . CONTROLS R E C E I V E D ONLY G A S T R I N P E N T A P E P T I D E THROUGHOUT THE E X P E R I M E N T . R A T I O S C A L C U L A T E D FROM DATA IN T A B L E S X I AND X I I . T A B L E XI 1 < P E P S I N S E C R E T I O N I N R E S P O N S E TO I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E ' DOG E X P NO, K K H M K K M P L L L 1 56 155 150 112 79 78 110 527 590 392 393 + S.E. P L A T E A U P E R I O D S 1 0 . 8 5 8 0 . 3 1 8 3 . 6 7 7 2 .175 0 . 5 0 4 0 . 1 6 5 2 . 3 8 5 0 . 3 1 0 Oo290 3 . 5 2 0 1 . 2 4 0 1.301 0 . 3 5 6 0 . 6 3 6 0 . 3 1 8 2 . 1 8 7 1 . 0 3 4 0 . 3 9 8 0 . 1 6 2 0 . 1 5 9 0 . 2 5 0 0 . 1 7 0 2 . 8 0 0 1 . 4 8 0 0 . 8 7 2 0 . 2 7 3 0 . 6 3 6 0 . 2 3 9 1 . 2 6 0 1.112 0 . 4 7 7 1 .530 0 . 0 8 0 0 . 2 0 0 0 . 6 4 0 0 . 1 2 0 0 . 8 9 0 A. 0 . 5 7 8 0 . 3 2 4 1 .350 0 . 9 0 8 0 . 4 5 0 0.081 0 . 2 4 2 0 . 2 9 0 0 . 2 9 0 0 . 6 0 0 0 . 5 6 0 0 . 7 9 5 0 . 3 1 8 1 . 6 3 8 0 . 9 2 4 0 . 1 2 6 0 . 1 6 2 0 . 1 6 2 0 . 2 0 0 0 . 1 7 0 0 . 6 0 0 0 . 7 7 0 8 0 . 5 5 7 0 . 1 6 2 1 . 2 6 0 0 . 8 0 3 0 . 3 1 8 0 . 1 5 9 0 . 1 6 5 0 . 3 2 0 0 . 1 7 0 0 . 1 2 0 1 . 2 8 0 0 . 4 7 7 0 . 2 3 9 0 . 6 7 2 0 . 9 0 9 0 . 4 5 0 0 . 1 5 9 0 . 2 4 3 0 . 2 8 0 0 . 1 7 0 0 . 2 9 0 0 . 5 8 0 0 . 6 5 3 0 . 1 4 4 0 . 5 1 5 0 . 1 0 4 0 . 5 3 3 0.141 0 . 4 8 3 0 . 1 3 0 0 . 4 0 6 0 . 0 7 0 0 . 5 5 7 0 . 2 4 3 0 . 5 0 1 1 . 0 5 0 0 . 3 3 0 0 . 2 3 9 0 . 5 9 9 0 . 3 0 0 0 . 1 7 0 0 . 4 1 0 1 . 160 0 . 5 0 5 0 . 0 9 4 0 . 6 4 8 0 . 2 4 3 0 . 9 7 5 0 . 5 2 5 0 . 5 6 7 0 . 3 4 5 0 . 2 6 0 0 . 1 7 0 0 . 4 1 0 0 . 5 1 0 0 . 4 6 5 0 . 0 7 0 1 M G TYROS I N E / 1 5 M I N 2 1.5 /JG/KG/HR 3 15 M I N DURATI ON T A B L E X I V E F F E C T O F I N T R A V E N O U S I N F U S I O N O F G . I . P . ON P E P S I N O U T P U T S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I D E 3 P L A T E A U P E R I O D S G. I .P . (1 . 0 >UG/KG/ HR ) 3 P O S T - I N F U S I O N . DOG E XP No. 1 2 3 4 5 6 7 8 9 H 191 . 0 . 5 7 0 0 . 6 5 0 0 . 7 5 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 H 190 0 . 1 6 5 0 . 0 5 5 0 . 6 0 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 M 194 0 . 7 2 2 , 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 M 193 0 . 9 4 4 0 .214 0 . 0 5 5 0 . 0 5 5 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 M 204 0 . 1 1 0 0 .056 0 . 0 5 5 0 . 0 5 5 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 M 183 0 . 3 8 5 0 . 4 0 5 0 . 5 0 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 L 547 0 . 9 3 0 0 .708 1.525 0 . 5 8 0 0 . 0 5 5 0 . 4 3 2 0 . 3 7 8 0 . 3 7 8 0 . 8 9 6 L 542 0 . 6 0 0 1.440 0 . 2 3 6 0 . 0 0 . 0 0 . 0 0 . 4 4 0 1 .640 0 .684 P 507 0 . 8 6 0 0 . 7 9 5 0 . 8 0 0 0 . 7 0 0 0 . 4 3 5 0 . 3 6 0 0 . 3 0 6 0 . 5 0 0 0 . 7 0 0 X 0 . 6 3 5 0 .360 0 .536 0 .167 0 . 0 7 0 0 . 0 9 9 0 . 0 8 5 0 . 2 7 9 0 . 2 5 0 + S . E . 0 . 1 0 0 0 .114 0 . 1 8 2 0 .104 0 . 0 6 0 0 . 0 6 5 0 . 0 5 6 0.181 0 . 1 2 2 P L A T E A U P E R I O O S ' G. •P. (0 . 5 J U G / K G / K R ) 3 P O S T - I N F U S I O N H 192 0 . 3 3 0 0 .224 0 . 1 6 5 0 .165 0 . 1 6 2 0 . 1 0 6 0.161 0 . 1 5 9 0 . 0 5 3 M 196 0 . 3 9 2 0 . 1 6 8 0 .112 0 .056 0 . 0 0 . 0 5 5 0 . 0 0 . 0 0 . 0 M 195 1.188 0 .560 0 . 1 6 5 0 . 1 0 9 0 . 1 1 2 0 . 0 0 . 0 0 . 0 0 . 0 L 800 0 . 9 5 0 0 . 6 4 0 0 . 8 1 0 0 .560 0 . 3 2 0 0 . 2 8 0 0 . 3 9 0 1 .460 1 .790 P 801 0 . 0 9 0 0 . 0 9 0 0 . 0 9 0 0 . 0 9 0 0 . 0 0 . 0 0 . 0 8 0 0 . 0 9 7 0 . 0 9 3 P 803 0 . 5 9 0 1.400 0 . 7 4 0 1.760 0 . 7 6 0 0 . 8 0 0 0 . 7 8 0 0 . 8 1 0 1 .100 P 804 0 . 2 7 5 0 .495 0 .864 0 . 8 2 5 0 . 6 3 6 0 . 5 2 0 0 . 6 0 5 O..864 0 . 9 3 5 X 0 . 5 4 5 0.511 0 .564 0 . 5 0 9 0 . 2 8 4 0 . 2 5 2 0 . 2 8 8 0 . 6 0 9 0 . 5 6 7 + S . E . 0 . 1 4 9 0 . 1 6 8 0 . 2 3 3 0 . 2 3 5 0 . 1 1 5 0 . 1 1 5 0 . 1 1 7 0 . 2 1 3 0 . 2 6 9 3 P L A T E A U P E R I O O S ' G. . P . ( 0 . 2 5 J U G / K G / H R ) 3 P O S T - I N F U S I O N M 197 0 . 6 6 0 0 .336 0 .324 0 . 1 6 5 0 . 1 6 2 0 . 0 0 . 0 5 4 0 . 1 1 0 0 . 1 1 2 M 198 0 . 5 5 0 0 .110 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 0 . 0 P 011 1.600 0 . 2 7 0 0 . 2 7 0 0 . 0 0 . 1 0 0 0 . 2 7 0 0 . 4 2 0 0 . 8 1 0 0 . 9 2 0 L 009 0 . 3 9 2 1.450 2 .066 2 . 6 6 0 1 .653 2 . 1 6 6 3 .591 2 . 2 8 0 1 . 6 5 3 L 010 1.416 1.180 2 . 2 8 0 2 . 9 0 0 1 .711 1 .566 1.482 1 .298 2 . 4 6 4 L 012 2 .006 1.860 1 .740 1 .403 1 . 7 7 0 1 .800 1.382 1 .770 1 . 9 8 0 x 1.104 0 .867 1.106 1.188 0 . 8 9 9 0 . 9 6 7 1.154 1.044 1 . 1 8 8 + S . E . 0 . 2 6 8 0 .294 0 .414 0 . 5 4 7 0 . 3 6 3 0.401 0 . 5 5 3 0 .371 0 . 4 1 2 1 MG T Y R O S I N E / 1 5 M I N 2 1 . 5 J J G / K G / H R 3 15 M I N C U R A T I ON - 80 -1.5/jg./kg./hr. Gastrin Pentapeptide F I G U R E 2 3 . E F F E C T OF A 6 0 MINUTE I N F U S I O N OF 0 . 2 5 , 0.5 AND 1.0,UG/KG/HR O F G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E O N B l C K E L P O U C H P E P S I N S E C R E T I O N S T I M U L A T E D B Y 1.5 J U G / K G / H R O F G A S T R I N P E N T A P E P T I D E . P E P S I N V A L U E S T A K E N F R O M T A B L E S X I I I A N D X I V . - 81 -T H E DOSE O F G . I . P . TO 2.0/JG/K'G/HR PRODUCED 90$ ( P < 0.0005) I N H I B I T I O N OF P E P S I N S E C R E T I O N S T I M U L A T E D BY 1.5 J U G/KG/HR OF G A S T R I N P E N T A P E P T I D E ( F l G . 25B} T A B L E X V I l ) . THE CONTROL V A L U E OF 0.483 MG T Y R O S I N E / 1 5 M I N F E L L TO 0.252 MG T Y R O S I N E / 15 M I N I N THE THIRD P E R I O D OF G . I . P . I N F U S I O N AT A DOSE OF 0.5 JUG/KG/HR AND 0.099 MG TYROSINE/15 M I N WITH A DOSE OF 1 .0 J U G/KG/HR. G . I . P . AT A DOSE OF 2.0 JUG/KG/HR REDUCED L E V E L S OF P E P S I N FROM A CONTROL V A L U E OF 0.483 MG T Y R O S I N E / 15 M I N TO 0.053 MG. TYROS I N E / 1 5 M I N . CONTROL V A L U E S FOR F I G S . 23 AND 253 WERE C A L C U L A T E D FROM DATA IN T A B L E X I I I . c) ANTRAL MOTOR A C T I V I T Y THE E F F E C T S OF THREE DOSES OF G . I . P . ON ANTRAL MOTOR A C T I V I T Y ARE SHOWN IN F I G . 24; T A B L E X V I . No I N H I B I T I O N COULD BE DEMONSTRATED BETWEEN CONTROL L E V E L S OF MOTOR A C T I V I T Y AND L E V E L S A F T E R I N F U S I O N OF 0.25 AND 0.5 JUG/KG/HR OF G . I . P . A DOSE OF 1.0 JUG/KG/HR OF G . I . P . PRODUCED 23$ ( P < 0.05) I N H I B I T I O N OF CONTROL L E V E L S OF ANTRAL MOTOR A C T I V I T Y . D O U B L I N G THE DOSE OF G . I . P . ( F I G . 25C; T A B L E X V I I ) Y I E L D E D 21$ I N H I B I T I O N ( P <0.05). CONTROL V A L U E S OF F l G S . 24 AND 25B WERE C A L C U L A T E D FROM T A B L E XV. V I I E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N ( S H G - l ) THE A V A I L A B I L I T Y OF A S M A L L Q U A N T I T Y OF S Y N T H E T I C HUMAN G A S T R I N I MADE P O S S I B L E A C O M P A R I S O N OF THE I N H I B I T O R Y T A B L E XV 1 = ANTRAL M O T I L I T Y R E S P O N S E TO I N T R A V E N O U S I N F U S I O N OF G A S T R I N P E N T A P E P T I D E DOG K K K M M M H H H P P P EXP NO. 1 56 1 5 5 1 54 1 5 3 1 5 2 151 1 5 9 1 6 0 1 50 4 0 0 4 0 7 4 0 4 x S.E. 1 1 8 9 147 2 4 3 1 0 5 59 41 9 0 1 2 6 2 5 4 5 3 5 1 5 6 2 5 4 1 8 3 . 3 3 8 . 3 194 107 2 0 9 104 74 3 9 57 146 251 564 145 1 9 8 162 1 1 0 122 111 66 30 8 4 '120 231 4 1 3 102 211 174.1 4 0 . 3 146.8 29.2 1 MOTOR A C T I V I T Y I N D E X / 1 5 M I N 2 1.5 JUG/KG/HR 3 1 5 M I N D U R A T I O N 1 5 5 . 9 32.9 3 P L A T E A U P E R I O D S 4 5 6 1 0 8 1 5 3 186 1 1 7 8 6 1 0 4 1 2 0 81 4 7 8 4 102 75 8 9 6 3 66 3 0 42 4 7 8 0 6 6 86 1 1 3 1 3 2 1 5 2 1 9 7 131 1 4 3 4 0 8 7 1 0 3 5 4 148 1 6 8 1 1 2 301 221 2 5 0 1 6 2 . 9 51 .8 1 3 5 . 2 2 6 . 3 7 8 9 1 3 4 1 1 3 134 8 7 9 5 74-4 5 5 0 65 9 3 8 4 1 1 0 6 8 6 8 69 36 3 8 5 9 7 5 71 6 5 1 2 5 1 2 8 119 2 1 0 1 3 5 144 5 4 8 4 1 6 3 9 2 1 3 8 1 7 8 1 5 7 261 2 1 0 221 1 5 1 . 9 4 0 . 7 1 3 2 . 2 2 9 . 7 134.1 2 7 . 3 oo ro T A B L E XVI E F F E C T O F I N T R A V E N O U S I N F U S I O N O F G . I . P . ON A N T R A L M O T I L I T Y S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I O E 3 P L A T E A U P E R I O D S G. I . P . (1.0 >UG/KG/HR) 3 P O S T - I N F U S 1 ON DOG E X P NO. l_ 1 2 3 4 5 6 7 8 9 H 191 53.8 60.5 77.6 54.9 33.6 55.0 59.5 70.6 95.4 H 190 ' 92.9 107.5 106.0 70.8 55.7 53.3 48.7 87.1 78.7 M 194 44.1 29.1 23.5 25.4 18.7 15.7 17.0 13.3 19.6 M 193 120.7 78.2 46.8 41.0 47.1 56.7 43.2 59.5 45.3 M 204 5.4 4.1 3.3 2.6 9.6 6.7 7.9 7.6 6.6 P 507 200.7 281.9 347.2 186.5 110.2 88.5 263.8 501.2 305.6 L 541 113.8 177.5 160.7 116.0 97.2 63.0 70.2 110.2 175.0 K 189 87.7 112.0 62.1 45.4 30.7 38.5 38.2 45.2 52.1 K 188 126.9 156.8 139.7 72.8 75.6 72.0 62.7 77.1 89.4 K 179 29.2 16.0 13.3 13.7 13.7 15.2 16.2 12.9 7 87.5 102.3 98.0 63.2 49.2 46.4 98.4 98.4 96.4 + S . E . 18.0 27.0 32.2 11.0 11.0 23.3. _ , 46.0 _ 46.0 30.8 3 P L A T E A U P E R I O D S G. I .P . (0.5 J U G / K G / H R ) 3 P O S T - I N F U S I O N H 192 27.9 34.3 30.4 12.4 15.1 56.3 23.9 35.2 31.8 M 196 58.8 70.0 54.8 56.1 63.4 54.0 43.6 40.1 51.1 M 195 83.8 78.2 70.4 80.6 70.6 42.2 41.6 51.6 70.4 P 801 25.4 18.4 36.3 46.4 48.0 40.3 30.5 49.6 41.9 P 803 77.1 101.2 146.9 205.9 214.9 180.6 234.6 177.0 ' 149.4 P 804 223.7 186.6 192.1 159.1 120.1 141.7 298.9 227.3 201.9 X 82.8 8f.4 88.5 93.4 88.6 87.2 112.2 96.8 68.8 + S . E . 29.8 „24._3_ 26^9_ 30.2 28.8 25.5 49.6 34.0 28.1 3 P L A T E A U P E R I O D S G. I . P . (0.25 J U G / K G / H R ) 3 P O S T - I N F U S I O N M 197 49.7 43.7 31.8 50.3 61.0 35.3 43.9 50.1 M 198 132.0 110.4 111.6 74.7 70.8 73.4 68.2 49.4 P 011 49.6 34.4 48.0 42.1 42.6 30.9 49.7 54.4 L 009 273.0 129.9 154.5 148.4 132.9 156.5 198.3 164.6 L 010 236.3 220.7 328.9 303.1 167.9 247.8 126.1 119.1 58.2 L 012 124.8 132.9 160.4 174.4 152.6 133.7 120.2 173.1 191.3 7 127.6 112.0 139.2 133". 3 104 ,T~ ~Ti'2.9 ~ TOTTO 101.7 + S . E . 42.5 27.8 43.6 40.5 21.5 34.0 24.1 23.8 1 M OTOR A C T I V I T Y I N D E X / 1 5 M I N 2 1.5 J J G / K G / H R 3 15 M I N O U R A T I O N - 84 -F I G U R E 2 4 . E F F E C T OF 6 0 M I N U T E I N F U S I O N OF 0.25» 0.5 AND 1.0 /JG/KG/HR OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON ANTRAL MOTOR A C T I V I T Y S T I M U L A T E D BY 1.5 JUG/ KG/HR OF G A S T R I N P E N T A P E P T I D E . R A T I O S C A L C U L A T E D FROM DATA I N T A B L E S XV AND X V I . T A B L E XVI I E F F E C T O F I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H + O U T P U T A S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I O E 3 P L A T E A U P E R I O D S G. . P . ( 2 . 0 U G / K G / H R ) P O S T - I N F U S 1 0 N ^ DOG E X P NO. 1 2 3 4 5 6 7 8 ? M 2 0 0 5 8 9 5 4 6 5 6 6 5 5 9 1 8 5 119 8 0 1 1 2 2 5 4 M 201 7 1 8 6 1 6 6 1 6 3 8 9 1 8 3 135 1 2 7 2 3 4 3 4 2 M 3 5 4 6 7 3 6 3 3 6 5 8 5 4 6 2 2 3 1 5 4 1 2 7 2 2 7 3 7 8 L 4 5 7 13H 1 3 7 5 1 4 7 0 7 9 5 3 0 7 2 2 8 2 1 6 3 6 4 7 0 6 L 4 5 8 1 5 0 8 1 5 2 5 1 6 0 0 8 6 9 3 8 2 3 2 9 2 4 9 6 2 7 9 8 6 X 9 6 0 . 4 9 3 9 . 0 9 8 2 . 0 6 3 1 . 6 2 5 6 . 0 193.0 1 5 9 . 8 312.8 5 3 3 . 2 + S.E. 1 8 7 . 6 2 1 0 . 4 2 2 7 . 1 8 7 . 8 3 8 . 6 3 8 . 7 31.3 8 8 . 0 1 3 6 . 6 E F F E C T O F I N T R A V E N O U S I N F U S I O N OF G . I . P . ON P E P S I N O U T P U T S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I O E 3 P L A T E A U P E R I O O S G. I . P . ( 2 . 0 J U G / K G / H R ) 3 P O S T - i N F U S I ON UOG E X P NO. 1 2 3 4 5 6 7 8 9 M 2 0 0 M 201 M 3 5 4 L . 4 5 7 L 4 5 8 0 . 4 5 6 0 . 2 2 4 0 . 2 2 4 0 . 9 1 8 0 . 2 2 4 0 . 2 2 4 0 . 6 2 7 0 . 5 6 0 0 . 4 4 8 1 . 5 0 0 1.711 1.440 1.27 6 1 . 1 5 9 1.260 0.0 0.0 0.0 0.0 0 . 1 6 2 0 . 0 5 2 0 . 0 5 4 0 . 0 5 3 0 . 3 9 2 0 . 2 1 2 0 . 1 6 2 0 . 1 0 0 0 . 1 6 8 0.0 0 . 0 5 3 0.0 0 . 4 4 0 0 . 1 0 6 0.0 0.0 0 . 0 5 3 0 . 1 5 4 0 . 2 0 8 0 . 2 1 6 0 . 2 1 4 0 . 2 1 6 0 . 1 6 8 0 . 5 6 0 0.0 0 . 5 6 0 X + S.E. 0.944 0 . 7 7 5 0 . 7 1 9 0 . 2 0 4 0 . 2 8 8 0 . 2 6 0 0 . 2 3 2 0 . 0 7 4 0 . 0 5 3 0.031 0 . 0 7 7 0 . 0 3 1 0.001 0 . 0 2 0 0 . 1 2 9 0.341 0 . 0 4 3 0 . 0 8 9 1 c E F F E C T O F I N T R A V E N O U S I N F U S I O N O F G . I . P . ON A N T R A L M O T I L I T Y S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I O E P L A T E A U P E R I O D S ' G . I . P . ( 2 . 0 J U G / K G / H R ) 3 P O S T - I N F U S I O N DOG E X P NO. 1 2 3 4 5 6 7 8 9 M 2 0 0 M 201 M 3 5 4 L 4 5 7 L 4 5 8 4 6 . 5 3 0 . 5 3 4 . 7 38.1 3 6 . 6 4 7 . 4 3 0 . 8 4 0 . 0 2 9 . 2 2 5 . 7 2 1 . 6 31.9 1 8 . 6 2 0 . 9 2 1 . 4 2 7 - 9 3 7 . 4 3 8 . 2 4 8 . 0 46.1 5 2 . 3 2 7 . 7 1 7 . 7 2 0 . 3 1 5 . 3 1 0 . 5 1 1 . 3 3 4 . 9 3 3.1 2 4 . 1 1 8 . 5 16.1 2 0 . 2 1 1 . 2 1 1 . 2 5 7 . 8 31.5 2 0 . 3 2 8 . 1 2 5 . 7 3 5 . 6 2 4 . 4 2 0 . 6 1 6 . 2 2 2 . 4 X + S.E. 31.9 2 9 . 9 3 2 . 9 4.8 3.8 4.2 2 9 . 0 31.6 2 2 . 3 2 1 . 3 5.4 6.6 5.2 6.8 2 8 . 8 2 7 . 6 7.4 2.8 1 A . ,UEQ H+/15 M I N B . MG T Y R O S I N E/15 M I N C . M O T O R A C T I V I T Y INDEX/15 M I N 2 1.5 J J G / K G / H R 3 15 M I N D U R A T I O N - 86 -F I G U R E 2 5 . E F F E C T OF A 60 MINUTE I . V . I N F U S I O N OF 2.0 JLIG/KG/ HR G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON:' A. B L C K E L POUCH H + S E C R E T I O N B. B L C K E L POUCH P E P S I N S E C R E T I O N C. ANTRAL POUCH MOTOR A C T I V I T Y S T I M U L A T E D BY 1.5 JUG/KG/HR OF G A S T R I N P E N T A P E P T I D E . R A T I O S OF THE G . I . P . S T U D I E S C A L C U L A T E D FROM DATA IN T A B L E X V I I . CONTROL DATA O B T A I N E D FROM T A B L E S X I , AND XV. H + OUTPUT ANO A N T R A L M O T I L I T Y E X P R E S S E O AS R A T I O S C A L C U L A T E D FROM DATA IN T A B L E S X I , XV AND X V I I . P E P S I N V A L U E S T A K E N D I R E C T L Y FROM T A B L E S X I I I AND X V I I . - 87 -P O T E N C Y OF G . I . P . A G A I N S T G A S T R I C S E C R E T I O N ANO MOTOR A C T I V I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E AND THE WHOLE G A S T R I N M O L E C U L E . DOGS USED IN THESE E X P E R I M E N T S WERE AS D E S C R I B E D ON P. 21 OF THE METHODS S E C T I O N ( P R E P A R A -T I O N No. 3 ) . THE DOSE OF 0.5 JJG/KG/HR OF SHG-I WAS C H O S EN AS B E I N G THAT WHICH WOULD G I V E THE SAME L E V E L OF H + S E C R E T I O N FROM B l C K E L P O U C H E S AS 1.5 J J G/KG/HR OF G A S T R I N P E N T A P E P T I D E . L I M I T E D Q U A N T I T I E S OF SHG-I D I C T A T E D THE USE OF ONLY ONE DOSE OF G . I . P . , 1.0 J JG/KG/HR G I V E N AS A ONE HOUR I N F U S I O N . E A C H P O I N T IN THE F I G U R E S OF T H I S STUDY R E P R E S E N T S 2 E X P E R I M E N T S IN E A C H OF 2 DOGS. A ) B I C K E L POUCH H + S E C R E T I O N THE E F F E C T OF 1.0 JUG/KG/HR G . I . P . ON A P L A T E A U OF H + S E C R E T I O N S T I M U L A T E D BY 0.5 /JG/KG/HR SHG-1 i s SHOWN IN F I G . 2 6 ; T A B L E X V I I I . T H I S DOSE OF G . I . P . PRODUCED 8 1 $ ( P < 0 . 0 0 0 5 ) I N H I B I T I O N OF H + S E C R E T I O N AS COMPARED TO 7 5 $ A G A I N S T A C 0 M P A R A 8 L E DOSE OF G A S T R I N P E N T A P E P T I D E . L E V E L S OF H + WERE REDUCED FROM A CONTROL V A L U E OF 9 5 9 . 7 PEQ H +/1 5 M I N TO A MEAN V A L U E OF 1 8 9 . 0 JJEQ H +/1 5 M I N IN THE T H I R D P E R I O D OF G . I . P . I N F U S I O N . B ) B I C K E L POUCH P E P S I N S E C R E T I O N THE E F F E C T OF 1.0 >UG/KG/HR G . I . P . ON A P L A T E A U OF P E P S I N OUTPUT S T I M U L A T E D BY 0 . 5 / J G / K G / HR SHG-I I S SHOWN IN F I G . 2 7 ; T A B L E X I X . A DOSE OF S H G - I , WHICH GAVE C O M P A R A B L E L E V E L S OF H + OUTPUT TO 1.5 JUG/KG/HR G A S T R I N P E N T A P E P T I D E , S T I M U L A T E D P E P S I N OUTPUT TO A G R E A T E R E X T E N T THAN THE P E N T A P E P T I D E ( T A B L E X I X ) . G . I . P . PRODUCED 8 5 $ ( P < 0 . 0 1 2 5 ) T A B L E XVI I I E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H + OUTPUT S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N I 2 3 P L A T E A U P E R I O D S DOG E X P NO. -1 2 3 4 5 6 7 8 9 P 5 7 0 P 571 L 5 7 2 L 5 7 3 4 7 0 5 0 0 5 5 0 4 9 6 5 0 0 5 0 5 5 2 0 5 3 0 5 0 0 4 8 0 500 4 9 0 5 2 0 5 7 0 5 8 0 5 6 0 5 8 0 5 7 5 1 0 0 9 1 1 0 9 1 2 2 7 1 1 8 3 1 3 5 0 1 4 8 2 1 4 7 5 1 4 5 2 1 7 7 0 1 1 3 4 1 1 8 3 1 3 5 0 1 1 3 4 1 1 8 0 1 2 7 2 1 0 2 6 1 0 4 2 1 0 6 6 X + S.E. 7 7 3 . 3 8 2 3 . 0 9 0 4 . 2 8 3 3 . 2 9 0 0 . 0 9 5 9 . 7 8 9 5 . 2 9 0 1 . 0 9 7 7 . 7 174.1 1 8 7 . 0 2 2 3 . 6 188.1 2 1 4 . 0 245.1 2 2 4 . 8 2 1 6 . 7 2 9 2 . 3 3 P L A T E A U P E R I O D S G. I .P. ( 1 . 0 JUG/KG/HR) 3 P O S T - i N F U S i O N P 5 7 5 P 576 L 5 7 7 L 5 7 8 5 8 9 6 1 0 5 5 4 3 8 0 4 0 0 3 9 0 1 0 6 6 1086 1 0 6 2 1 5 6 6 1566 1 5 0 0 2 1 8 1 4 6 1 0 0 1 4 3 2 0 8 9 4 5 2 4 7 7 9 0 5 1 3 2 9 7 3 2 9 1 2 8 8 5 4 5 3 0 7 3 8 3 151 2 2 8 1 2 0 2 3 0 5 1 3 6 7 2 9 0 2 1 1 1 4 7. ± S.E. 9 0 0 . 2 9 1 5 . 5 8 7 6 . 5 2 6 4 . 3 2 6 0 . 0 2 5 2 . 5 6 2 6 . 0 3 2 4 . 5 1 8 9 . 0 2 2 5 . 5 259.1 1 1 8 . 6 6 6 . 0 7 8 . 5 4 2 1 . 5 5 6 1 . 0 1 8 3 . 2 2 1 1 . 8 1 /JEQ H + / 1 5 M I N 2 0.5 /JG/KG/HR 3 1 5 M I N D U R A T i O N - 89 -F IGURE 2 6 . E F F E C T OF A ONE HOUR I .V . INFUSION OF. 1 . 0 /JG/KG/ HR OF GASTRIC INHIBITORY P O L Y P E P T I D E ON B L C K E L POUCH H + S E C R E T I O N ST IMULATED BY 0 . 5 J U G / K G / H R OF S Y N T H E T I C HUMAN GASTRIN I, ( S H G - l ) . CONTROLS R E C E I V E D SHG-l ONLY. EACH PLOT ON THE GRAPH R E P R E S E N T S THE MEAN OF 4 EXPERIMENTS IN 2 DOGS. RATIOS WERE C A L C U L A T E D FROM DATA IN T A B L E X V I I I . T A B L E X I X E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY S Y N T H E T I C HUMAN G A S T R I N I 3 P L A T E A U P E R I O D S DOG E X P NO. 1 - 2 3 4 5 6 7 8 9 P 5 7 0 P 571 L 572 L 5 7 3 1.375 1.344 1.595 1.296 1 . 3 5 0 1.560 1.700 1.600 1.560 1.836 1.456 1.570 1.650 1.760 1.800 1.760 1.800 1.670 1.856 1.475 2 . 8 3 2 3.074 2 . 9 4 0 4 . 7 1 2 3 . 9 5 3 3.780 3 . 3 3 9 1.325 1.550 2 . 0 4 0 1.627 1.684 1.440 1.276 1.232 1.824 X + S.E. 1.593 1.456 2 . 0 0 9 1.911 1 . 9 3 3 2 . 3 7 8 2 . 1 7 2 2 . 1 0 3 2 . 0 9 8 0.137 0.031 0 . 2 9 3 0.396 0.346 0.781 0 . 6 0 3 0 . 5 7 0 0 . 4 1 5 3 P L A T E A U P E R I O D S G. I .P. ( 1 . 0 JUG/KG/HR ) P O S T - 1 N F U S I O N P 575 P 576 L 5 7 7 L 5 7 8 1.836 1.140 1.432 1.605 1.275 1.275 1.539 1.344 1.375 1.566 2.160 2 . 4 0 0 0.312 0.0 0.0 0.265 0.364 0 . 0 5 2 0.104 0.260 1.060 0 . 8 1 0 0 . 6 1 6 0 . 3 2 4 2 . 2 0 4 1.045 0 . 5 3 0 O.648 0 . 4 1 6 0 . 7 9 5 0.624 0 . 8 0 0 0 . 8 1 0 1.232 1.512 1.508 X + S.E. 1.636 1.479 1.620 0.063 0 . 2 3 0 0.260 0 . 9 8 5 0.476 0.312 0 . 3 7 4 0 . 4 3 9 0 . 2 6 4 0.151 O.O89 0.840 1 . 0 8 3 0 . 2 3 6 0.176 1 MG T Y R O S I N E / 1 5 M I N 2 0.5 /JG/KG/HR 3 1 5 M I N D U R A T I O N 0.5/jg./kg./hr. Synthetic Human Gastrin I c 'E m a> c '55 o E 3 Q. o c 'in a. CL 0.8 0.0 15 min. periods F I G U R E 2 7 . E F F E C T O F A 6 0 M I N U T E I . V . I N F U S I O N O F 1.0 JUG/ K G / H R O F G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON B I C K E L P O U C H P E P S I N S E C R E T I O N S T I M U L A T E D B Y 0.5 J U G / K G / HR O F S H G - l . E A C H P L O T ON T H E G R A P H R E P R E S E N T S T H E M E A N O F 4 E X P E R I M E N T S IN 2 D O G S . P E P S I N V A L U E S T A K E N F R O M T A B L E X I X . - 9 1 -- 9 2 -INHIBITION OF THE HIGHER PLATEAU OF PEPSIN OUTPUT STIMULATED BY S H G - l . PEPSIN LEVELS WERE REDUCED FROM A CONTROL VALUE OF 2 . 1 7 2 MG TYROSINE/15 MIN TO 0 . 3 7 4 MG TYROSINE/15 MIN IN THE FOURTH PERIOD OF G.I .P. INFUSION. c ) ANTRAL MOTOR ACTIVITY G . I . P . IN A DOSE OF 1 . 0 JUG/KG/HR PRODUCED 5 1 $ (P < 0 . 0 5 ) INHIBITION OF ANTRAL MOTILITY STIMULATED BY S H G - l ( FIG. 2 8 ; TABLE X X ) . ANTRAL MOTOR ACTIVITY INDEX WAS REDUCED FROM A MEAN OF 4 0 . 5 IN THE CONTROL STUDIES TO A MEAN OF 1 3 . 6 DURING G . I . P . INFUSION. VIII EFFECT OF G . I . P . ON GASTRIC SECRETION AND MOTOR ACTIVITY STIMULATED BY HISTAMINE DIHYDROCHLORIDE THE ANIMAL PREPARATION AND EXPERIMENTAL DESIGN WERE AS USED IN THE GASTRIN PENTAPEPTIDE STUDY INVOLVING THE USE OF G . I . P . THE CRITERION FOR CHOOSING THE DOSE OF HISTAMINE USED WAS THE SAME AS THAT INVOLVED IN SELECTING THE DOSE OF GASTRIN PENTAPEPTIDE, NAMELY THAT WHICH WOULD YIELD 6 0 - 7 0 $ OF MAXIMUM POUCH SECRETION TO HISTAMINE. FIG. 2 9 SHOWS THE H OUTPUT FROM BICKEL POUCHES OF 4 DOGS IN RESPONSE TO THE INTRAVENOUS INFUSION OF HISTAMINE DIHYDROCHLORIDE IN DOSES OF 5 . 0 , 1 0 . 0 , 2 0 . 0 , AND 4 0 . 0 JUG/KG/HR. EACH POINT IN THE FIGURE REPRESENTS THE MEAN S . E . OF 3 OBSERVATIONS. ALL OF THE DOGS VOMITED WHEN THE INFUSION OF HISTAMINE WAS INCREASED TO 2 0 . 0 JUG/KG/HR AND ABOVE. A DOSE OF 1 0 . 0 JUG/KG/HR WAS SELECTED AS BEING THAT DOSE WHICH GAVE APPROXIMATELY 6 0 $ OF MAXIMUM H + T A B L E XX E F F E C T O F I N T R A V E N O U S I N F U S I O N O F G . I . P . O N A N T R A L M O T I L I T Y S T I M U L A T E D B Y S Y N T H E T I C H U M A N G A S T R I N I 2 P L A T E A U P E R I O D S ^ D O G E X P N O . 1 2 3 4 5 6 7 8 9 P 570 P 571 L 572 L 573 55.0 60.0 59.0 57.0 61.5 58.6 60.3 57.1 61.5 59.3 53.4 59.6 63.0 54.7 48.9 58.6 60.1 58.7 25.5 39.9 35.8 32.8 23.6 23.8 40.8 43.4 44.9 37.6 48.1 75.9 45.9 32.7 30.7 27.9 37.9 24.8 X + S . E . 44.4 50.3 57.5 49.6 43.1 40.5 46.9 49.6 47.4 7.8 4.3 8.3 6.7 8.9 8.1 7.6 5.3 8.4 3 P L A T E A U P E R I O D S G. I . P . (1.0 / J G / K G / H R ) 3 P O S T - I N F U S ION P 575 P 576 L 577 L 578 61.0 48.9 53.0 19.7 23.7 33.7 14.2 11.5 10.2 40.4 49.3 68.6 22.7 16.6 26.9 18.6 10.3 10.0 tO.O 10.0 13.1 21.8 7.8 16.0 52.9 37.1 19.7 26.4 41.8 35.1 12.9 21.5 24.3 22.0 36.6 57.8 7. t S . E . 33.8 33.3 41.3 10.6 9.4 12.6 24.7 18.8 13.6 15.2 9.7 7.6 6.0 5.5 28.9 34.1 6.4 8.4 1 > J E Q H+/15 M I N 2 0.5 J U G / K G / H R 3 15 M I N D U R A T I O N - 94 -F I G U R E 2 8 . E F F E C T OF A 6 0 M I N U T E I . V . I N F U S I O N OF 1 . 0 JUG/ K G / H R OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON A N T R A L MOTOR A C T I V I T Y S T I M U L A T E D BY 0 . 5 J U G / K G / H R OF SHG-l. E A C H P L O T ON T H E G R A P H R E P R E S E N T S T H E MEAN OF 4 E X P E R I M E N T S IN 2 D O G S . R A T I O S WERE C A L C U L A T E D FROM D A T A IN T A B L E XX. - 95 -O 5 10 2 0 Histamine Dihydrochloride /jg/kg/hr (I.V.) F I G U R E 2 9 . THE H + OUTPUT FROM B I C K E L P OUCHES OF 4 DOGS, L , P, S AND HU, IN R E S P O N S E TO THE I N F U S I O N OF H I S T A M I N E D I H Y D R O C H L O R I D E IN DOSES OF 5 . 0 , 1 0 . 0 , 2 0 . 0 AND 4 0 . 0 /JG/KG/HR. EACH P O I N T R E P R E S E N T S THE MEAN OF 6 O B S E R V A T I O N S IN E A C H A N I M A L MADE A F T E R A P L A T E A U OF H + S E C R E T I O N HAD B E E N E S T A B L I S H E D . - 9 6 -OUTPUT FROM THE POUC H E S TO H I S T A M I N E S T I M U L A T I O N . T H E S E H + O U T P U T S WERE S I M I L A R TO THOSE O B T A I N E D WITH THE I N F U S I O N OF 1 . 5 / U G / K G / H R G A S T R I N P E N T A P E P T I D E ( F I G . 1 1 ) . THE A C T I O N OF G . I . P . ON AN I N F U S I O N OF 5 . 0 J U G / K G / H R OF H I S T A M I N E WAS ALSO O B S E R V E D . TWO DOSES OF G . I . P . ( 2 . 0 AND 4 . 0 JUG/KG/HR) WERE USED I N THE L A T T E R S T U D Y . THE R E L A T I V E L Y LOW L E V E L S OF I N H I B I T I O N OF H + SE C RE T I 0 N P ROD UCE D BY 2 . 0 / J G / K G / H R OF G . I . P . A G A I N S T H I S T A M I N E ( 4 5 $ ) WAS THE B A S I S FOR U S I N G 4 . 0 JUG/KG/HR A G A I N S T H I S T A M I N E AT THE 1 0 . 0 JUG/KG/HR L E V E L . AT THE 5 . 0 UG L E V E L » E A C H P O I N T I N THE F I G U R E S R E P R E S E N T S 6 O B S E R V A T I O N S I N 3 DOGS. AT THE 1 0 . 0 JUG L E V E L , E A C H P O I N T I N THE F I G U R E S R E P R E S E N T S 8 O B S E R V A T I O N S I N 4 DOGS. A) B I C K E L POUCH H + S E C R E T I O N G . I . P . I N A DOSE OF 4 . 0 >UG/KG/HR PRODUCED 4 0 $ ( P < 0 . 0 5 ) I N H I B I T I O N OF H + S E C R E T I O N S T I M U L A T E D BY 1 0 . 0 /JG/KG/HR H I S T A M I N E ( F I G . 3 0A; T A B L E X X I ) . L E V E L S OF H + S T I M U L A T E D BY 1 0 . 0 /JG/KG/HR OF H I S T A M I N E WERE REDUCED FROM 7 8 7 J-EQ H+/15 M I N TO 5 2 8 BY 4 . 0 /JG/KG/HR OF G . I . P . IN DOSES OF 2 . 0 AND 4 . 0 JUG/KG/HR, G . I . P . PRODUCED 4 5 $ ( P < 0 . 0 0 5 ) AND 5 5 $ ( P < 0 . 0 0 2 5 ) I N H I B I T I O N OF H* S E C R E T I O N S T I M U L A T E D BY 5 . 0 /JG/KG/HR OF H I S T A M I N E ( F I G . 3 0B; T A B L E XXI I ) . L E V E L S OF H + S T I M U L A T E D BY 5 . 0 JUG/KG/HR OF H I S T A M I N E WERE REDUCED FROM 5 5 6 JUEQ H + / 1 5 M I N TO 3 3 0 JUEQ H + / 1 5 M I N BY 2 . 0 JUG/KG/HR OF G . I . P . , AND TO 2 8 7 BY 4 . 0 AJG/KG/HR OF G . I . P . AT THE P E R I O D OF MAXIMUM S E C R E T O R Y I N H I B I T I O N , S I G N I F I C A N T D I F F E R E N C E S E X I S T E D BETWEEN THE V A L U E S AT THE 2 . 0 AND 4 . 0 T A B L E XXI E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H* OUTPUT S T I M U L A T E D BY H I S T A M I N E DIHYDROCHLORIDE--1 P L A T E A U P E R I O D S ' DOG ~ Hu Hu S s L L P P E X P NO. 5 0 0 501 502 5 0 3 504 505 506 5 0 7 5 0 8 _i_ 5 3 0 371 4 3 4 3 3 4 4 6 2 1 3 3 3 1 0 6 6 1 0 0 9 9 0 7 ________ 3 4 _ 5 2 8 535 6 6 4 5 0 4 5 9 9 585 4 5 4 3 1 2 3 5 0 4 4 0 4 7 3 4 7 7 4 6 2 5 1 8 549 1 3 7 9 1 3 5 7 1 3 5 7 1 0 1 4 1151 1151 8 4 7 906 906 8 0 0 8 1 0 8 1 0 7 1 4 7 2 0 732 5 1 8 6 8 0 4 1 6 4 3 2 5 3 9 1516 1 3 5 4 8 9 0 7 8 0 6 7 8 5 9 8 5 3 0 5 3 0 589 4 2 4 5 8 0 8 0 9 675 421 4 3 0 4 1 8 4 1 8 4 0 2 4 0 8 281 3 5 0 6 1 6 6 2 7 562 519 1 3 1 7 1 3 3 4 1 4 7 9 1 3 9 8 1351 1 5 1 6 1 5 4 8 1 5 3 9 9 2 0 8 6 0 8 2 0 8 7 0 7 9 0 8 0 0 8 5 0 8 2 0 7 6 0 7 8 7 811 7 9 7 X ± S . E . 7 1 9 1 2 1 . 4 1 0 8 . 1 1 1 0 . 4 1 1 7 . 4 7 8 9 1 3 1 . 7 1 2 2 . 9 1 3 1 . 5 1 4 7 . 5 1 3 9 . 3 P L A T E A U P E R I O D S ' G . I . P . P O S T - I N F U S I O N ' Hu Hu L L P P S S 5 1 0 511 5 1 2 5 1 3 5 1 4 5 1 5 5 1 6 5 1 7 ± S . E . 7 5 3 8 8 7 1 5 4 2 1 1 3 3 1 0 0 9 1 1 0 3 4 7 3 4 9 7 745 9 3 6 1 3 4 4 1 0 0 9 8 0 9 1 0 3 4 5 2 3 481 713 9 0 8 1314 1 0 4 4 8 1 2 8 8 9 512 513 7 7 8 6 6 0 8 8 7 9 6 9 6 9 5 9 0 4 4 7 4 535 6 0 0 6 7 5 6 7 8 9 5 8 543 7 0 9 4 4 0 4 2 9 5 2 4 5 3 0 6 9 9 7 9 2 4 9 3 572 3 8 3 386 9 2 5 1 2 5 . 4 8 6 0 1 0 0 . 5 8 3 8 9 5 . 0 7 3 8 6 3 . 2 6 2 9 6 0 . 2 547 5 0 . 1 3 8 5 491 5 5 0 4 9 5 562 756 8 9 0 8 7 0 9 0 5 7 5 4 8 8 9 9 5 0 5 0 8 6 5 0 7 6 7 5 4 0 6 8 4 8 5 3 3 1 8 4 0 0 4 4 3 3 3 4 3 8 0 3 9 0 5 2 8 6 1 6 7 0 2 7 1 . 4 6 8 . 8 7 5 . 6 1 JUEQ H + / 1 5 MIN 2 1 0 . 0 /JG/KG/HR 3 H I S T A M I N E ONLY . 4 ONE HOUR I N F U S I O N ( 4 . 0 JUG/KG/HR; T A B L E X X I I E F F E C T O F I N T R A V E N O U S I N F U S I O N O F G . I . P . O N H + O U T P U T S T I M U L A T E D B Y H I S T A M I N E O I H Y O R O C H L O R I D E ^ P L A T E A U P E R I O D S DO G E X P N O . 1 2 5 4 5 6 7 8 9 Hu 700 405 447 528 484 491 550 525 681 499 Hu 701 546 600 652 614 678 764 626 626 626 L 702 - 472 424 413 380 410 523 405 387 387 L 705 632 631 582 556 545 594 622 638 578 P 704 541 529 529 540 570 485 535 535 509 p 705 838 742 562 610 683 707 622 540 700 7. 522.1 562.3 541.0 530.6 562.8 600.5 555.8 567.6 549.8 + S. E . 61.7 49.1 30.1 35.9 43.4 45.6 35.5 43.1 44.7 3 P L A T E A U P E R I O D S G. I . P . (2.0 J U G / K G / HR ) 3 P O S T - i N F U S i O N Hu 711 355 360 369 326 290 205 220 281 347 Hu 710 375 421 408 404 305 349 374 374 427 Hu 712 354 374 387 385 367 257 260 275 372 L 715 1080 1264 1216 935 589 398 372 474 616 P 750 575 536 557 575 463 451 494 610 610 P 714 482 514 469 429 366 218 188 311 456 P 713 626 622 572 578 504 448 402 549 539 x 549.5 584.4 568.2 518.5 412.0 329.4 350.0 410.5 481.0 + S. E . 97.5 118.7 112.1 78.1 41.6 40.9 41.6 51.0 41 .3 3 P L A T E A U P E R I O O S G . I . P . (4.0 J U G / K G / H R ) 3 P O S T - i N F U S i O N Hu 717 355 307 311 253 227 160 150 133 200 Hu 716 413 403 416 378 245 220 194 254 260 M 777 600 596 550 525 442 366 551 435 520 L 721 1116 1155 1392 1534 810 352 276 306 437 L 731 579 477 518 523 535 451 512 316 375 P 718 525 543 517 385 290 259 244 386 424 P 720 540 559 591 538 403 519 324 405 468 p 719 975 946 884 772 594 564 465 664 765 637.8 620.7 647.3 613.5 445.2 331.3 287.0 362.3 431.1 + s. E . 94.5 100.9 121.2 142.1 70.5 46.3 34.0 54.8 60.7 1 JJEQ H+/15 M I N 2 5.0 J J G / K G / H R 3 H I S T A M I N E O N L Y - 99 -10 O Aig/kg/hr. Histomine Dihydrochloride 4.0/ug/kg/hr G.I.P ° — • Control dota G.I.P. 0 1 2 3 « 5 « 7 e » 15 min. periods B o — o Control doto a - . - a 2 0 jug/kg/hr • — • 4.0 « -T- - i 1 1 r- I i e 9 2 3 4 9 15 mm periods F I G U R E 3 0 . ( A ) E F F E C T OF A ONE HOUR I N F U S I O N OF 4.0 /JG/KG/ HR OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON B L C K E L POUCH H + S E C R E T I O N S T I M U L A T E D BY 1 0.0 JU G/K G / HR OF H I S T A M I N E D I H Y D R O C H L O R I D E . E A C H P L O T ON THE GRAPH R E P R E S E N T S THE MEAN OF 8 E X P E R I M E N T S I N 4 DOGS. R A T I O S WERE C A L C U L A T E D FROM DATA IN T A B L E XX I . 5 ( B ) E F F E C T OF I N F U S I O N S OF 2.0 AND 4 . 0 / J G / K G / HR OF G . I . P . ON B L C K E L POUCH H + S E C R E T I ON S T I M U -L A T E D BY THE I N F U S I O N OF 5.0 JU G/K G/HR. OF H I S T A M I N E D I H Y D R O C H L O R I D E . E A C H P L O T ON THE GRAPH R E P R E -S E N T S THE MEAN OF 6 E X P E R I M E N T S I N 3 DOGS. R A T I O S WERE C A L C U L A T E D FROM DATA IN T A B L E X X I I . - 1 0 0 -JUG/KG/HR L E V E L S ( P < 0 . 0 5 ) . B) B I C K E L POUCH P E P S I N S E C R E T I O N G. L P . I N A DOSE OF 4 . 0 JUG/KG/HR PRODUCEO 5 5 $ ( P < 0 . 0 5 ) I N H I B I T I O N OF P E P S I N OUTPUT D U R I N G 10 .0 J U G / K G / H R H I S T A M I N E I N F U S I O N S (F|G. 3 1A; T A B L E XX I I I ). P E P S I N L E V E L S D U R I N G THE I N F U S I O N OF 10 . 0 J UG/KG/HR OF H I S T A M I N E WERE REDUCED FROM 0 . 8 3 8 MG T Y R O S I N E / 1 5 M I N TO 0 . 3 3 2 MG T Y R O S I N E / 1 5 M I N BY 4 . 0 JUG/KG/HR OF G. I . P . DOSES OF 2 . 0 AND 4 . 0 JUG/ KG/HR OF G . I . P . PRODUCED 7 5 $ ( P < 0 . 0 0 0 5 ) AND 8 3 $ ( P < 0 . 0 1 2 5 ) I N H I B I T I O N OF P E P S I N S E C R E T I O N S T I M U L A T E D BY 5 . 0 J U G / K G / H R OF H I S T A M I N E ( F|G. 3 1B J T A B L E X X I V ) BUT THE D I F F E R E N C E BETWEEN THE P E P S I N V A L U E S A T THE TWO L E V E L S OF G . I . P I N F U S I O N WERE NOT S I G N I F I C A N T ( P > 0.10). P E P S I N L E V E L S D U R I N G THE I N F U S I O N OF 5 . 0 J U G / K G / H R OF H I S T A M I N E WERE RE D U C E D FROM 1 . 2 5 5 MG T Y R O S I N E / 1 5 M I N TO 0 . 3 0 4 MG T Y R O S I N E / 1 5 M I N BY 2 . 0 JUG/KG/HR OF G . I . P . AND TO 0 . 2 1 6 MG T Y R O S I N E / 1 5 M I N BY 4 . 0 JUG/KG/HR OF G . I . P . C ) BlCKEL POUCH MOTOR A C T I V I T Y G . I . P . I N A DOSE OF 4 . 0 JUG/KG/HR PRODUCED 6 0 $ ( P < 0 . 0 5 ) I N H I B I T I O N OF BlCKEL POUCH MOTOR A C T I V I T Y D U R I N G I N F U S I O N OF 1 0 . 0 JUG/KG/HR OF H I S T A M I N E (FlG. 3 2A; T A B L E X X V ) . V A L U E S FOR MOTOR A C T I V I T Y I N D E X D U R I N G THE I N F U S I O N OF 10 . 0 JUG/KG/HR OF H I S T A M I N E WERE REDUCED FROM 6 1 . 4 TO 2 8 . 3 BY 4 . 0 JUG/KG/HR OF G . I . P . IN DOSES OF BOTH 2 . 0 AND 4 . 0 JUG/ KG/HR G . I . P . PRODUCED I N H I B I T I O N OF BlCKEL POUCH MOTOR A C T I V I T Y D U R I N G I N F U S I O N OF 5.0jUG/KG/HR OF H I S T A M I N E ( F I G . 3 2 B J T A B L E X X V I ) . A S A M P L E R E C O R D I N G OF THE E F F E C T T A B L E XXI I I E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G.I.P. ON P E P S I N OUTPUT 1 S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E P L A T E A U P E R I O D S ' DOG EX P N O . Hu 5 0 0 Hu 501 Hu 5 0 2 S 5 0 3 S 5 0 4 L 5 0 5 L 5 0 6 P 5 0 7 P 5 0 8 7 ± S.E. 1 8 0.324 0.0 0 . 1 1 7 1.026 0 . 9 6 9 1.121 0.342 2 . 8 5 0 0 . 6 5 0 0.330 0.0 0 . 1 1 9 0.440 0.550 0.855 0.560 1.682 0.500 0.162 0.280 0.052 0.385 0.216 0.600 1.083 0.969 0.610 0.324 0.280 0.051 0.424 0.392 0.812 1.254 1.040 0.480 0.432 0.100 0 . 0 5 8 0.432 0.550 0.885 1.197 0.916 0 . 6 20 0 . 3 1 2 0.0 0 . 0 84 0 . 6 0 5 1 . 2 1 0 0 . 6 9 0 1.488 0.978 0 . 7 0 0 0.171 0.0 0 . 0 7 0 0 . 5 3 0 0 . 7 2 8 1.218 1.487 2.296 1.050 0.540 0 . 0 5 0 0.055 1.026 0.106 1.450 2 . 5 2 0 1.711 0 .700 0 . 2 0 8 0 . 2 1 6 0 . 5 7 0 0.795 0.660 1.392 1.120 1 .000 0.680 0.822 0.286 0.559 0.161 0.484 0.11 8 0.562 0.130 0.576 0.122 0.674 0.164 0 . 8 3 8 0 . 2 5 0 0.906 0.284 0.742 0.126 - o Hu L L P P S S 571 5 1 2 5 1 3 5 1 4 5 1 5 5 1 6 5 1 7 P L A T E A U P E R I O D S ' 0.385 1.121 3.840 3.068 1.003 1.080 0.864 0.572 0.984 1.260 2.850 0.855 0.605 1.080 0.440 1.218 1.200 1.682 0.741 0.440 1.458 G.I.P. 0.350 O.696 0.580 0.969 0.986 0.436 1.113 0 . 1 5 0 0.684 0.371 0.448 0.285 0 . 2 1 2 0 . 5 5 0 0 . 1 0 4 0 . 5 5 0 0 . 5 3 0 0 . 6 1 6 0 . 0 5 3 0 . 1 0 8 0 . 5 3 0 0.051 0.371 0.448 0.378 0.162 0.107 0 . 8 1 0 P O S T - I N F U S I O N ' 0.0 1.197 0.986 2.296 0.342 0.108 0.908 0.224 1.100 1.276 1 .711 1.682 0.432 1.21 9 + S.E. 1.623 0.487 1.172 0 . 2 9 3 1.025 0.184 0.732 0.109 0.382 0.070 0 . 4 0 6 0.094 0.332 0.094 0. 8 3 3 0.298 1.092 0 . 2 1 4 1 MG TYROS I N E / 1 5 M I N 2 10.0 >JG/KG/HR 3 H I S T A M I N E ONLY 4 ONE HOUR I N F U S I O N ( 4 . 0 /JG/KG/HR) T A B L E X X I V EFFECT OF INTRAVENOUS INFUSION OF G . I . P . ON PEPSIN OUTPUT STIMULATED BY HISTAMINE 0 IHYOROCHLOR I OE^ 1 Doc EXP NO. 1 2 ? „ 4 . « u r t n n 5 6 7 8 9 Hu 700 0.791 1.220 0.989 0.887 0.776 1.130 0.887 0.887 0.887 Hu 701 1.766 0.623 0.611 0.611 0.600 0.588 0.611 0.611 0.611 L 7035 0.997 1.162 0.840 0.810 0.825 0.795 0.840 0.905 0.489 L 702 0.884 0.959 1.158 1.826 2.558 2 . 5 1 1 2.698 2.093 1.116 P 705 1.847 0.659 0.494 0.513 1.499 0.923 0.485 0.923 0.923 P 704 1.360 0.820 0.820 0.791 1.385 1.583 2.770 1.979 1.612 X 1.274 . 0.907 0.818 0.906 1.273 1.255 1.381 1.233 0.939 + S . E . 0.184 0.100 0.094 0.192 0.294 0.284 0.431 0.256 0.161 PLATEAU PERIOOS' G . I . P . (2.0 /JG/KG/HR ) POST-iNFUSiON' Hu Hu L P P P 711 710 715 730 714 713 0.686 0.150 1.782 1.564 4.187 0.756 1.272 0.104 2.376 1.485 4.187 0.935 1.040 0.265 2.695 1.786 2.915 0.884 0.663 0.157 0.880 1.380 1.595 0.715 0.350 0.057 0.385 1.300 0.371 0.168 0.400 0.057 0.102 1.060 0.156 0.054 0.550 0.157 0.102 1.300 0.114 0.051 0.530 0.180 0.357 1.590 1.326 0.056 0.880 0.210 2.430 1 .590 2.568 0.220 7 ± S . E . 1.520 0.580 1.727 0.577 1.597 0.430 0.898 0.212 0.438 0.178 0.304 0.158 0.379 0.197 0.673 0.256 1.316 0.427 PLATEAU PERIODS' G. I . P . (4.0 AJG/KG/HR) POST-INFUSION' Hu Hu M L P P P 717 716 777 721 718 720 719 0.530 0.742 0.594 1.110 3.074 2.226 2.337 0.208 0.848 0.375 1.540 2.016 2 . 3 1 0 1.904 0.153 0.810 0.935 2.880 0.935 1.925 1.425 0.385 0.324 0.832 3.000 0.520 1.568 1.566 0.112 0.051 0.260 0.570 0.100 1.590 0.583 0.0 0.100 0.0 0.255 0.052 0.825 0.285 0.0 0.102 0.105 0.636 0.530 1.070 0.750 0.051 0.106 0.053 0.714 1 .680 1.242 2.072 0.371 0.364 0.622 0.848 1 .272 2.080 1.472 t I . E . 1.516 0.380 1.3H 0.316 1.294 0.334 1.170 0.361 0.466 0.202 0.216 0.109 0.456 0.148 0.845 0.314 1.004 0.238 1 MG TYROSINE/15 MIN 2 5.0 /JG/KG/HR 3 HISTAMINE ONLY - 103 -F IGURE 3 1 . (A) E F F E C T OF A 6 0 MINUTE INFUSION OF 4.0 JJG/KG/ HR OF GASTRIC INHIBITORY P O L Y P E P T I D E ON B L C K E L POUCH P E P S I N S E C R E T I O N DURING THE INFUSION OF 1 0 . 0 JUG/KG/HR OF H ISTAMINE DIHYDROCHLORIDE. EACH PLOT ON THE GRAPH REPRESENTS THE MEAN OF 7 E X P E R I -MENTS IN 4 DOGS. PE P S I N VALUES TAKEN FROM TA B L E XXI I I . ( B) E F F E C T OF INFUSIONS OF 2.0 AND 4.0 J U G / K G / H R OF G . I . P . ON B L C K E L POUCH P E P S I N S E C R E T I O N DURING THE INFUSION OF 5.0 J U G / K G / H R OF HISTAMINE D IHYDRO-C H L O R I D E . EACH PLOT ON THE GRAPH REPRESENTS THE MEAN OF 6 EXPERIMENTS IN 3 DOGS. P E P S I N VALUES TAKEN FROM T A B L E X X I V . - 1 0 4 -OF G . I . P . ON F U N D I C MOTOR A C T I V I T Y I S SHOWN I N F l G . 3 3 . A S WITH P E P S I N , NO S I G N I F I C A N T D I F F E R E N C E WAS PRODUCED BY D O U B L I N G THE DOSE OF G . I . P . FROM 2 . 0 TO 4 . 0 / J G/KG/HR . V A L U E S FOR MOTOR A C T I V I T Y I N D E X D U R I N G THE I N F U S I O N OF 5 . 0 / J G / K G / H R OF H I S T A M I N E WERE REDUCED FROM 5 6 . 2 TO 3 9 . 2 BY 2 . 0 /JG/KG/HR OF G . I . P . AND TO 3 8 . 0 BY 4 . 0 / J G / K G / H R OF G . I . P . IX E F F E C T OF G . I . P . ON I N S U L I N - S T I M U L A T E D G A S T R I C S E C R E T I O N DOGS USED IN S E C R E T O R Y S T U D I E S I N V O L V I N G THE PURE I N H I B I T O R Y P O L Y P E P T I D E ( G . I . P . ) WERE P R E P A R E D WITH A THOMAS CANNULA IN THE V A G A L L Y I N N E R V A T E D G A S T R I C REMNANT ( P R E P A R A T I O N NO. 3 ) . I N S U L I N H Y P O G L Y C A E M I A WAS USED AS A MEANS OF VA G A L S T I M U L A T I O N . I N S U L I N WAS G I V E N AS A R A P I D I N T R A V E N O U S I N J E C T I O N OF 0 . 5 U N I T S / K G IN A L L E X P E R I M E N T S . G . I . P . WAS G I V E N AS AN I N T R A V E N O U S I N F U S I O N OVER ONE HOUR AT A DOSE OF 4 . 0 J UG/KG/HR. C O L L E C T I O N FROM THE G A S T R I C REMNANT AND A N A L Y S I S OF H AND P E P S I N ARE D E S C R I B E D IN THE METHODS S E C T I O N , P. 2 3 . A L A R G E DEGREE OF V A R I A B I L I T Y OCCURRED I N THE MAXIMUM H + AND P E P S I N O UTPUTS I N D I F F E R E N T DOGS TO THE SAME DOSE PER KG OF I N S U L I N . T H I S COULD BE E X P L A I N E D BY V A R I A T I O N IN THE. S I Z E OF THE G A S T R I C REMNANT. B E C A U S E OF THE L A R G E DEGREE OF V A R I A T I O N I N R E S U L T S ANO THE R E L A T I V E L Y S M A L L NUMBERS OF O B S E R V A T I O N S COMPARED TO OTHER S E C R E T O R Y S T U D I E S , THE R E S U L T S OF A L L E X P E R I M E N T S ARE P R E S E N T E D ONLY IN T A B U L A R FORM, WITH F I G U R E S R E P R E S E N T I N G THE R E S U L T S OF ONE E X P E R I M E N T . A TOTAL OF 6 E X P E R I M E N T S T A B L E XXV E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON F U N D I C M O T I L I T Y S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E 2 1 P L A T E A U P E R I O D S ' DOG E X P NO. 1 8 Hu Hu Hu L L P P 5 0 0 501 5 0 2 5 0 5 5 0 6 5 0 7 5 0 8 + S.E. 3 8 . 9 7 9 - 4 ' 7 5 . 0 1 2 . 3 1 3 . 3 8 5 . 0 6 5 . 0 4 8 . 3 117.4 8 2 . 0 6.8 18.1 7 9 . 0 6 7 . 0 7 5 . 3 1 3 7 . 8 9 5 . 6 7.9 23.1 67.6 58.0 9 6 . 5 111.1 8 5 . 0 7.9 2 9 . 8 8 7 . 0 6 9 . 0 8 8 . 6 8 4 . 0 8 7 . 0 1 6 . 2 39.1 7 2 . 0 5 3 . 0 9 3 . 7 83.1 7 9 . 0 7.5 2 6 . 7 7 0 . 0 7 0 . 0 5 2 . 7 11.7 59.8 14.6 70.7 1 7 . 0 69.4 14.1 6 2 . 8 1 0 . 5 6 1 . 4 1 2 . 0 8 8 . 8 9 3 . 7 8 8 . 8 1 0 2 . 2 1 2 0 . 7 1 1 0 . 0 81 .2 7 9 . 0 8 3 . 0 1 7 . 2 1 3 . 7 1 8 . 5 18.6 6 7 . 7 64.1 8 3 . 0 7 5 . 0 8 6 . 0 6 7 . 0 6 5 . 0 6 6 . 0 6 5 . 4 7 7 . 8 7 3 . 7 1 2 . 8 1 2 . 6 1 0 . 9 Hu Hu L L P P 5 1 0 511 5 1 2 5 1 3 5 1 4 5 1 5 P L A T E A U P E R I O D S ' 4 8 . 0 6 5 . 0 7 7 . 5 2 0 . 7 1 0 7 . 7 1 0 0 . 0 6 3 . 0 6 3 . 0 2 2 . 5 20.2 117.6 50.8 73.9 6 9 . 0 34.0 18.0 8 7 . 9 80.6 G . I . P . 8 3 . 2 4 6 . 0 10.0 2 2 . 7 5 1 . 9 91.4 52.6 3 7 . 0 1 0 . 0 18.5 6 6 . 3 6 1 . 8 4 8 . 8 2 4 . 0 10.0 1 5 . 3 5 7 . 2 2 4 . 5 4 7 . 8 2 6 . 0 1 2 . 5 1 4 . 3 4 4 . 6 2 8 . 8 P O S T - I N F U S I O N ' 6 7 . 5 6 9 . 0 1 4 . 8 4 7 . 7 1 3 2 . 6 6 6 . 0 8 5 . 5 8 5 . 0 10.0 3 8 . 0 9 0 . 0 1 1 0 . 5 6 8 . 2 x + S.E. 6 9 . 8 1 3 . 3 56.2 14.5 6 0 . 6 11.4 4 9 . 2 14.2 3 9 . 4 10.6 2 8 . 3 8.6 2 9 . 0 6.0 6 6 . 3 1 5 . 7 16.7 1 MOTOR A C T I V I T Y I N D E X / 1 5 MIN 2 1 0 . 0 JUG/KG/HR 3 H I S T A M I N E ONLY 4 ONE HOUR I N F U S I O N ( 4 . 0 ^ U G / K G / H R ) T A B L E X X V I E F F E C T OF INTRAVENOUS I N F U S I O N OF G . I . P . ON FUNOIC M O T I L I T Y STIMULATED BY H I S T A M I N E DIHYDROCHLORIDE P L A T E A U 3 PERIOOS DOG EXP NO. 1 2 3 4 5 6 7 8 9 Hu 7 0 0 4 0 5 9 4 5 4 8 4 4 5 9 1 2 5 3 6 0 Hu 701 41 7 0 3 4 6 2 5 9 8 6 6 9 6 6 6 6 P 7 0 2 1 5 9 7 11 7 8 7 11 8 P 7 0 3 9 7 7 9 7 7 15 1 5 1 2 L 7 0 4 3 7 2 7 8 0 9 4 7 3 41 3 8 4 5 3 2 L 7 0 5 6 3 2 9 4 0 4 0 54 1 3 6 7 7 3 4 6 9 X 3 4 . 2 3 3 . 5 3 5 . 5 4 4 . 0 4 0 . 6 5 6 . 2 4 6 . 3 3 7 . 3 4 1 . 2 + S. E. 8.0 1 0 . 6 11.1 13.1 1 1 . 3 2 0 . 2 1 2 . 5 8.8 1 1 . 2 P L A T E A U 3 PERIOOS G. I .P ( 2 . 0 UG/KG/HR) I 3 POST- i NFUSiON Hu 7 1 0 5 4 1 0 2 1 0 6 4 7 51 55 3 4 6 9 7 3 Hu 711 91 7 6 6 7 76 6 8 71 81 8 2 1 2 7 Hu 7 1 2 4 8 4 0 6 8 54 4 8 39 3 6 5 7 4 9 P 7 1 3 1 0 2 91 9 2 66 71 37 8 4 7 8 96 P 7 1 4 1 1 7 1 0 2 9 6 5 8 52 2 8 4 3 1 1 5 1 2 4 L 7 1 5 5 2 61 3 0 2 4 5 1 0 1 8 4 7 X 7 7 . 3 7 8 . 6 7 6 . 5 5 0 . 5 4 9 . 0 3 9 . 2 4 6 . 3 6 9 . 8 5 6 . 0 + S. E. 12.1 10.1 1 1 . 7 10 . 5 9.8 9.2 1 2 . 9 13.1 1 4 . 5 P L A T E A U 3 PERIODS G.1.P. ( 4 . 0 UG/KG /HR) 3 P O S T - I N F U S I O N H 7 1 6 . 71 8 4 8 4 4 4 2 6 2 6 3 4 4 8 6 2 P 7 1 8 9 2 71 71 3 8 31 66 8 9 1 7 6 6 0 H 7 1 7 6 0 56 56 8 8 66 4 9 3 9 6 0 7 8 P 7 1 9 7 2 4 9 4 9 56 16 36 61 1 4 8 6 2 P 7 2 0 71 7 2 7 2 9 5 52 4 5 7 4 9 9 9 9 L 721 6 5 4 0 4 0 41 3 6 2 1 4 5 5 y 7 2 . 6 5 2 . 0 5 2 . 0 6 0 . 3 3 2 . 3 3 8 . 0 4 9 . 8 9 0 . 8 6 9 . 3 + A S. E. 4.5 6.7 6.7 1 0 . 2 9.5 8.4 1 2 . 7 2 5 . 3 6.7 1 MOTOR A C T I V I T Y I N D E X / 1 5 MIN 2 5.0 JUG/KG/HR 3 H I S T A M I N E ONLY - 1 0 7 -I IS min. periods —© Control doto 2.0 jUQ./koVhr. -•• 4,0 • • • — i 1 1 1— 0 2 4 10 min. periods F I G U R E 3 2 . ( A ) E F F E C T OF A ONE HOUR I N F U S I O N OF 4.0 /JG/KG/ HR OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON B L C K E L POUCH MOTOR A C T I V I T Y D U R I N G THE I N F U S I O N OF 10 . 0 / J G / K G / H R OF H I S T A M I N E D I H Y D R O C H L O R I D E . E A C H P L O T ON THE GRAPH R E P R E S E N T S THE MEAN OF 6 E X P E R I M E N T S I N 3 DOGS. R A T I O S WERE C A L C U L A T E D FROM DATA I N T A B L E XXV. ( B ) E F F E C T OF A 6 0 M I N U T E I N F U S I O N OF 2.0 AND 4.0 JJG/ K G / H R OF G . I . P . ON B I C K E L POUCH MOTOR A C T I V I T Y D U R I N G THE I N F U S I O N OF 5.0 J UG/KG/HR OF H I S T A M I N E D I H Y D R O C H L O R I D E . E A C H P L O T ON THE GRAPH R E P R E S E N T S THE MEAN OF 6 E X P E R I M E N T S I N 3 DOGS. R A T I O S WERE C A L C U L A T E D FROM DATA I N T A B L E X X V I . - 1 0 8 -60 0 I 2 0 JUQ Aq/hr Gostric Inhibitory Polypeptide 60 0 1 j Time in Minutes 30 . "5 F I G U R E 3 3 . S A M P L E R E C O R D I N G OF B I C K E L POUCH MOTOR A C T I V I T Y B E F O R E , D U R I N G AND A F T E R THE 6 0 M I N U T E I N F U S I O N OF 2.0 /JG/KG/HR OF G A S T R I C I N H I B I T O R Y P O L Y -P E P T I D E ON A BACKGROUND I N F U S I O N OF 5.0 IMG/KG/H R OF H I S T A M I N E D I H Y D R O C H L O R I D E . - 1 0 9 -W E R E C A R R I E D OUT I N 3 DOGS. A) G A S T R I C REMNANT H S E C R E T I O N G . I . P . IN A DOSE OF 4 . 0 JJG/KG/HR PRODUCED 4 0 - 7 0 $ + I N H I B I T I O N OF G A S T R I C REMNANT H S E C R E T I O N S T I M U L A T E D BY 0 . 5 U N I T S / K G OF I N S U L I N ( T A B L E XXVI I ) . F I G . 34 SHOWS THE R E S U L T S OF A P A I R OF E X P E R I M E N T S . IN T H I S F I G U R E A P E A K CONTROL H V A L U E OF 1 , 8 6 8 JJEQ H / 1 5 M I N WAS PRODUCED COMPARED TO 7 0 8 JUEQ H /1 5 M I N D U R I N G G . I . P . I N F U S I O N . B ) G A S T R I C REMNANT P E P S I N S E C R E T I O N G . I . P . PRODUCED 30 - 4 5 $ I N H I B I T I O N OF P E P S I N S T I M U L A T E D BY I N S U L I N H Y P O G L Y C A E M I A ( T A B L E XXVI I l ) . F l G . 35 SHOWS THE R E S U L T S OF A P A I R OF E X P E R I M E N T S . IN T H I S F I G U R E A P E A K CONTROL P E P S I N L E V E L OF 3 4 . 9 MG T Y R O S I N E / 1 5 M I N WAS PRODUCED COMPARED TO 1 7 . 1 MG T Y R O S I N E / 1 5 M I N D U R I N G G . I . P . I N F U S I ON. X E F F E C T OF G . I . P . ON H + S E C R E T I O N AND VOLUME OF P A N C R E A T I C J U I C E IN THE A N A E S T H E T I Z E D CAT D U R I N G THE I N F U S I O N OF G A S T R I N P E N T A P E P T I D E C A TS WERE P R E P A R E D A C C O R D I N G TO THE P R E P A R A T I O N D E S C R I B E D ON P. 21 OF THE METHODS S E C T I O N . G A S T R I C C O L L E C T I O N S WERE MADE A C C O R D I N G TO THE PROCEDURE D E S C R I B E D ON P. 24 AND A N A L Y S I S OF P A N C R E A T I C S E C R E T I O N D E S C R I B E D ON P. 2 8 . A BACKGROUND I N F U S I O N OF 1 1 . 6 U/HR OF S E C R E T I N WAS G I V E N TO S T I M U L A T E FLOW OF P A N C R E A T I C J U I C E IN THE F A S T E D C A T S . A F T E R THREE P E R I O D S IN WHICH VOLUME OF P A N C R E A T I C J U I C E WAS A P P R O X I M A T E L Y 1 . 0 M L / 1 5 M I N U T E S , AND H + L E V E L S WERE < 1 0 0 /JEQ H + / 1 5 M I N , I N F U S I O N OF 1 . 5 P G / K G / H R G A S T R I N P E N T A P E P T I D E WAS BEGUN. ONCE A P L A T E A U OF H + S E C R E T I O N - 1 1 0 -T A B L E XXVI I C O M P A R I S O N OF THE A C T I O N OF G . I . P . 1 ON H + S E C R E T I O N 2 S T I M U L A T E D BY I N S U L I N H Y P O G L Y C A E M I A DOG 1 N S U L 1 N 0 1 POST 2 - I N S U L I N P E R I O D S ^ 3 4 5 6 P I N S U L 1 N - 1 7 0 5 1 8 6 8 1 5 6 6 1 4 6 6 1 0 0 3 3 2 8 1 N S U L 1 N + G . I . P . - 5 3 8 7 0 8 3 4 0 5 5 8 3 5 9 io I N H I B I T I O N - 6 8 6 2 7 8 6 2 6 4 H 1NSUL1N - 3 3 8 5 8 6 3 0 8 0 6 2 7 3 0 4 6 3 9 7 4 3 2 9 1 N S U L 1 N + G . I . P . - 1 9 2 3 5 9 1 6 5 3 2 4 4 0 2 9 4 1 2 7 io I N H I B I T I O N - 4 3 31 46 4 5 ' 3 5 L . 1 N S U L 1 N - 3781 8 8 5 4 8 8 0 9 7 9 6 2 7 5 6 7 5 4 7 0 1 N S U L 1 N + G . I . P . - 1001 5 3 5 0 5 3 2 3 4 7 6 8 4 7 5 4 io I N H I B I T I O N - 7 4 4 0 4 0 4 0 3 7 1 G . I . P . I N F U S E D AT A DOSE OF 4 . 0 / J G / K G / H R 2 0 . 5 U N I T S / K G I N S U L I N I N T R A V E N O U S L Y 3 EACH V A L U E R E P R E S E N T S THE MEAN H + OUTPUT I N 2 E X P E R I M E N T S , I N JJEQ / 1 5 M I N . - 111 -- I n s u l i n 0 .5 units/kg. G.I.P. 4.0/j.g/kg/hr 2 0 0 0 n 15 min. periods F I G U R E 34. E F F E C T OF A 6 0 M I N U T E I N F U S I O N OF 4.0 JUG/KG/HR OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON S E C R E T I O N OF H + FROM THE G A S T R I C REMNANT S T I M U L A T E D BY R A P I D I N T R A V E N O U S I N J E C T I O N OF 0.5 U N I T S / K G OF I N S U L I N . DATA FROM A S I N G L E E X P E R I M E N T (DOG P OF T A B L E XXVI I ) . CONTROL R E C E I V E D ONLY I N S U L I N . - 1 1 2 -T A B L E X X V I I I C O M P A R I S O N OF THE A C T I O N OF G . I . P . ^ ON P E P S I N OUTPUT S T I M U L A T E D BY I N S U L I N H Y P 0 G L Y C A E M I A ^ DOG 1NSUL1N 0 1 P O S T 2 - 1 N S U L I N P E R 3 4 3 1 ODS 5 6 P I N S U L 1 N - 2 5 . 1 3 4 . 9 2 3 . 8 1 9 . 6 1 4 . 9 6 . 6 1NSUL 1N + G . I . P . - 1 5 . 3 1 7 . 1 1 2 . 4 1 4 . 5 9 . 5 io I N H I B I T I O N - 3 9 5 1 4 8 2 6 3 6 H 1 N S U L 1 N - 1 2 0 . 8 1 5 4 . 0 6 7 . 5 4 8 . 2 3 0 . 3 2 1 . 9 1 N S U L 1 N + G . I . P . - 5 2 . 2 6 0 . 4 3 8 . 3 3 0 7 8 . 9 io I N H I B I T I O N - 5 7 6 1 4 3 3 8 3 8 L 1NSUL 1 N - 6 1 . 7 7 7 . 8 6 2 . 5 5 7 . 5 4 8 . 3 3 8 . 2 1 N S U L 1 N + G . I . P . - 2 9 . 3 5 1 . 9 5 0 . 1 4 1 . 9 3 7 . 3 io I N H I B I T I O N - 5 3 3 3 2 0 2 7 2 3 1 G . I . P . I N F U S E D AT A DOSE OF 4 . 0 / JG/KG/HR 2 0 . 5 U N I T S / K G I N S U L I N I N T R A V E N O U S L Y 3 E A C H V A L U E R E P R E S E N T S THE MEAN P E P S I N OUTPUT IN 2 E X P E R I M E N T S , I N MG T Y R O S I N E / 1 5 M I N . - 1 1 3 -- Insulin 0.5 units/kg. O.I.P. 4 .0/jg/kg/hr . 40.0-, 0 0 -f 1 1 1 1 1 1 1 0 I 2 3 4 5 6 7 15 min. per iods F IGURE 3 5 . E F F E C T OF A 6 0 MINUTE INFUSION OF 4 . 0 JUG/KG/HR OF GASTRIC INHIBITORY P O L Y P E P T I D E ON P E P S I N S E C R E T I O N FROM THE GASTRIC REMNANT ST IMULATED BY 0 . 5 UNITS/KG OF I N S U L I N . DATA FROM A S I N G L E EXPERIMENT (DOG P OF T A B L E XXVI I L ) . - 114 -Glucag< G.I.P. Secre G.I.P. - G a s t r i c I n h i b i t o r y P o l y p e p t i d e F IGURE 36. S I M I L A R I T I E S IN STRUCTURE OF S E C R E T I N , GLUCAGON AND G . I . P . - 1 1 5 -ANO P A N C R E A T I C J U I C E FLOW RATE HAD B E E N E S T A B L I S H E D , ONE HOUR I N F U S I O N S OF G . I . P . WERE G I V E N . THE DOSE OF P E N T A -P E P T I D E WAS CHOSEN AS THAT WHICH WOULD Y I E L D -^2-60$ OF MAXIMUM H S E C R E T I O N IN R E S P O N S E TO G A S T R I N P E N T A P E P T I D E . DOSE R E S P O N S E C U R V E S TO GRADED DOSES OF P E N T A G A S T R I N R E P O R T E D BY KONTUREK ET AL ( 1 9 6 9 ) WERE USED TO D E T E R M I N E THE A P P R O X I M A T E V A L U E S FOR MAXIMUM H + OUTPUT FROM THE CAT STOMACH. THE R E S U L T S OF E X P E R I M E N T S I N V O L V I N G 4 CATS ARE P R E S E N T E D IN T A B L E X X I X . A ) E F F E C T OF G . I . P . ON H + S E C R E T I O N FROM THE CAT STOMACH S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E THE DATA FROM E X P E R I M E N T S I N WHICH 4.0 JJG/KG/HR OF G . I . P . WAS I N F U S E D A G A I N S T A P L A T E A U OF H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E I S P R E S E N T E D I N T A B L E X X I X . NO S I G N I F I C A N T I N H I B I T I O N OF P R E I N F U S I O N L E V E L S OF H + S E C R E T I O N R E S U L T E D FROM THE I N F U S I O N OF G . I . P . ( P > 0 . 1 0 ) . H L E V E L S OF 6 8 7 - 7 4 8 JJEQ H / 1 5 M I N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E F E L L TO A LOW OF ONLY 6 5 0 /JEQ H +/1 5 M I N D U R I N G G . I . P . I N F U S I ON. B ) E F F E C T OF G . I . P . ON VOLUME OF P A N C R E A T I C J U I C E D U R I N G THE I N F U S I O N OF G A S T R I N P E N T A P E P T I D E THE DATA P R E S E N T E D I N T A B L E X X I X SHOWS THAT I N F U S I O N OF G . I . P . D I D NOT I N H I B I T THE VOLUME OF P A N C R E A T I C J U I C E B E I N G S T I M U L A T E D BY S E C R E T I N . MEAN P L A T E A U V A L U E S OF 2.4 - 2.5 ML OF P A N C R E A T I C J U I C E / 1 5 M I N WERE M A I N T A I N E D D U R I N G AND A F T E R G . I . P . I N F U S I O N . T A B L E X X I X E F F E C T OF G . I . P . ON H + OUTPUT AND VOLUME OF P A N C R E A T I C J U I C E DURING THE INTRAVENOUS INFUSION OF GASTRIN P E N T A P E P T I D E ^ IN THE CAT PL A T E A U PERIODS G. I .P. ( 4 . 0 >JG/KG/HR) PO S T -1N F U S1 ON PERIOOS EX P .No. 1 2 3 4 5 6 7 8 9 1 0 11 A 1 1 0 A 111 A 1 1 2 A 1 1 3 9 3 0 8 9 6 1 0 5 0 6 5 5 6 2 2 7 3 5 7 1 8 7 1 5 7 0 0 4 9 5 5 1 5 506 8 2 3 8 4 8 8 2 8 8 2 0 7 7 7 8 3 7 7 3 3 670 6 8 0 6 8 0 6 1 6 7 1 5 5 1 5 396 481 3 9 2 7 5 6 8 7 0 9 1 0 8 7 5 7 1 0 7 2 5 6 8 0 7 0 0 7 0 0 6 7 5 6 8 0 6 9 0 3 8 5 396 3 6 0 x 6 9 9 . 5 6 8 7 . 0 7 4 7 . 7 + S.E. 9 0 . 0 8 0 . 7 1 1 2 . 6 698.7 6 9 0 . 2 6 6 4 . 7 6 4 9 . 2 6 8 . 2 1 0 5 . 3 75.2 9 1 . 3 6 3 7 . 7 666.5 6 5 7 . 5 7 5 5 . 0 8 5 . 2 99.1 1 1 3 . 0 6 0 . 0 PL A T E A U PERIODS G. .P. ( 4 . 0 JUG/KG/ HR ) POST - I N F U S I O N PERIODS EXP NO. 1 2 3 4 5 6 7 8 9 1 0 11 A 1 1 0 2.6 2.6 2.5 2.2 2.6 3.0 2.8 2.6 2.4 2.3 A 111 2.4 2.3 •2.3 2.1 2.0 2.4 2.3 2.5 2.6 2.3 A 1 1 2 2.3 2.5 2.4 2.3 2.2 2.5 2.5 2.5 2.1 2.6 A 1 1 3 2.6 2.7 2.8 3.0 2.7 2.8 2.9 2.8 2.6 2.7 X 2.4 2.5 2.5 2.4 2.4 2.7 2.6 2.6 2.4 2.5 ± S.E. 0.3 0.1 0.1 0.2 0.2 0.1 0.1 0.1 0.1 0.1 1 JJEQ H + / 1 5 MIN 2 ML/1 5 MIN 3 1.5 UG/KG/HR - 1 1 7 -XI E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON F A S T I N G BLOOD GLUCOSE L E V E L S BLOOD G L U C O S E L E V E L S WERE MONITORED IN C O N S C I O U S DOGS ( P R E P A R A T I O N NO. 3 » P . 21 ) AND IN ACUTE R A B B I T S , P R E P A R E D AS D E S C R I B E D ON P. 2 3 OF THE METHODS S E C T I O N . BLOOD GLUCOSE L E V E L S WERE D E T E R M I N E D A C C O R D I N G TO THE METHOD D E S C R I B E D ON P. 2 8 . A) BLOOD G L U C O S E L E V E L S IN E X P E R I M E N T S I N V O L V I N G THE I N H I B I T I O N OF G A S T R I N P E N T A P E P T I D E S T I M U L A T E D H S E C R E T I O N IN 2 S E P A R A T E O B S E R V A T I O N S IN ONE DOG, BLOOD GLUCOSE L E V E L S WERE MONITORED THROUGHOUT E X P E R I M E N T S I N WHICH A + P L A T E A U OF H S E C R E T I O N WAS E S T A B L I S H E D BY A C O N STANT I N F U S I O N OF 1.5 JUG/KG/HR OF G A S T R I N P E N T A P E P T I D E FOLLOWED BY A ONE HOUR I N F U S I O N OF 1.0 JJG/KG/HR G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E . F l G . 3 7 SHOWS THAT A DOSE OF G . I . P . WHICH Y I E L D E D 7 0 $ I N H I B I T I O N OF H S E C R E T I O N PRODUCED NO H Y P E R -G L Y C A E M I C R E S P O N S E IN THE DOG. WHEREAS L E V E L S OF H + S E C R E T I O N F E L L FROM 1,700 JJEQ H +/1 5 M I N TO 6 5 0 JJEQ H +/1 5 M I N , BLOOD G L U C O S E L E V E L S R E M A I N E D BETWEEN 8 0 AND 9 0 MG/100 ML. 8 ) C O M P A R I S O N OF E Q U I M O L A R I N J E C T I O N S OF GLUCAGON AND G . I . P . ON BLOOD GLUCOSE L E V E L S IN THE DOG AND THE R A B B I T S I N G L E I N T R A V E N O U S I N J E C T I O N S OF 1 0 . 0 / J G / K G GLUCAGON WERE G I V E N BEFORE AND A F T E R S I N G L E I N J E C T I O N S OF E Q U I M O L A R AMOUNTS OF G . I . P . ( H . O / J G / K G ) . THE DOSE OF GLUCAGON USED PRODUCED A H Y P E R G L Y C A E M I C R E S P O N S E ( 7 0 - 1 0 0 $ - 118 -1.5 /jg./kg./hr. Gastrin Pentopeptide O.I.P. 1.0 / j g / k g / h r I 8 0 0 n o-\ 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 O 2 4 6 8 10 12 14 16 15 min. periods FIGURE 3 7 . L E V E L S OF B I C K E L POUCH H + OUTPUT IN U E Q / 1 5 M I N , AND BLOOD GLUCOSE L E V E L S IN MG/100 ML DURING THE INFUSION OF 1 . 0 / J G / K G / H R OF G . I . P . ON A P L A T E A U OF H + OUTPUT S T I M U L A T E D BY 1 . 5 / J G / K G / H R OF GASTRIN P E N T A P E P T I D E . - 1 1 9 -I N C R E A S E IN F A S T I N G BLOOD GLUCOSE L E V E L S ) IN THE DOG AND R A B B I T WHICH L A S T E D UP TO ONE HOUR. T A B L E XXX G I V E S THE BLOOD GL U C O S E L E V E L S F O L L O W I N G GLUCAGON AND G . I . P . I N J E C T I O N S IN 6 E X P E R I M E N T S C A R R I E O OUT IN ACUTE R A B B I T S . F L G . 3 8 SHOWS A PL O T OF THE DATA OF ONE OF T H E S E S I X E X P E R I M E N T S . IN T H I S E X P E R I M E N T BLOOD GL U C O S E L E V E L S ROSE FROM A P R E -I N J E C T I O N L E V E L OF 1 1 5 MG/100 ML TO A P E A K OF 1 7 5 MG/100 ML-3 0 M I N U T E S A F T E R GLUCAGON I N J E C T I O N . IN THE SAME E X P E R I M E N T , G . I . P . I N J E C T I O N PRODUCEO NO I N C R E A S E I N THE P R E — I N J E C T I O N BLOOD G L U C O S E L E V E L OF 1 3 5 MG/100 ML. ONE E X P E R I M E N T OF THE SAME D E S I G N AS ABOVE WAS C A R R I E D OUT IN E A C H OF TWO C O N S C I O U S DOGS ( T A B L E XXXI ) . T H E S E R E S U L T S I N D I C A T E T H A T , BOTH IN THE C O N S C I O U S DOG AND ACUTE R A B B I T , G . I . P . IN DOSES UP TO 1 4 T I M E S THAT R E Q U I R E D TO PRODUCE H I G H L Y S I G N I F I C A N T I N H I B I T I O N OF A C I D S E C R E T I O N , HAD NO H Y P E R G L Y -C A E M I C E F F E C T S . X I I E F F E C T OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ON B I C K E L POUCH P E P S I N OUTPUT S T I M U L A T E D BY S E C R E T I N DOGS USED I N T H I S STUOY WERE P R E P A R E D AS I N P R E P A R A T I O N NO. 3> P. 21 OF THE METHODS S E C T I O N . G . I . P . WAS G I V E N AS A 1 HOUR I N F U S I O N AT A DOSE OF 2.0 JUG/KG/HR A G A I N S T A P L A T E A U OF P E P S I N OUTPUT S T I M U L A T E D BY THE I N T R A V E N O U S I N F U S I O N OF 2 U N I T S / K G / H R OF S E C R E T I N . T A B L E X X X I I SHOWS THAT G . I . P . PRODUCED NO S I G N I F I C A N T I N H I B I T I O N OF CONTROL L E V E L S OF P E P S I N OUTPUT S T I M U L A T E D BY S E C R E T I N ( P > 0 . 1 5 ) . THE LOWEST MEAN V A L U E FOR P E P S I N OUTPUT D U R I N G G . I . P . T A B L E XXX E F F E C T O F E Q U I M O L A R I N J E C T I O N S O F G L U C A G O N A N D G . I . P . 3 ON F A S T I N G B L O O D G L U C O S E L E V E L S I N T H E R A B B I T T I M E I N M I N 60 0 20 30 45 60 90 120 0 20 30 45 60 90 120 0 20 30 45 E X P NO. G L U C A G O N G . I . P . G L U C A G O N 1 127 208 219 238 232 182 130 150 160 158 140 146 135 168 160 240 260 230 2 0 0 1 1 105 110 200 212 130 105 130 132 140 168 148 168 155 160 168 296 285 290 220 11 1 89 100 H O 110 95 95 80 89 80 90 95 112 107 104 107 145 132 147 125 IV 110 135 175 175 135 135 135 135 120 127 135 131 135 130 135 220 230 205 180 V 115 250 275 225 190 160 115 105 95 85 80 80 85 80 90 180 250 210 160 VI 100 • 185 170 175 155 120 95 95 100 105 95 93 95 9 8 95 210 260 195 150 1 G L U C A G O N A D M I N I S T E R E D A S A S I N G L E I N T R A V E N O U S I N J E C T I O N 2 G . I . P . A D M I N I S T E R E D A S A S I N G L E I N T R A V E N O U S I N J E C T I O N 3 BLOOD G L U C O S E A S MG/100 M L - 121 -w v > CD CD CO o o O T3 O O CO. lO.O/jg./kg. Glucagon r- l4 .0/ jg ./kg . G.I.P. c 2 8 0 i E O O \ di £ 2 0 0 -I 2 0 -4 0 o — © Glucagon A - - A G.I.P. A ^ ' A ^ A - A - A - - - A - - - A r IO.O/jg./kg. Glucagon i i i i r 30 60 - 1 — r 90 120 0 T — i — r 30 — i — r 60 -1 r 90 —I 120 1 1— 30 -i 1 60 Time in Minutes F IGURE 38. E F F E C T OF S I N G L E RAPID INTRAVENOUS I N J E C T I O N S OF 1 0 . 0 JUG/KG OF GASTRIC INHIBITORY P O L Y P E P T I D E AND H . O JUG/KG OF GLUCAGON ON BLOOD SUGAR L E V E L S IN THE A N A E S T H E T I Z E D R A B B I T . DATA FROM E X P E R I -MENT N o . V OF T A B L E X X X . T A B L E XXXI E F F E C T OF EQUIMOLAR I N J E C T I O N S OF GLUCAGON AND G . I . P . 3 ON F A S T I N G BLOOD GLUCOSE L E V E L S IN THE DOG TIME IN M I N 0 2 0 30 4 3 6 0 9 0 1 2 0 0 2 0 3 0 4 3 6 0 9 0 1 2 0 0 2 0 3 0 4 5 6 0 E X P NO. GLUCAGON G . I . P . GLUCAGON P . 4 0 0 8 8 1 2 0 155 9 5 8 8 8 0 8 7 9 7 8 3 8 6 8 9 8 5 8 5 8 3 8 2 1 3 0 1 6 5 1 2 0 1 0 0 S . 4 0 1 81 131 190 1 4 0 1 0 0 8 2 81 7 3 6 7 6 7 7 0 8 0 7 2 7 3 7 5 1 2 5 1 8 5 1 3 0 9 5 1 GLUCAGON ADMINISTERED AS A S INGLE INTRAVENOUS I N J E C T I O N 2 G . I . P . ADMINISTERED AS A S INGLE INTRAVENOUS I N J E C T I O N I 3 BLOOD GLUCOSE AS MG/100 ML __ ro ro i T A B L E XXXI I E F F E C T OF INTRAVENOUS INFUSION OF G . I . P . ON P E P S I N OUTPUT S T I M U L A T E D BY S E C R E T I N 3 PL A T E A U PERIODS DOG EXP NO. 1 2 3 4 5 6 7 8 9 S 001 H 0 0 2 P 0 0 3 L 0 0 4 K 0 0 5 2 . 1 4 5 ' 2.646 2 . 0 8 0 1.890 1.890 2 . 4 3 8 2 . 3 4 0 2 . 9 1 5 3.360 2 . 1 6 0 4.240 4.505 4.600 2 . 9 1 2 4 . 6 2 0 2 . 6 0 0 2 . 2 3 6 4 . 9 0 0 2 . 5 0 0 2 . 2 3 0 2.340 2 . 6 5 0 2 . 4 7 5 2 . 8 5 0 2 . 5 6 0 2 . 4 9 0 2 . 6 0 0 1.961 2 . 9 1 6 1.500 2.080 2 . 2 2 6 2 . 3 9 7 2 . 5 4 4 2 . 0 4 0 2 . 4 6 4 2 . 1 7 0 2 . 5 6 0 3.180 2. 9 0 0 2 . 8 0 0 2 . 3 0 0 2 . 3 5 6 2 . 4 0 0 2 . 4 9 0 7 ± S.E. 2.187 2 . 9 1 8 2.721 2.824 2 . 4 6 0 2.921 2 . 4 8 0 2 . 4 1 6 3.162 0 . 0 8 3 0.347 0 . 5 2 0 0.479 0 . 1 8 7 0 . 4 3 3 0 . 0 4 4 0.144 0.464 3 PL A T E A U PERIODS 4 G . I . P . 3 PO S T - I N F U S I O N S 0 0 6 H 0 0 7 L 0 0 8 P 0 0 9 K 0 1 0 1.092 1.166 1.300 1.612 1.820 1.700 0.475 0 . 9 3 0 0 . 8 9 0 1.683 3.100 5.050 2 . 1 7 3 2.597 3.180 1.537 1 . 3 2 5 0 . 6 7 6 0 . 8 8 3 2 . 7 5 6 2 . 3 6 5 1.326 1.508 0. 8 8 0 1 . 005 0 . 6 2 0 0 . 8 2 5 6.477 6 . 1 8 8 4 . 5 7 6 4.056 2 . 9 1 6 3 . 3 3 9 3.021 2 . 9 6 8 0 . 9 3 0 1.306 1.092 0 . 8 8 4 0 . 6 9 0 0 . 8 2 5 3.672 5.044 2.544 2 . 3 8 5 + S.E. 1.407 1.922 2 . 4 2 4 0.288 0 . 4 1 2 0.761 2 . 9 1 3 2 . 8 4 4 2 . 0 4 3 2 . 0 4 8 0.967 0.931 0 . 7 6 7 0.632 1.785 2 . 0 8 8 0.571 0 . 7 8 9 1 MG T Y R O S I N E/15 MIN 2 2.0 UNITS/KG/HR 3 SE C R E T I N ONLY 4 ONE HOUR INFUSION - 1 2 4 -INFUSION WAS 2 . 0 4 3 MG T Y R O S I N E/15 MIN COMPARED TO A CORRESPONDING MEAN VALUE OF 2 . 9 2 1 IN THE CONTROL S T U D I E S . ONE EXPERIMENT WAS CARRIED OUT IN EACH OF F IVE DOGS. X I I I E F F E C T OF GA S T R I C INHIBITORY PO L Y P E P T I D E ON GASTRIC SE C R E T I O N AND MOTOR AC T I V I T Y IN THE UNSTIMULATED DOG DOGS USED WERE PREPARED ACCORDING TO PREPARATION NO. 3» P. 21 OF THE METHODS S E C T I O N . THE DOSE OF 2.0 JUG/KG/HR OF G . I . P . WAS THAT WHICH GAVE 8 3 $ INH IB IT ION OF GASTRIN P E N T A P E P T I D E ST IMULATED H + S E C R E T ION IN THE SAME AN I M A L S . A) B I C K E L POUCH H + OUTPUT A ONE HOUR INFUSION OF 2.0 /JG/KG/HR OF G . I . P . PRODUCED 5 7 $ ( P < 0 . 0 5 ) INH IB IT ION OF UNSTIMULATED B l C K E L POUCH H"*" : S E C R E T I ON ( T A B L E XXX I I I ) . MEAN L E V E L S OF H + S E C R E T I O N VARYING FROM 5 3 TO 5 9 UEQ H + / 1 5 MIN WERE REDUCED + TO A LOW VALUE OF 2 4 *JEQ H / 1 5 MIN DURING G . I.P. I N F U S I O N . B) B I C K E L POUCH P E P S I N OUTPUT G . I . P . IN A DOSE OF 2.0 JJG/KG/HR PRODUCED 6 6 $ ( P < 0 . 0 5 ) INH IB IT ION OF UNSTIMULATED P E P S I N S E C R E T I O N FROM B l C K E L POUCHES ( T A B L E XXXI I I ) . MEAN L E V E L S OF P E P S I N OUTPUT VARYING FROM 0 . 4 1 5 TO 0 . 6 9 7 MG. T Y R O S I N E/15 MIN WERE REDUCED TO A LOW VALUE OF 0 . 1 5 5 MG T Y R O S I N E / 1 5 MIN DURING G . I . P . I N F U S I O N . c) ANTRAL AND B I C K E L POUCH MOTOR A C T I V I T Y G . I . P . IN A DOSE OF 2.0 JJG/KG/HR PRODUCED NO INHIB IT ION T A B L E X X X I I I E F F E C T OF I N T R A V E N O U S I N F U S I O N OF G . I . P . ON H + O U T P U T , P E P S I N O U T P U T , A N T R A L A N D F U N O I C MOTOR A C T I V I T Y * I N T H E U N S T I M U L A T E D A N I M A L B A S A L G . I . P . P O S T — I N F U S I O N Doc E X P N O . 1 2 3 4 5 6 7 8 9 10 11 12 13 M 540 P 541 P 542 H 543 L 544 42 28 22 25 24 24 38 36 38 36 77 88 62 110 106 106 99 42 36 42 38 41 26 29 27 26 28 11 16 20 27 27 27 28 76 48 37 32 42 42 26 25 25 23 18 21 60 38 30 31 28 26 47 59 70 90 90 31 35 36 43 X + S . E . 53.0 5 6 . 6 5 9 . 0 52.4 19.0 15.2 15.9 13.1 39.8 31.4 24.0 26.2 9.4 6.3 2 .6 1.8 4 0 . 6 38.4 44.2 46.2 7.7 8.3 12.3 15.2 B A S A L G . I . P . 4 P O S T — I N F U S I O N M 540 P 541 P 542 H 543 L 544 0 .906 0 .807 0 . 3 7 0 0 .297 0 .390 1 .045 1 .312 0 .850 0 .450 0.350 0 .210 0 .200 0 .195 0 .650 0 .200 0 .310 0 .320 0 .330 0 .785 0 .650 0 . 330 0 .370 0 .310 0 .160 0 .120 0 .100 0 .095 0 .620 0 .401 0 .301 0 . 250 0 .100 0 .080 0 . 0 9 0 0 . 0 7 0 0 .295 0 .200 0 .195 0 . 2 0 0 0 .265 0 .270 0 .150 0 .160 0 . 1 1 0 0 .435 0 . 630 0 . 850 0 . 250 0 . 3 6 0 0 .720 0 .850 0 .100 0 .150 0 . 1 9 0 0 .260 0 .260 0 . 2 9 0 0 . 3 0 0 0 .340 0 .200 0 . 1 9 0 0 .265 0 . 3 1 0 + I . E . 0 .697 0 .501 0 .453 0 .499 0 .415 0 .097 0.137 0 .148 0 .202 0 .109 0.288 0 . 2 1 4 0 .167 0 . 1 5 5 0 .089 0 .054 0 .031 0 . 0 3 3 0.184 0 . 2 8 5 0 . 4 2 1 0 . 5 2 2 0 .034 0 . 0 5 3 0 . 1 0 6 0.134 B A S A L 4 G . I . P . P O S T - I N F U S I O N M 540 P 541 P 542 H 543 80.0 50.0 61.2 6 2 . 4 4 5 . 6 36.9 19.5 32.1 5 4 . 4 3 7 . 7 33.8 22.8 48.2 20.0 40.7 80.4 63.7 79.2 62.0 56.4 65.2 15.0 20.2 19.7 1 0 . 8 53.4 1 4 . 6 3 9 . 6 17.9 48.1 64.7 9 6 . 0 80.7 64.4 70.3 65.5 70.1 92.5 85.5 55.4 67.2 34.7 39.4 51.7 42.0 3 5 . 6 19.4 5 9 . 6 50.1 X + S . E . 29.8 41.9 55.0 48.8 10.1 6.7 12.0 5.3 48.9 40.3 52.9 4 3 . 6 13.1 13.3 16 .1 17.2 56.8 5 3 . 6 58.0 57.3 13.7 14.9 3.2 6.8 B A S A L G . I . P . 4 P O S T - I N F U S I O N M 540 P 541 P 542 H 543 47.2 5 3 . 0 86.0 4 7 . 6 52.0 30.7 3 1 . 6 25.5 3 5 . 6 85.7 62.3 2 5 . 6 37.5 42.0 1 5 . 6 9.7 14.7 1 3 . 6 3 5 . 6 21.0 1 8 . 6 17.2 25.0 15.0 9 .6 10.0 3 0 . 6 15.7 1 8 . 6 14.5 10.5 8.4 5 .6 8.7 2 5 . 6 46.0 5 7 . 6 48.9 18.7 22.6 3 5 . 6 22.0 20.1 3 2 . 6 37.5 42.0 15.6 27.2 13-4 15.8 + S . E . 66.4 40.4 38.2 31.3 35.8 27.2 10.5 16.5 7.1 8.0 2 5 . 4 15.0 13.1 1 2 . 6 5.4 2.5 3.2 1.9 20.0 32.1 36.0 32.1 2.0 5.0 9.0 7 .9 1 JJEQ H+/15 M I N 2 MC T Y R O S I N E / 1 5 M I N 3 MOTOR A C T I V I T Y I N O E X / 1 5 M I N 4 2.0 / J G / K C / H R - 126 -OF SPONTANEOUS L E V E L S OF ANTRAL MOTOR A C T I V I T Y , HOWEVER THE INFUSION PRODUCED 63$ (P < 0 .025) INHIBIT ION OF B l C K E L POUCH MOTOR A C T I V I T Y . MEAN VALUES OF MOTOR ACT IV ITY INDEX VARYING FROM 31.3 TO 66.4 WERE REDUCED TO A LOW VALUE OF 12.6 DURING G.I.P. INFUSION. D I S C U S S I O N P R E P A R A T I O N S C O N T A I N I N G CCK-PZ, I N A D O I T I O N TO C A U S I N G G A L L BLAOOER C O N T R A C T I O N ANO E N Z Y M E S E C R E T I O N BY THE P A N C R E A S , HAVE B E E N SHOWN TO E X E R T V A R I O U S E F F E C T S ON THE G A S T R O -I N T E S T I N A L T R A C T . THEY HAVE B E E N D E S C R I B E D AS P O S S E S S I N G I N H I B I T O R Y A C T I V I T Y FOR EXOGENOUS G A S T R I N - S T I M U L A T E 0 H + S E C R E T I O N ( G I L L E S P I E AND GROSSMAN, 1 9 6 4 ) AND ENDOGENOUS G A S T R I N - S T I M U L A T E D H + S E C R E T I O N (BROWN AND MAGEE, 1 9 6 7 ) . S I M I L A R CCK-PZ P R E P A R A T I O N S , HOWEVER, HAVE B E E N SHOWN BY MAGEE AND NAKAMURA ( 1 9 6 6 ) ANO MURAT AND WHITE ( 1 9 6 6 ) TO S T I M U L A T E A C I D S E C R E T I O N WHEN G I V E N A L O N E , AS WELL AS TO I N H I B I T BOTH B A S A L AND S T I M U L A T E D MOTOR A C T I V I T Y OF THE FUNDUS ( J O H N S O N ANO MAGEE, 1 9 6 5 ; BROWN, JOHNSON AND MAGEE, 1 9 6 7 ) . IN AN A T T E M P T TO E X P L A I N THE A P P A R E N T L Y A M B I G U O U S E F F E C T S OF CCK-PZ ON A C I D S E C R E T I ON, S T E N I N G , JOHNSON AND GROSSMAN ( 1 9 6 9 B ) PUT FORWARD AN H Y P O T H E S I S OF C O M P E T I T I V E I N H I B I T I O N BETWEEN THE CCK-PZ AND G A S T R I N M O L E C U L E S FOR A COMMON R E C E P T O R S I T E I N V O L V E D IN THE S T I M U L A T I O N OF H + . T H I S THEORY WAS S U P P O R T E D BY I D E N T I F I C A T I O N OF THE S I M I L A R -I T I E S BETWEEN THE C— TERM I N A L P E N T A P E P T I D E S OF BOTH M O L E C U L E S . S I N C E A L L OF THE A B O V E - C I T E D E X P E R I M E N T A L F I N D I N G S I N V O L V E D THE USE OF IMPURE CCK-PZ P R E P A R A T I O N S , THE G A S T R I C E F F E C T S MAY HAVE B E E N PRODUCED BY A GENTS OTHER THAN CCK-PZ. T H E I N I T I A L STUDY R E P O R T E D IN T H I S T H E S I S , WHICH P R O V I D E D THE B A S I S FOR THE' S U B S E Q U E N T I S O L A T I O N OF G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E , WAS U N D E R T A K E N TO D E T E R M I N E WHETHER I N FACT A L L - 1 2 7 -- 128 -O F T H E D E S C R I B E D E F F E C T S O F CCK-PZ P R E P A R A T I O N S ON T H E U N S T I M U L A T E D A N I M A L W E R E D U E T O T H E H O R M O N E , OR W H E T H E R S O M E O F T H E S E E F F E C T S W E R E D U E TO O T H E R M A T E R I A L S P R E S E N T IN T H E E X T R A C T S . T H E A P P R O A C H TO T H I S P R O B L E M I N V O L V E D A C O M P A R I S O N O F T H E E F F E C T S O F TWO P U R I T I E S O F CCK-PZ D E S I G N A T E D A S 1 0 $ P U R E ( 2 5 0 I . D . U . / M G ) A N D 4 0 $ P U R E ( 1 , 5 0 0 I . D . U . / M G ) ON T H E G A S T R I C P A R A M E T E R S O F H + S E C R E T I O N , P E P S I N S E C R E T I O N A N D A N T R A L M O T O R A C T I V I T Y ( B R O W N A N D P E D E R S O N , 1 9 7 0 ) . R E S U L T S I N D I C A T E D T H A T T H E 4 0 $ P U R E CCK-PZ H A D A G R E A T E R A C I D -S T I M U L A T O R Y E F F E C T O N S Y M P A T H E T I C A L L Y A N D V A G A L L Y D E N E R V A T E D F U N D I C P O U C H E S T H A N T H E 1 0 $ P U R E M A T E R I A L ( F L G . 1 0 ) , T H E G A L L B L A D D E R E F F E C T B E I N G I D E N T I C A L . AT T H E T I M E O F T H I S S T U D Y P O S S I B L E E X P L A N A T I O N S F O R T H E R E S U L T S W E R E T H A T , E I T H E R A G A S T R I C S E C R E T O R Y S T I M U L A N T WAS S E L E C T I V E L Y C O N C E N -T R A T E D D U R I N G T H E P U R I F I C A T I O N P R O C E D U R E S , OR T H A T A N I N H I B I T O R Y M A T E R I A L W A S P R O P O R T I O N A T E L Y R E M O V E O . D E T R A C T I N G F R O M T H E F O R M E R P O S S I B I L I T Y WAS T H E E X I S T I N G E V I D E N C E C O N C E R N I N G T H E S I M I L A R I T I E S B E T W E E N T H E G A S T R I N A N D CCK-PZ M O L E C U L E S , W H I C H S U G G E S T E D T H A T A C I D - S E C R E T O R Y S T I M U L A T I O N WAS A N I N H E R E N T A C T I O N O F C C K - P Z . T H E F A C T T H A T B O T H P R E P A R A T I O N S O F CCK-PZ E X E R T E D A S I M I L A R D E G R E E O F S T I M U L A -T I O N O F A N T R A L P O U C H M O T I L I T Y S U G G E S T E D T H A T T H I S S T I M U L A -T O R Y E F F E C T WAS A F E A T U R E O F T H E CCK-PZ M O L E C U L E . T H E P E P S I N R E S P O N S E ( F I G . 7? T A B L E I) U N D E R W E N T C H A N G E S S I M I L A R I N K I N D T O T H O S E O F H + S E C R E T I O N U P O N I N C R E A S I N G T H E P U R I T Y O F CCK-PZ P R E P A R A T I O N S I N J E C T E D . T H E O B S E R V A T I O N S IN T H I S - 1 2 9 -STUDY MADE T E N A B L E THE H Y P O T H E S I S THAT IN P U R I F Y I N G CCK-PZ FROM 1 0 $ TO 4 0 $ , AN I N H I B I T O R Y M A T E R I A L FOR G A S T R I C A C I D S E C R E T I O N WAS REMOVED. ONCE I T HAD B E E N E S T A B L I S H E D THAT TWO P U R I T I E S OF CCK-PZ PRODUCED D I F F E R E N T D E G R E E S OF A C I D S T I M U L A T I O N , A C O M P A R I S O N OF THE I N H I B I T O R Y P O T E N C Y OF T H E S E TWO P R E P A R A T I O N S ON G A S T R I N P E N T A P E P T I D E - S T I M U L A T E D H + S E C R E T I O N WAS U N D E R T A K E N . A L L OF THE A C T I O N S OF THE WHOLE G A S T R I N M O L E C U L E HAVE B E E N D E S C R I B E D AS B E I N G P O S S E S S E D BY THE C - T E R M I N A L T E T R A P E P T I D E A M I D E : TRP - MET - A S P - PHE - N H 2 ( T R A C Y AND GREGORY, 1 9 6 4 ) , A L T H O U GH I T HAS B E E N SHOWN TO BE ONLY ONE T W E L F T H AS P O T E N T ON A MOLAR B A S I S AS THE WHOLE M O L E C U L E ( G R O S S M A N , 1 9 7 0 ) . SOME A C Y L D E R I V A T I V E S HAVE A C T I V I T Y S E V E R A L T I M E S THAT OF THE T E T R A P E P T I D E . ONE OF T H E S E I S THE B - A L A N Y L D E R I V A T I V E OF THE C - T E R M I N A L TE T R A P E P T I D E A M I D E , N - T - B U T Y L O X Y C A R B O N Y L -B - ALA - TRP - MET - A S P - PHE - NH2» OTHERWISE KNOWN AS G A S T R I N P E N T A P E P T I D E OR P E N T A G A S T R I N . T H I S M A T E R I A L WAS USED AS A S T I M U L A N T OF G A S T R I C S E C R E T I O N B E C A U S E OF I T S C O M M E R C I A L A V A I L A B I L I T Y AND THE F A C T THAT I T HAD B E E N W I D E L Y USEO I N BOTH HUMAN AND A N I M A L S T U D I E S . THE R E A S O N I N G I N V O L V E D WAS THAT I F AN I N H I B I T O R Y M A T E R I A L WAS REMOVED D U R I N G P U R I F I -C A T I O N OF CCK-PZ, THEN T H I S WOULD BE I N D I C A T E D BY A D E C R E A S E IN I N H I B I T I O N OF G A S T R I N P E N T A P E P T I 0 E - S T I M U L A T E D H + S E C R E T I O N . THE R E S U L T S P R E S E N T E D IN F I G . 1 2 ; T A B L E V I N D I C A T E D THAT T H I S WAS IN F A C T THE C A S E , WITH THE 4 0 $ PURE M A T E R I A L Y I E L D I N G A S I G N I F I C A N T L Y L E S S E R OEGREE OF I N H I B I T I O N OF H + S E C R E T I O N THAN THE 1 0 $ PURE M A T E R I A L ( P < 0 . 0 0 5 ) . - 130 -T H E O B S E R V A T I O N T H A T P A R T I A L P U R I F I C A T I O N O F C C K - P Z R E S U L T E D IN I N C R E A S E D P O T E N C Y F O R H + S T I M U L A T I O N A N D D I M I N I S H E D P O T E N C Y F O R T H E I N H I B I T I O N O F G A S T R I N - S T I M U L A T E D H + S E C R E T I O N L E D TO A T T E M P T S T O S E P A R A T E A G A S T R I C I N H I B I T O R D I S T I N C T F R O M C C K - P Z U S I N G T H E 1 0 $ P U R E P R E P A R A T I O N A S S T A R T I N G M A T E R I A L . T H E I N I T I A L S T A G E S O F T H I S P U R I F I C A T I O N P R O C E D U R E , T H E P R O D U C T O F W H I C H WAS C A L L E D E G I , W E R E D E S C R I B E D IN T H E R E S U L T S S E C T I O N , P A G E 51 A N D S U M M A R I Z E D IN F I G . 1 3 . S I N C E T H E C H E M I C A L N A T U R E O F EGI WAS N O T C O M P L E T E L Y E L U C I D A T E D , I T WAS I M P O R T A N T TO D E T E R M I N E W H E T H E R OR N O T T H E I N H I B I T O R Y P O T E N C Y O F T H E M A T E R I A L C O U L D B E E X P L A I N E D B Y C C K - P Z A N D / O R S E C R E T I N A C T I V I T Y . A S S A Y S IN T H E G U I N E A P I G A N D C A T I N D I C A T E D T H A T L E S S T H A N 1 0 I . D . U . / M G O F C C K - P Z W E R E P R E S E N T A N D N O S E C R E T I N C O U L D B E D E T E C T E D B Y T H E A S S A Y P R O C E D U R E E M P L O Y E D . T H E A S S A Y S ( F | G S . 1 5 A N D 1 6 ) I N D I C A T E D T H A T T H E F I R S T S T A G E IN T H E P U R I F I C A T I O N O F G A S T R I C I N H I B I -T O R Y P O L Y P E P T I D E P R O D U C E D A F R A C T I O N (EG I ) W H I C H W O U L D S I G N I F I C A N T L Y I N H I B I T H + A N D P E P S I N O U T P U T S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I D E . H + O U T P U T S D E C R E A S E D F R O M A M E A N O F 6 1 8 JUEQ/10 M I N TO 1 6 8 / J E Q / 1 0 M I N , A N D P E P S I N O U T P U T S F E L L F R O M 0.326 MG T Y R O S I N E / 1 0 M I N T O 0 . 0 8 0 MG T Y R O S I N E / 1 0 M I N . T H E F I N D I N G T H A T EGI I N H I B I T E D P E P S I N S E C R E T I O N S U P P O R T E D T H E R E S U L T S O F T H E F I R S T S T U D Y ( F l G . 9) W H I C H S U G G E S T E D T H A T D U R I N G T H E P U R I F I C A T I O N O F C C K - P Z A N I N H I B I T O R O F P E P S I N O U T P U T MAY H A V E B E E N R E M O V E D . I N A N A T T E M P T TO P U R I F Y T H E G A S T R I C I N H I B I T O R P R E S E N T I N E G I , S E V E R A L P U R I F I C A T I O N P R O C E D U R E S W E R E A T T E M P T E D . - 131 -C H R O M A T O G R A P H Y O F EGI ON S E P H A D E X G25 Y I E L D E D 3 F R A C T I O N S , ( B R O W N , P E D E R S O N , J O R P E S A N D M U T T , 1 9 6 9 ) . T H E R E S U L T S O F T H E CCK-PZ A N D E N T E R O G A S T R O N E A S S A Y S O N T H E S E F R A C T I O N S ( F I G . 1 7 ) I N D I C A T E D T H A T F R A C T I O N 2 , R E F E R R E D TO A S EGI G 2 5 - F R 2 , W A S T H E P U R E S T P R E P A R A T I O N O F T H E I N H I B I T O R Y M A T E R I A L . A S S A Y S F O R E N T E R O G A S T R O N E A C T I V I T Y , H O W E V E R , R E V E A L E D N O S I G N I F I C A N T I N C R E A S E I N I N H I B I T O R Y A C T I V I T Y C O M P A R E D T O E G I . T H E E F F E C T S O F EGI G 2 5 ~ F R 2 O N E N D O G E N O U S G A S T R I N R E L E A S E D B Y P E R F U S I N G A N I S O L A T E D A N T R A L P O U C H W I T H 0 . 1 $ A C H W E R E I N V E S T I G A T E D . T H E R E S U L T S O F T H I S S T U D Y I N D I C A T E D T H A T T H I S F R A C T I O N P R O D U C E D 7 0 $ I N H I B I T I O N O F H + A N D P E P S I N O U T P U T S A N D A N T R A L M O T O R A C T I V I T Y ( F L G S . 1 8 , 1 9 A N D 2 0 ) . T H I S S T U D Y G A V E T H E F I R S T I N D I C A T I O N T H A T T H E I N H I B I T O R Y M A T E R I A L U N D E R I N V E S T I G A T I O N W O U L D I N H I B I T G A S T R I C M O T O R A C T I V I T Y . IT I S K N O W N T H A T G A S T R I N T E T R A -P E P T I D E A N D G A S T R I N S T I M U L A T E A N T R A L M O T O R A C T I V I T Y ( V J A C O B Y A N D M A R S H A L L , 1 9 6 9 ) . T H E S E O B S E R V A T I O N S , P L U S T H E D A T A I N T H E F I R S T S T U D Y ( B R O W N A N D P E D E R S O N , 1 9 7 0 ) S H O W I N G T H A T CCK-PZ P R E P A R A T I O N S S T I M U L A T E D A N T R A L M O T O R A C T I V I T Y , S U G G E S T E D T H A T T H E S H A R E D C - T E R M I N A L P E N T A P E P T I D E O F CCK-PZ A N D G A S T R I N W A S R E S P O N S I B L E F O R T H E S T I M U L A T I O N . T H E R E S U L T S S U G G E S T E D T H A T T H E I N H I B I T O R B E I N G P U R I F I E D A C T S O N A L L G A S T R I C P A R A M E T E R S A F F E C T E D B Y G A S T R I N W H I C H H A D B E E N I N V E S T I G A T E D , N A M E L Y H + O U T P U T , P E P S I N O U T P U T A N D A N T R A L M O T O R A C T I V I T Y . T H E F I N D I N G T H A T EGI G 2 5 " F R 2 I N H I B I T E D A N T R A L M O T O R A C T I V I T Y D I D N O T F I T W I T H T H E O B S E R V A T I O N ( F I G . 8 ) T H A T B O T H P U R I T I E S O F CCK-PZ S T I M U L A T E D A N T R A L - 1 3 2 -MOTOR A C T I V I T Y TO A S I M I L A R D E G R E E . P O S S I B L E E X P L A N A T I O N S COULD BE THAT THE AMOUNT OF I N H I B I T O R REMOVED BY P U R I F I -C A T I O N FROM THE 1 0 $ TO THE 4 0 $ PURE S T A G E WAS NOT S U F F I C I E N T TO PRODUCE A D I F F E R E N C E IN DEGREE OF S T I M U L A T I O N OF A N T R A L MOTOR A C T I V I T Y , BUT S U F F I C I E N T TO E F F E C T A S I G N I F I C A N T I N C R E A S E I N S T I M U L A T I O N OF H + OUTPUT, OR THAT THE DOSE OF CCK-PZ USED WAS AT OR ABOVE MAXIMUM FOR S T I M U L A T I O N OF A N T R A L MOTOR A C T I V I T Y . IN THE L A T T E R C A S E REMOVAL OF THE AMOUNT OF G . I . P . I N V O L V E D IN THE P U R I F I C A T I O N S T A G E WOULD t NOT I N C R E A S E THE DEGREE OF S T I M U L A T I O N OF A N T R A L M O T I L I T Y . IN S T U D I E S WHICH I N V O L V E D G A S T R I N P E N T A P E P T I D E OR S Y N T H E T I C HUMAN G A S T R I N I ( S H G - l ) , THE E F F E C T OF G . I . P . ON B l C K E L POUCH MOTOR A C T I V I T Y COULD NOT BE A S C E R T A I N E D . THE R E A S O N FOR T H I S WAS THAT AT THE COMMENCEMENT OF G A S T R I N I N F U S I O N , A L L S P O N T A N E O U S MOTOR A C T I V I T Y P R E S E N T IN THE POUCHES BECAME C O M P L E T E L Y I N H I B I T E D . THE S T A G E S IN P U R I F I C A T I O N AND A S S A Y S OF EGI TO E G I I I ( P U R E G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ) WERE O U T L I N E D IN THE R E S U L T S S E C T I O N , PAGE 6 9 , AND S U M M A R I Z E D IN F L G . 1 3 . THE F I N A L P U R I F I C A T I O N P R O C E D U R E S ARE AS R E P O R T E D BY BROWN, MUTT AND P E D E R S O N ( 1 9 7 0 ) . T H I S WORK R E V E A L E D THAT THE M A T E R I A L WAS A P O L Y P E P T I D E AND A L S O D E S C R I B E D SOME OF THE S T R U C T U R A L F E A T U R E S WHICH ARE D I S C U S S E D L A T E R . WORK ON THE C H E M I S T R Y OF THE P O L Y P E P T I D E WAS C O N T I N U E D BY BROWN ( 1 9 7 1 ) WITH THE E L U C I D A T I O N OF THE AMINO A C I D C O M P O S I T I O N AND THE S E Q U E N C E OF THE T R Y P T I C P E P T I D E S . THE I N H I B I T O R Y P O L Y P E P T I D E WAS H E N C E F O R T H R E F E R R E D TO AS G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E . - 133 -T H E S E Q U E N C E O F P O R C I N E G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E ( G . I . P . ) H A S NOW B E E N E L U C I D A T E D . IT I S A 4 3 A M I N O A C I D R E S I D U E P O L Y P E P T I D E W I T H T H E A M I N O A C I D S E Q U E N C E T Y R - A L A -G L U - G L Y - T H R - P H E - I L E - S E R - A S P - T Y R - S E R - I L E - A L A - M E T - A S P - L Y S - I L E -A R G - G L N - G L N - A S P - P H E - V A L - A S N - T R P - L E U - L E U - A L A - G L N - G L N - L Y S - G L Y -L Y S - L Y S - S E R - A S P - T R P - L Y S - H I S - A S N - I L E - T H R - G L N ( B R O W N A N D D R Y B U R G H , 1 9 7 1 ) . T H E C A L C U L A T E D M O L E C U L A R W E I G H T O F T H E P O L Y P E P T I D E I S 5 » 1 0 5 • D U R I N G A L L S T A G E S O F T H E E L U C I D A T I O N O F T H E C H E M I C A L N A T U R E O F G . I . P . , C O M P A R I S O N S W E R E M A D E B O T H S T R U C T U R A L L Y A N D P H Y S I O L O G I C A L L Y TO T H E C H E M I C A L L Y I D E N T I F I E D G A S T R O - I N T E S T I N A L H O R M O N E S S E C R E T I N A N D C H O L E -C Y S T O K I N I N - P A N C R E O Z Y M I N . P R E L I M I N A R Y A M I N O A C I D A N A L Y S E S R E P O R T E D B Y B R O W N EJT AJ- ( 1 9 7 0 ) F I R S T D E M O N S T R A T E D D I F F E R E N C E S B E T W E E N T H E I N H I B I T O R Y P O L Y P E P T I D E A N D C C K - P Z . T H E 3 3 A M I N O A C I D C C K - P Z M O L E C U L E H A D B E E N S H O W N TO H A V E 2 P R O L I N E R E S I D U E S (MU T T A N D J O R P E S , 1 9 6 8 ) . IN A D D I T I O N , T H E A N A L Y S E S O F G . I . P . S H O W E D A H I G H G L U T A M I C A C I D / G L U T A M I N E C O N T E N T A N D A P R E P O N D E R A N C E O F L Y S I N E O V E R A R G I N I N E . T H I S W A S I N C O N T R A S T T O C C K - P Z W H I C H P O S S E S S E D A S I N G L E G L U T A M I C A C I D / G L U T A M I N E R E S I D U E , 3 A R G I N I N E S A N D A S I N G L E L Y S I N E . T H I S D I S T I N C T I O N F R O M C C K - P Z W A S I M P O R T A N T I N T H A T I M P U R E P R E P A R -A T I O N S O F C C K - P Z H A D S E R V E D A S T H E S T A R T I N G M A T E R I A L F O R T H E P U R I F I C A T I O N O F G . I . P . ( F L G . 1 3 ) . O N C E T H E A M I N O A C I D S E Q U E N C E W A S C O M P L E T E D , C O M P A R I S O N S W E R E M A D E T O T H E S T R U C T U R E O F O T H E R K N O W N GL H O R M O N E S A N D R E L A T E D P O L Y P E P T I D E H O R M O N E S . IT W A S S H O W N B Y B R O W N A N D D R Y B U R G H ( 1 9 7 1 ) T H A T 9 O F T H E F I R S T 26 A M I N O A C I O S O F G . I . P . - 1 3 4 -O C C U R R E D I N T H E S A M E P O S I T I O N A S I N S E C R E T I N ( F | G . 3 6 ) . AS A R E S U L T O F W E L L — D O C U M E N T E D S T R U C T U R A L S I M I L A R I T I E S B E T W E E N G L U C A G O N A N D S E C R E T I N ( J O R P E S , 1 9 6 8 ) , A C O M P A R I S O N O F T H E S T U R C T U R E S O F G L U C A G O N , S E C R E T I N A N D G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E W A S M A D E . T H I S C O M P A R I S O N ( B R O W N A N D D R Y B U R G H , 1 9 7 1 ) R E V E A L E D T H A T 1 5 O F T H E F I R S T 2 6 A M I N O A C I D S O F G . I . P . O C C U R R E D I N S I M I L A R P O S I T I O N S A S I N P O R C I N E G L U C A G O N . O N C E I T H A D B E E N A S C E R T A I N E D T H A T T H E P O L Y P E P T I D E W A S P U R E , I T W A S O F I N T E R E S T T O L O O K A T T H E P O T E N C Y O F G. I.P. A S A N I N H I B I T O R O F G A S T R I C P A R A M E T E R S A G A I N S T W H I C H T H E G A S T R O I N T E S T I N A L H O R M O N E S S E C R E T I N A N D - C C K - P Z H A D B E E N U S E D I N T H E P A S T . A N O T H E R O B J E C T I V E O F S T U D I E S U S I N G T H E P U R E M A T E R I A L W A S T O D E T E R M I N E I F G . I . P . W A S E F F E C T I V E A S A N I N H I B I T O R O F G A S T R I C S E C R E T I O N A G A I N S T S T I M U L A N T S T H A T W E R E R E S I S T A N T TO I N H I B I T I O N B Y S E C R E T I N A N D C C K - P Z , E . G . H I S T A M I N E . IT W A S H O P E D T H A T E V I D E N C E A S TO T H E M O D E O F A C T I O N O F G. I.P . W O U L D B E R E V E A L E D B Y L O O K I N G A T T H E R A N G E O F I T S E F F E C T I V E N E S S A G A I N S T G A S T R I C S E C R E T I O N S T I M U L A T E D B Y B O T H N E R V O U S A N D H O R M O N A L P A T H W A Y S . AS A R E S U L T O F T H E S T R U C T U R A L S I M I L A R I T I E S O F G. I.P . T O S E C R E T I N A N D G L U C A G O N , A T T E M P T S W E R E M A D E TO D E T E R M I N E I F G. I.P . M I M I C K E D A N Y O F T H E P H Y S I O L O G I C A L A C T I O N S O F T H E S E H O R M O N E S . T H I S P O S S I B I L -I T Y W A S H E I G H T E N E D B Y T H E F A C T T H A T B O T H S E C R E T I N A N D G L U C A -G O N S H A R E D W I T H G . I . P . T H E A B I L I T Y T O I N H I B I T G A S T R I N -S T I M U L A T E D H + S E C R E T I O N ( L L N A N D S P R A Y , 1 9 6 8 ) , A S W E L L A S S H A R I N G S T R U C T U R A L F E A T U R E S . T H E P U R E P O L Y P E P T I D E W A S G I V E N I N D O S E S U P T O 2 0 . 0 J U G / K G - 135 -I N THE ACUTE R A B B I T WHILE M O N I T O R I N G A R T E R I A L BLOOD P R E S S U R E . E V E N THE L A R G E S T DOSES Y I E L D E D NO D E T E C T A B L E CHANGE IN BLOOD P R E S S U R E . DOSES OF G . I . P . USED IN S E C R E T O R Y S T U D I E S I N DOGS PRODUCED NO CHANGES IN R E C T A L T E M P E R A T U R E S , I N D I C A T I N G AN A B S E N C E OF P Y R O G E N I C E F F E C T S . GLUCAGON HAS B E E N SHOWN BY D Y C K , R U D I C K , HOEXTER AND J A N O W I T Z (1969) TO I N H I B I T S E C R E T I N - S T I M U L A T E D P A N C R E A T I C E X O C R I N E S E C R E T I O N IN THE DOG, AN O B S E R V A T I O N THAT WAS I N SHARP C O N T R A S T TO THE OTHER P H Y S I O L O G I C A L P R O P E R T I E S WHICH IT P O S S E S S E D IN COMMON WITH S E C R E T I N , NAMELY THE C H O L E R E T I C ( M O R R I S , S A R D I AND B R A D L E Y , 1967)» 1NSUL 1 NOTROP1 c ( S A M O L S , MARRI AND M A R K S , 1965) AND I N H I B I T O R Y E F F E C T S ON G A S T R I C A C I D S E C R E T I O N ( L I N AND S P R A Y , 1968). FOR T H I S REASON THE E F F E C T OF I N F U S I O N OF G . I . P . ON VOLUME OF P A N C R E A T I C J U I C E WAS O B S E R V E D . B E C A U S E OF THE S T R U C T U R A L S I M I L A R I T I E S BETWEEN GLUCAGON AND G . I . P . , BLOOD G L U C O S E L E V E L S WERE MONITORED D U R I N G E X P E R I M E N T S I N WHICH G . I . P . WAS I N F U S E D . THE A V A I L A B I L I T Y OF A S M A L L Q U A N T I T Y OF SHG-I MADE P O S S I B L E A C O M P A R I S O N OF THE P O T E N C Y OF G . I . P . WITH G A S T R I C P A R A M E T E R S S T I M U L A T E D BY BOTH G A S T R I N P E N T A P E P T I D E AND THE WHOLE G A S T R I N M O L E C U L E . ONE OF THE R E A S O N S THAT SHG-I WAS E M P L O Y E D WAS THAT IT WOULO MORE C L O S E L Y M I M I C THE NORMAL P H Y S I O L O G I C A L S I T U A T I O N . ONE STUDY I N V O L V E D THE I N T R A V E N O U S I N F U S I O N OF G . I . P . I N DOGS THAT HAD B E E N F A S T E D . IN T H E S E E X P E R I M E N T S , A N T R A L AND F U N D I C MOTOR A C T I V I T Y WERE MONITORED ALONG WITH H + AND P E P S I N L E V E L S . THE R A T I O N A L E FOR T H I S STUOY WAS THE F A C T - 136 -T H A T A T L E A S T O N E O T H E R G A S T R O I N T E S T I N A L H O R M O N E , C C K - P Z , W H E N G I V E N I N T R A V E N O U S L Y , H A D B E E N S H O W N TO E X E R T O P P O S I T E E F F E C T S O N G A S T R I C S E C R E T I O N W H E N G I V E N A L O N E ( P R E S H A W A N D G R O S S M A N , 1 9 6 5 ) F R O M T H O S E W H E N G I V E N I N C O N J U N C T I O N W I T H G A S T R I N ( J O H N S O N A N D G R O S S M A N , 1 9 7 0 ) . P U R E G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E W A S A D M I N I S T E R E D I N D O S E S O F 0.25* 0 . 5 , 1.0 A N D 2.0 J U G / K G / H R A G A I N S T A P L A T E A U O F H + S E C R E T I O N S T I M U L A T E D B Y G A S T R I N P E N T A P E P T I D E . T H E P L A T E A U O F H + S E C R E T I O N A C H I E V E D W A S 6 0 - 7 0 $ O F M A X I M U M P O U C H O U T P U T T O T H E S T I M U L A N T , T H E A I M B E I N G T O R E M A I N W I T H I N A P H Y S I O L O G I C A L R A N G E O F A C I D S E C R E T I O N . T H E A C I 0 R E S P O N S E S O F 2 D O G S TO D I F F E R E N T D O S E S O F G A S T R I N P E N T A -P E P T I D E ( F L G . 1 1 ) I L L U S T R A T E D T H A T T H E D O S E U S E D A C H I E V E D 6 0 - 7 0 $ O F M A X I M U M H + O U T P U T . ' S I N C E G A S T R I N P E N T A P E P T I D E H A D B E E N S H O W N A L S O T O S T I M U L A T E P E P S I N O U T P U T A N D A N T R A L M O T O R A C T I V I T Y ( H I R S C H O W I T Z , 1 9 6 7 ; J A C O B Y A N D M A R S H A L L , 1 9 ^ 9 ) , T H E S E P A R A M E T E R S W E R E M O N I T O R E D . T H E D A T A I N D I C A T E D T H A T A T A D O S E O F 2 . 0 J U G / K G / H R G . I . P . P R O D U C E D 8 5 $ I N H I B I T I O N O F P E N T A P E P T I D E - S T I M U L A T E D H A N D 9 0 $ I N H I B I T I O N O F P E P S I N O U T P U T ( F I G . 2 5 ) . T H E R E S U L T S S U G G E S T E D T H A T T H E T H R E S H O L D J . D O S E L E V E L F O R S I G N I F I C A N T I N H I B I T I O N O F H S E C R E T I O N W A S L E S S T H A N 0.25" J J G / K G / H R , W H E R E A S F O R S I G N I F I C A N T P E P S I N I N H I B I T I O N T H E T H R E S H O L D L E V E L W A S B E T W E E N 0.25 A N D 0.5 J U G / K G / H R . T H E L A T T E R F I N D I N G M A Y B E A F U N C T I O N O F T H E V A R I A B I L I T Y O F P E P S I N L E V E L S R A T H E R T H A N A N I N D I C A T I O N T H A T T H E T H R E S H O L D F O R S I G N I F I C A N T I N H I B I T I O N O F P E P S I N D I F F E R S F R O M T H A T O F H +. I T A P P E A R E D T H A T G . I . P . W A S L E S S P O T E N T - 1 3 7 -AS AN I N H I B I T O R O F A N T R A L MOTOR A C T I V I T Y THAN FOR THE P A R A -M E T E R S OF H + AND P E P S I N S E C R E T I O N . T H I S WAS I N D I C A T E D BY THE FACT THAT A DOSE OF 1 . 0 / J G / K G / H R OF G . I . P . WAS R E Q U I R E D TO PRODUCE S I G N I F I C A N T I N H I B I T I O N OF ANTR A L MOTOR A C T I V I T Y . AS S U C H , THE DEGREE OF I N H I B I T I O N ( 2 3 $ ) WAS VERY S M A L L COMPARED WITH H + AND P E P S I N ( 7 5 - 8 0 $ ) , IN A D D I T I O N , D O U B L I N G THE DOSE OF G . I . P . TO 2.0 /JG/KG/HR PRODUCED NO F U R T H E R I N H I B I T I O N OF A N T R A L A C T I V I T Y , I N D I C A T I N G THAT MAXIMUM L E V E L S OF I N H I B I T I O N HAD B E E N A C H I E V E D . ONE P O S S I B L E E X P L A N A T I O N FOR THE S M A L L AMOUNT OF I N H I B I T I O N COULD BE THAT G A S T R I N P E N T A -P E P T I D E WAS A MORE P O T E N T S T I M U L A N T FOR ANTR A L MOTOR A C T I V I T Y THAN OF THE OTHER P A R A M E T E R S S T U D I E D , AND THAT THE DOSE E M P L O Y E D WAS P R O D U C I N G M A X I M A L MOTOR A C T I V I T Y R E S P O N S E S . AN A L T E R N A T E P O S S I B I L I T Y COULD BE THAT THE A C T I O N OF THE P E N T A -P E P T I D E ON MOTOR A C T I V I T Y WAS MORE R E S I S T A N T TO I N H I B I T I O N BY G . I . P . THAN H + OR P E P S I N S E C R E T I O N . THE FORMER P O S S I B I L -I T Y WAS S U P P O R T E D BY THE WORK OF J A C O B Y ANO M A R S H A L L ( 1 9 6 9 ) WHO FOUND THAT A P E A K R E S P O N S E OF A N T R A L MOTOR A C T I V I T Y I N THE DOG WAS P R E S E N T AT DOSES OF G A S T R I N P E N T A P E P T I D E AS LOW AS 1.0 JUG/KG/HR. GREGORY AND TR A C Y ( 1 9 6 4 ) WERE THE F I R S T TO REPORT THAT THERE WERE 2 G A S T R I N S , G A S T R I N I AND G A S T R I N I I . BOTH G A S T R I N S ARE S I M I L A R I N AMINO A C I O SEQUENCE E X C E P T THAT G A S T R I N I I HAS A S U L P H A T E E S T E R I F I E D TO THE T Y R O S Y L R E S I D U E AT P O S I T I O N 1 2 . SHG-L WAS G I V E N I N SUCH A DOSE AS TO Y I E L D E Q U I V A L E N T L E V E L S OF H + S E C R E T I O N FROM B L C K E L POUCHES AS A C H I E V E D WITH 1.5 JJG/KG/HR OF G A S T R I N P E N T A P E P T I D E . A DOSE - 138 -O F 0.5 / J G / K G / H R O F S H G - I W A S F O U N D T O B E S U I T A B L E . T H I S AGREED WITH THE FINDINGS OF HlRSCHOWITZ (1968) WHO SHOWED THAT GASTRIN I WAS ABOUT 3 TIMES AS POTENT AS GASTRIN PENTAPEPT IOE ON A WEIGHT BASIS IN STIMULATING H + S E C R E T I O N , ANO THE STATEMENT OF GROSSMAN (1970) THAT THE T E T R A P E P T I D E AMIDE OF GASTRIN POSSESSED ONE-TWELFTH THE A C T I V I T Y OF THE WHOLE GASTRIN MOLECULE ON A MOLAR B A S I S . THE DATA PRESENTED IN F l G S . 22 AND 26 INDICATED THAT G . I . P . WAS MORE E F F E C T I V E AS AN INHIBITOR OF THE WHOLE MOLECULE THAN GASTRIN PENTAPEPT IDE WITH RESPECT TO H S E C R E T I O N . A DOSE OF G . I . P . THAT PRODUCED 75$ INHIBIT ION OF GASTRIN P E N T A P E P T I D E - S T I M U L A T E D H SECRETION Y IELDED 85$ INHIBIT ION OF ACID L E V E L S STIMULATED BY THE WHOLE GASTRIN M O L E C U L E . O F INTEREST WAS THE OBSERVATION THAT A DOSE OF S H G - I THAT PRODUCED COMPARABLE L E V E L S OF H + OUTPUT TO GASTRIN P E N T A P E P T I D E YIELOED PEPSIN L E V E L S THAT WERE APPROXIMATELY 3i_ TIMES HIGHER ( T A B L E S X I I I AND X I X ) . T H I S WAS IN CONTRAST TO THE FINDINGS OF HlRSCHOWITZ (1968) WHO REPORTED THAT GASTRIN PENTAPEPT IDE STIMULATED PEPSIN SECRETION 3 TIMES AS STRONGLY AS GASTRIN I . G . I . P . PRODUCED SLIGHTLY GREATER INHIBIT ION OF THE HIGHER L E V E L S OF PEPSIN THAN IN THE P E N T A -PEPT IDE STUDIES (85$ AS COMPARED WITH 78$). G . I . P . REDUCED PEPSIN L E V E L S FROM A MEAN OF 2.378 MG T Y R O S I N E / 1 5 MIN TO A MEAN OF 0.312 MG T Y R O S I N E / 1 5 MIN IN THE S H G - I STUDIES AND FROM A MEAN OF 0.500 MG T Y R O S I N E / 1 5 MIN TO A MEAN OF 0.050 M G T Y R O S I N E / 1 5 M I N I N T H E G A S T R I N PENTAPEPT IDE S T U O I E S . I F T H E A S S U M P T I O N I S M A D E T H A T P A R I E T A L C E L L S H A V E - 139 -R E C E P T O R S F O R T H E G A S T R I N M O L E C U L E , O N E G A S T R I N M O L E C U L E P R O D U C E S T H E S A M E D E G R E E O F S T I M U L A T I O N O F T H E R E C E P T O R A S 1 2 G A S T R I N P E N T A P E P T I D E M O L E C U L E S A T S U B M A X I M A L D O S E S . T H E G R E A T E R I N H I B I T O R Y P O T E N C Y O F G . I . P . A G A I N S T S H G - I - S T I M U L A T E D H + S E C R E T I O N M A Y B E D U E TO T H E F A C T T H A T I N T H E D O S E S U S E D I N T H E S T U D Y , G . I . P . W I T H A M O L E C U L A R W E I G H T O F 5,105 C A M E M U C H C L O S E R TO E Q U A L L I N G T H E N U M B E R O F M O L E C U L E S O F S H G - l ( M W 2 , 1 1 4 ) I N F U S E D , T H A N I T D I D G A S T R I N P E N T A P E P T I D E ( M W A P P R O X I M A T E L Y 7 5 0 ) . I F G . I . P . A N D G A S T R I N W E R E C O M P E T I N G F O R T H E S A M E R E C E P T O R S I T E , T H E N T H E A B O V E N U M E R I C A L C O N S I D -E R A T I O N C O U L D B E O F I M P O R T A N C E . A L T E R N A T I V E L Y , G . I . P . M A Y I N T E R A C T W I T H G A S T R I N E I T H E R I N T H E B L O O D OR A T T H E L E V E L O F T H E P A R I E T A L C E L L . T H E P A R T O F T H E G A S T R I N M O L E C U L E A B S E N T F R O M T H E P E N T A P E P T I D E M A Y C O N T R I B U T E TO T H E I N T E R -A C T I O N B E T W E E N T H E W H O L E G A S T R I N M O L E C U L E A N D G . I . P . , I N C R E A S I N G I T S E F F I C I E N C Y A S A N I N H I B I T O R . A L T H O U G H A N T R A L M O T I L I T Y W A S I N H I B I T E D TO A M U C H L E S S E R D E G R E E ( 5 1 $ ) T H A N W E R E T H E P A R A M E T E R S O F H + O R P E P S I N ( F L G S . 2 6 , 2 7 A N O 2 8 ) , T H I S L E V E L O F I N H I B I T I O N W A S T W I C E T H A T P R O D U C E D A G A I N S T P E N T A P E P T I D E - S T I M U L A T E D A N T R A L M O T I L I T Y . T H E S A M E A R G U M E N T U S E D I N T H E D I S C U S S I O N O F T H E G R E A T E R P O T E N C Y O F G . I . P . A G A I N S T H + A N D P E P S I N O U T P U T S T I M U L A T E D B Y SHG - L A S C O M P A R E D W I T H G A S T R I N P E N T A P E P T I D E C O U L D A P P L Y T O A N T R A L M O T O R A C T I V I T Y . A N O T H E R P O S S I B L E R E A S O N C O U L D B E T H E F A C T T H A T P L A T E A U L E V E L S O F A N T R A L M O T O R A C T I V I T Y S T I M U L A T E D B Y SHG - L W E R E O N E T H I R D O F T H O S E P R O D U C E D B Y P E N T A P E P T I D E S T I M U L A T I O N . T H E L A T T E R F I N D I N G WAS T H E D I R E C T - HO -O P P O S I T E TO THE O B S E R V A T I O N THAT SHG-I WAS A MORE PO T E N T S T I M U L A T O R OF P E P S I N S E C R E T I O N , ANO NO E X P L A N A T I O N CAN BE O F F E R E D AT P R E S E N T FOR E I T H E R PHENOMENON. H I S T A M I N E I S ONE OF THE MOST P O T E N T S T I M U L A N T S OF G A S T R I C H + S E C R E T I O N , BUT IT I S NOT KNOWN FOR C E R T A I N I F H I S T A M I N E P A R T I C I P A T E S IN A P H Y S I O L O G I C A L M E C H A N I S M FOR THE S T I M U L A T I O N OF H + S E C R E T I O N . THE USE OF H I S T A M I N E AS A G A S T R I C S E C R E T O R Y S T I M U L A N T IN THE CONTEXT OF T H I S T H E S I S WAS N E C E S S A R Y AS A R E S U L T OF P R E V I O U S E X P E R I M E N T A L WORK I N V O L V I N G THE S E A R C H FOR E N T E R O G A S T R O N E . F E N G , HOU AND L L M ( 1 9 2 9 ) WERE THE F I R S T TO O B S E R V E THAT FAT I N THE DUODENUM WOULD I N H I B I T H I S T A M I N E - S T I M U L A T E D H + S E C R E T I O N FROM D E N E R V A T E D STOMACH P O U C H E S , T H E R E F O R E BY A HUMORAL M E C H A N I S M . KOSAKA AND L l M ( 1 9 3 0 A ) FOUND THAT THE CRUOE C H O L E C Y S T 0 K I N I N OF IVY AND OLDBERG ( ( 1 9 2 8 ) WOULD I N H I B I T HI STAM I N E - S T I M ULATED H + O U T P U T . S I N C E FAT I N T H E DUODENUM WAS SHOWN BY IVY ( 1 9 3 4 ) TO BE A P O T E N T S T I M U L U S FOR G A L L B L A D O E R C O N T R A C T I O N , P R E S U M A B L Y 8Y THE R E L E A S E OF ENDOGENOUS CCK-PZ, I T COULD BE H Y P O T H E S I Z E D THAT CCK-PZ WAS THE A C T I V E AGENT R E S U L T I N G I N I N H I B I T I O N OF H I S T A M I N E - S T I M U L A T E D H + S E C R E T I O N WHEN FAT WAS P L A C E D I N THE DUODENUM. T H I S WAS NOT, HOWEVER, THE C O N C L U S I O N OF K O S A K A AND L l M ( 1 9 3 0 B ) , WHO THOUGHT THAT I V Y ' S C H O L E C Y S T O K I N I N P R E P A R A T I O N C O N T A I N E D AN I M P U R I T Y WHICH WAS R E S P O N S I B L E FOR THE I N H I B I T I O N OF HI STAM I N E - S T I M U L A T E D H S E C R E T I O N . THEY A T T E M P T E D TO I S O L A T E THE M A T E R I A L WHICH THEY NAMED E N T E R O G A S T R O N E . T H E H Y P O T H E S I S OF KOSAKA AND L l M HAD B E E N G I V E N S U P P O R T BY THE F I N D I N G THAT A H I G H L Y - HI -P U R I F I E D C C K - P Z P R E P A R A T I O N D I D N O T I N H I B I T H I S T A M I N E -S T I M U L A T E D H+ S E C R E T I O N I N T H E D O G ( J O H N S O N A N D G R O S S M A N , 1 9 6 9 ) . T H E S A M E G R O U P S H O W E D T H A T H I S T A M I N E - S T I M U L A T E D H + S E C R E T I O N W A S N O T I N H I B I T E D B Y S E C R E T I N , A N D C O N C L U D E D T H A T A H O R M O N E O T H E R T H A N C C K - P Z O R S E C R E T I N W A S R E L E A S E D B Y T H E P R E S E N C E O F F A T I N T H E D U O D E N U M . F R O M T H E A B O V E , I T C A N B E S T A T E D T H A T A N Y P R I N C I P L E S E E K I N G TO F U L F I L L T H E C L A S S I C A L D E F I N I T I O N O F E N T E R O G A S T R O N E ( K O S A K A A N D L l M , 1930B) M U S T B E E F F E C T I V E I N I N H I B I T I N G H I S T A M I N E - S T I M U L A T E D H + S E C R E T I O N I N E X T R I N S I C A L L Y D E N E R V A T E D S T O M A C H P O U C H E S I N T H E D O G . IN S T U D I E S I N V O L V I N G T H E U S E O F H I S T A M I N E , T H E D O S E U S E D W A S O N L Y O N E Q U A R T E R T H A T W H I C H W A S O F T E N Q U O T E D I N T H E L I T E R -A T U R E A S B E I N G U S E D I N S E C R E T O R Y S T U D I E S I N D O G S . T H E P O U C H R E S P O N S E S TO D I F F E R E N T D O S E S O F H I S T A M I N E I N D I C A T E T H A T A O O S E O F 20.0 J J G / K G / H R O F H I S T A M I N E Y I E L D E D N E A R - M A X I M A L P O U C H R E S P O N S E F O R T H I S S T I M U L U S ( F | G . 2 9 ) . A N O T H E R F A C T I N S U P P O R T O F T H E U S E O F L O W E R D O S E S O F H I S T A M I N E W A S T H A T T H E P L A T E A U L E V E L S O F H + O U T P U T ( T A B L E X X I ) ( A P P R O X I M A T E L Y 0.8 M E Q H + /15 M I N ) C O M P A R E D F A V O U R A B L Y T O P L A T E A U L E V E L S O F H+ O U T P U T C I T E D I N T H E L I T E R A T U R E ( J O H N S O N A N D G R O S S M A N , 1 9 6 9 ) E V E N T H O U G H T H E H I S T A M I N E D O S E I N T H E C I T E D S T U D Y W A S 40.0 J U G / K G / H R . T H E S E H+ O U T P U T S A L S O C O M P A R E D F A V O U R -A B L Y W I T H T H O S E A C H I E V E D F O R G A S T R I N P E N T A P E P T I D E . AN A D D I T I O N A L F A C T O R R U L I N G A G A I N S T T H E H I G H E R D O S E S O F H I S T A M I N E W A S T H A T A L L D O G S V O M I T E D W H E N T H E I N F U S I O N O F H I S T A M I N E W A S I N C R E A S E D T O A N D A B O V E 20. 0 JU G / K G / H R . A L T H O U G H G . I . P . W A S F O U N D T O I N H I B I T ' H I S T A M I N E -- 142 -STIMULATED H + SECRET I ON FROM DENERVATED FUNDIC POUCHES, IT WAS FOUND TO BE MUCH L E S S E F F E C T I V E THAN AGAINST GASTRIN P E N T A P E P T I D E - OR S H G - I - S T IMULATED H + S E C R E T I O N . USING A DOSE OF HISTAMINE ( 1 0 . 0 J U G / K G / H R ) THAT Y IELDED COMPARABLE L E V E L S OF H + OUTPUT TO 1 • 5 JU G/K G/H R OF GASTRIN P E N T A P E P T I D E , G . I . P . WAS L E S S THAN 5 0 $ AS E F F E C T I V E AS AN INHIBITOR. T W I C E T H E D O S E OF G . I . P . R E Q U I R E D TO Y I E L D 85$ I N H I B I T I O N OF GASTRIN P E N T A P E P T I D E - S T I M U L A T E D H + SECRETION RESULTED IN ONLY 5 5 $ INHIBIT ION OF H I S T A M I N E - S T I M U L A T E D H + SECRETION ( F I G S . 25A AND 3 0 A ) . D O U B L I N G T H E DOSE OF G . I . P . D I D NOT GREATLY INCREASE THE DEGREE OF INHIBIT ION OF H + ST IMULATED BY HISTAMINE INFUSION ( F l G . 3 0 s ) . THIS INDICATED THAT MAXIMUM INHIBIT ION BY G . I . P . WAS BEING PRODUCED. I T WAS P O S S I B L E THAT THE L E V E L S OF HISTAMINE USED WERE UNPHYSIO -LOGICAL AND THAT NO INHIBITOR COULD PRODUCE A GREATER DEGREE OF I N H I B I T I O N . COMPARISONS OF THIS NATURE CANNOT BE MADE SINCE THE CHEMICALLY IDENTIF IED HORMONES SECRET IN AND C C K - P Z BOTH FA IL TO INHIBIT H I S T A M I N E - S T I M U L A T E D H + S E C R E T I O N . ONE P IECE OF CIRCUMSTANTIAL EVIDENCE IMPLICATING G . I . P . IN A KNOWN INHIBITORY MECHANISM WAS THE FACT THAT G . I . P . PRODUCED THE SAME DEGREE OF INHIBITION OF HISTAMINE— STIMULATED H + SECRETION AS DID FAT IN THE DUODENUM (JOHNSON AND G R O S S M A N , 1969). IN T H E I R S T U D I E S 5 0 $ I N H I B I T I O N OF H + SECRETION STIMULATED BY HISTAMINE WAS THE MAXIMUM OBTAINED. HlRSCHOWITZ ( 1 9 6 8 ) REPORTED THAT GASTRIN PENTAPEPTIDE WAS A MUCH BETTER STIMULANT FOR PEPSIN SECRETION THAN H I S T A M I N E . THE DATA PRESENTED IN TABLES X I I I AND X X I I I - 143 -I N D I C A T E D T H A T IN S T U D I E S U S I N G H I S T A M I N E AT A DOSE L E V E L OF 1 0 . 0 p G / K G / H R AND G A S T R I N P E N T A P E P T I D E , OF 1 . 5 J U G / K G / H R , P L A T E A U L E V E L S WERE A P P R O X I M A T E L Y E Q U A L . G . I.P. P R O D U C E D 5 5 - 8 0 $ I N H I B I T I O N OF P E P S I N S E C R E T I O N IN T H E H I S T A M I N E S T U D I E S . D O U B L I N G T H E DOSE OF G . I.P. FROM 2 . 0 TO 4 . 0 JUG/KG/ HR P R O D U C E D NO S I G N I F I C A N T I N C R E A S E IN T H E I N H I B I T I O N OF P L A T E A U L E V E L S OF P E P S I N S E C R E T I O N ( F l G . 3 1 B ) , I N D I C A T I N G T H A T A N E A R - M A X I M U M D E G R E E OF I N H I B I T I O N WAS B E I N G E X E R T E D AT T H E 2 . 0 / J G / K G / H R L E V E L . S l N C E T H E B L O O D - B O R N E A G E N T R E L E A S E D WHEN F A T WAS P L A C E D IN T H E DUODENUM HAD B E E N SHOWN TO I N H I B I T P E P S I N S E C R E T I O N S T I M U L A T E D BY H I S T A M I N E ( A L L E Y E_T A_L, 1 9 3 4 ) , C A N D I D A T E S FOR T H I S R O L E MUST BE C A P A B L E OF T H I S A C T I O N . H I S T A M I N E HAD B E E N SHOWN BY J A C O B Y AND M A R S H A L L ( 1 9 6 9 ) TO BE A POOR S T I M U L A N T OF G A S T R I C A N T R A L M O T I L I T Y . TH I S WAS FOUND TO BE T H E C A S E IN T H E S E S T U D I E S , AND T H E R E F O R E T H I S P A R A M E T E R HAS NOT B E E N Q U A N T I T A T E D IN I N H I B I T O R Y S T U D I E S I N V O L V I N G H I S T A M I N E . I N F U S I O N OF G A S T R I N P E N T A P E P T I D E OR SHG - L I N H I B I T E D U N S T I M U L A T E D F U N D I C P O U C H MOTOR A C T I V I T Y . FOR T H I S R E A S O N T H E R E WAS NO M E A N S OF D E T E R M I N I N G I F G . I.P. I N H I B I T E D F U N D I C MOTOR A C T I V I T Y D U R I N G G A S T R I N S T I M U L A T I O N O F O T H E R P A R A M E T E R S . B E C A U S E OF T H E N O R M A L L Y H I G H D E G R E E OF V A R I A T I O N IN B L C K E L P O U C H MOTOR A C T I V I T Y , IT WAS D I F F I C U L T TO D E T E R M I N E I F H I S T A M I N E HAD ANY E F F E C T ON T H I S P A R A M E T E R . S U B J E C T I V E L Y , IT A P P E A R E D AS I F S P O N T A N E O U S L Y O C C U R R I N G B U R S T S OF MOTOR A C T I V I T Y B E C A M E MORE R E G U L A R A F T E R T H E C O M M E N C E M E N T OF H I S T A M I N E I N F U S I O N . TH I S P O I N T IS I L L U S -T R A T E D BY T H E S M A L L D I F F E R E N C E S IN T H E MEAN V A L U E S FOR - U 4 -U N S T I M U L A T E D B l C K E L POUCH MOTOR A C T I V I T Y ( T A B L E XXXI I I ) AND THE L E V E L S OF B l C K E L POUCH MOTOR A C T I V I T Y D U R I N G H I S T A M I N E I N F U S I O N ( T A B L E X X V ) . I N F U S I O N OF G . I . P . PRODUCED 5 5 - 6 0 $ I N H I B I T I O N OF MOTOR A C T I V I T Y , AND AS WITH P E P S I N , D O U B L I N G THE DOSE OF G . I . P . DID NOT PRODUCE I N C R E A S E D I N H I B I T I O N . G . I . P . , U N L I K E THE G A S T R O I N T E S T I N A L HORMONES CCK-PZ AND S E C R E T I N , W I L L I N H I B I T H + S E C R E T I O N , P E P S I N S E C R E T I O N AND F U N D I C MOTOR A C T I V I T Y S T I M U L A T E D BY H I S T A M I N E . L U C I E N , I T O H , S U N , M E Y E R , C A R L T O N AND S C H A L L Y ( 1 9 6 9 ) E M P L O Y I N G T E C H N I Q U E S S I M I L A R TO THOSE USED IN THE P U R I F I C A T I O N OF THE E S T A B L I S H E D G A S T R O I N T E S T I N A L P O L Y P E P T I D E S , I S O L A T E D AN I N H I B I T O R Y S U B S T A N C E OR E N T E R O G A S T R O N E FROM THE DUODENAL MUCOSA. THE AUTHORS HAD NOT P R O C E E D E D WITH P U R I F I C A T I O N TO THE S T A G E OF I D E N T I F Y I N G THE C H E M I C A L NATURE OF THE I N H I B I T O R Y M A T E R I A L . L U C I E N , ITOH AND S C H A L L Y ( 1 9 7 0 ) DEMONSTRATED THAT A S I N G L E I N J E C T I O N OF 0.5 MG OF T H E I R I N H I B I T O R REDUCED A C I D S E C R E T I O N S T I M U L A T E D BY H I S T A M I N E D I H Y D R O C H L O R I D E BY 1 8 $ . A DOSE OF 2.0 MG WAS R E Q U I R E D TO PRODUCE A MAXIMUM I N H I B I T I O N OF 3 5 $ . E X T R A N E O U S F A C T O R S MAY HAVE B E E N O P E R A T I N G TO M O D IFY S E C R E T I O N D U R I N G H I S T A M I N E I N F U S I O N IN THE STUDY OF L U C I E N EJ_ M. ( 1 9 7 0 ) . THE DOG P R E P A R A T I O N USED IN T H I S STUDY WAS SUCH THAT THE A N I M A L S S T I L L P O S S E S S E D ANTRA WITH I N T A C T I N N E R V A T I O N . IT HAD B E E N SHOWN BY A N D E R S S O N AND GROSSMAN ( 1 9 6 5 ) THAT BACKGROUND VAGAL R E L E A S E OF ENDOGENOUS G A S T R I N FROM AN I N N E R V A T E D ANTRUM P O T E N T I A T E D S T I M U L A T I O N OF H + S E C R E T I O N BY H I S T A M I N E . S I N C E THE DEGREE OF I N H I B I T I O N PRODUCED BY THE I N H I B I T O R OF L U C I E N ___T M._ ( 1 9 7 0 ) I S SO - 145 -S L I G H T , IT C O U L D H A V E B E E N P R O D U C E D BY I N H I B I T I N G T H E A C I O R E S P O N S E P R O D U C E D BY E N D O G E N O U S L Y R E L E A S E D G A S T R I N . T H E N E C E S S I T Y FOR U S I N G S U C H H I G H D O S E S O F M A T E R I A L (0.5 AND 2.0 MG) I N D I C A T E D E I T H E R T H A T T H E E N T E R O G A S T R O N E WAS NOT P U R E , OR E L S E D I F F E R E N T FROM G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E . T H E L A T T E R H Y P O T H E S I S C O U L D WELL BE S O , BUT B I O C H E M I C A L DATA ON T H E E N T E R O G A S T R O N E OF L U C I E N JE_T AJL (1970) MUST BE MADE A V A I L A B L E B E F O R E T H I S CAN BE A S C E R T A I N E D . S E C R E T I N HAS B E E N SHOWN BY WAY (1970) TO E X E R T NO I N H I B I T I O N ON P A V L O V P O U C H H + S E C R E T I O N S T I M U L A T E D BY I N S U L I N OR 2-D E O X Y G L U C O S E . NO DATA WERE A V A I L A B L E R E G A R D I N G T H E E F F E C T S OF CCK-PZ ON V A G A L L Y I N D U C E D A C I D S E C R E T I O N . O L I V E O I L IN T H E DUODENUM WAS SHOWN BY A L L E Y JET AJ. (1934) TO I N H I B I T G A S T R I C S E C R E T I O N FROM T H E M A I N S T O M A C H S T I M U -L A T E D BY SHAM F E E D I N G , AND T H E R E F O R E BY A V A G A L M E C H A N I S M . D O G S U S E D IN S T U D I E S I N V O L V I N G G . I . P . WERE P R E P A R E D WITH T H O M A S C A N N U L A E IN T H E G A S T R I C R E M N A N T , T H U S P R O V I D I N G A M E A N S OF C O L L E C T I N G V A G A L L Y I N D U C E D G A S T R I C S E C R E T I O N . WAY (1970) D E M O N S T R A T E D T H A T S E C R E T I N WOULD I N H I B I T T H E A C I D S E C R E T O R Y R E S P O N S E OF P A V L O V P O U C H E S TO 2-D E O X Y -D-G L U C O S E AND I N S U L I N H Y P O G L Y C A E M I A I F T H E V A G A L L Y I N N E R -V A T E D A N T R U M WAS L E F T I N T A C T . A N T R E C T O M Y E L I M I N A T E D I N H I -B I T I O N OF A C I D S E C R E T I O N BY S E C R E T I N IN T H E SAME D O G S , T H E A U T H O R I N T E R P R E T E D T H E A B O V E E V I D E N C E AS I N D I C A T I N G T H A T IN T H E FORMER C A S E , S E C R E T I N HAD B E E N I N H I B I T I N G V A G A L L Y R E L E A S E D A N T R A L G A S T R I N . IN T H E S T U D Y IN WHICH S E C R E T I O N FROM T H E G A S T R I C R E M N A N T WAS M E A S U R E D , T H E DOGS - 1 4 6 -U S E D WERE P R E P A R E D WITH I S O L A T E D V A G A L L Y D E N E R V A T E D A N T R A L P O U C H E S , A P R E P A R A T I O N WHICH P R E C L U D E D T H E V A G A L R E L E A S E OF G A S T R I N . AS AN A D D E D P R E C A U T I O N , IN C O N T R O L E X P E R I M E N T S IN WHICH I N S U L I N A L O N E WAS G I V E N , T H E A N T R A L P O U C H WAS P E R -F U S E D WITH 0 . 1 M HCL , A P R O C E D U R E WHICH HAD B E E N SHOWN TO B L O C K A L L M E C H A N I S M S OF G A S T R I N R E L E A S E (WOODWARD, L .YON, L A N D O R AND D R A G S T E D T , 1 9 5 4 ) . T H E A B S E N C E OF ANY D E C R E A S E IN P E A K A C I D R E S P O N S E TO I N S U L I N I N D I C A T E D THAT T H E R E HAD B E E N NO B A C K G R O U N D V A G A L R E L E A S E OF G A S T R I N . G . I . P . P R O D U C E D A P P R O X I M A T E L Y 5 0 $ I N H I B I T I O N OF G A S T R I C R E M N A N T H + AND P E P S I N S E C R E T I O N S T I M U L A T E D BY I N S U L I N H Y P O G L Y C A E M I A ( F L G S . 3 4 AND 3 5 ) . G . I . P . WAS L E S S E F F E C T I V E A G A I N S T I N S U L I N - S T I M U L A T E D H + S E C R E T I O N THAN A G A I N S T G A S T R I N P E N T A P E P T I D E , AN E F F E C T S I M I L A R TO T H A T S E E N WITH H I S T A M I N E . G . I . P . HAS B E E N SHOWN TO BE A P O T E N T I N H I B I T O R OF A C I D S E C R E T I O N FROM D E N E R V A T E D P O U C H E S IN T H E DOG S T I M U L A T E D BY E N D O G E N O U S G A S T R I N , E X O G E N O U S G A S T R I N P E N T A P E P T I D E , SHG-L, H I S T A M I N E , AND I N S U L I N H Y P0G L Y C A E M I A . T H E F A C T THAT G . I . P . WAS E F F E C T I V E A G A I N S T D I F F E R E N T S T I M U L A N T S S U G G E S T E D T H A T T H E I N H I B I T O R MAY HAVE B E E N A C T I N G AT T H E L E V E L OF T H E P A R I E T A L C E L L D I R E C T L Y OR AT A F I N A L PATHWAY COMMON TO A L L O F T H E S T I M U L A N T S , AS O P P O S E D TO B E I N G A S P E C I F I C A N T A G O N I S T OF G A S T R I N AS HAS B E E N P O S T U L A T E D FOR S E C R E T I N ( G R O S S M A N , 1 9 7 0 ) . IN O P P O S I T I O N TO T H E C O N C E P T OF A G E N E R A L I Z E D I N H I B I T O R Y A C T I O N AT T H E P A R I E T A L C E L L ARE T H E R E S U L T S D E M O N S T R A T I N G T H E G R E A T E R P O T E N C Y OF G . I . P . A S AN I N H I B I T O R OF G A S T R I C S E C R E T I O N S T I M U L A T E D BY T H E WHOLE G A S T R I N M O L E C U L E - 147 -OR G A S T R I N P E N T A P E P T I D E AS COMPARED WITH H I S T A M I N E OR V A G A L L Y INDUCED S E C R E T I ON. ONE HOUR I N T R A V E N O U S I N F U S I O N S OR S I N G L E I N J E C T I O N S OF G . I . P . PRODUCED NO I N H I B I T I O N OF H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E IN THE A N A E S T H E T I Z E D CAT ( T A B L E X X I X ) . THE DOSE OF G . I . P . E M P L O Y E D WAS 4 T I M E S THAT R E Q U I R E D TO PRODUCE 75$ I N H I B I T I O N OF D E N E R V A T E D POUCH H + S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E IN THE DOG. T H I S L A C K OF I N H I B I T I O N MAY NOT BE C O N S I D E R E D UNUSUAL IN THE L I G H T OF THE F A C T THAT IN THE C A T , G A S T R I N - S T I M U L A T E D G A S T R I C S E C R E T I O N WAS FOUND BY S T E N I N G E_T M_ ( 1 9 6 9 A ) TO BE MUCH L E S S S E N S I T I V E TO I N H I B I T I O N BY S E C R E T I N THAN I N THE DOG. IN A D D I T I O N , CCK-PZ P R E P A R A T I O N S WHICH WERE WELL-D0CUMENTED I N H I B I T O R S OF G A S T R I N - S T I M U L A T E D H + S E C R E T I O N IN THE DOG D I D NOT I N H I B I T S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E IN THE CAT (WAY AND GROSSMAN* U N P U B L I S H E O , 1 9 7 1 ) . DYCK J__T J__L ( 1 9 " 9 ) HAD SHOWN THAT GLUCAGON IN DOSES AS LOW AS 1.0 UG/KG/HR WOULD I N H I B I T VOLUME AND P R O T E I N OUTPUT OF P A N C R E A T I C J U I C E S T I M U L A T E D BY S E C R E T I N AND CCK-PZ IN THE DOG. B E C A U S E OF THE S I M I L A R I T I E S OF G . I . P . TO GLUCAGON ( F I G . 36) G . I . P . I N F U S I O N S WERE G I V E N I N T R A V E N O U S L Y TO THE A N A E S T H E T I Z E D CAT ON A BACKGROUND OF S E C R E T I N - S T I M U L A T E D FLOW OF P A N C R E A T I C J U I C E . G A S T R I C C O L L E C T I O N S WERE MADE C O N C U R R E N T L Y WITH THE P A N C R E A T I C S T U D I E S IN T H E S E E X P E R -I M E N T S , WITH A C I D S E C R E T I O N S T I M U L A T E D BY A CONSTANT I N F U S I O N OF G A S T R I N P E N T A P E P T I D E . G A S T R I N P E N T A P E P T I D E IN THE DOSE USED D I D NOT PRODUCE ANY O B S E R V A B L E I N C R E A S E S IN VOLUME - 1 4 8 -EVEN THOUGH THIS HAS BEEN DEMONSTRATED TO BE A P H Y S I O L O G I C A L ACTION OF GASTRIN (PRESHAW, COOKE AND GROSSMAN, 1 9 6 5 ) . L A C K OF INH IB IT ION OF S E C R E T I N - S T I M U L A T E D VOLUME OF P A N C R E A T I C J U I C E INDICATED THAT G . I . P . AT THE DOSES USED IN THIS STUDY DID NOT HAVE A G L U C A G 0 N - L I K £ ACTION ON THIS PARAMETER IN THE C A T . IN EXPERIMENTS INVOLVING B O T H ' C O N S C I O U S DOGS AND A N A E S T H E T I Z E D R A B B I T S , BLOOD GLUCOSE L E V E L S WERE MONITORED DURING INTRAVENOUS ADMINISTRAT ION OF BOTH GLUCAGON AND G . I . P . G . I . P . WAS GIVEN BOTH AS A S I N G L E I N J E C T I O N AND AS A ONE HOUR I N F U S I O N . DURING A T Y P I C A L EXPERIMENT IN THE DOG IN WHICH G . I . P . WAS GIVEN AS A ONE HOUR INFUSION AGAINST GASTRIN P E N T A P E P T I D E - S T I M U L A T E D H + S E C R E T I O N , NO INCREASE IN BLOOD SUGAR L E V E L S WAS NOTED ( F | G . 5 7 ) . IN THE RABBIT AND THE DOG, S I N G L E I N J E C T I O N S OF G . I . P . WERE GIVEN AT A DOSE OF 1 4 . 0 JUG/KG. T H I S DOSE WAS C A L C U L A T E D AS BEING EQUIMOLAR TO A DOSE OF 1 0 . 0 JUG/KG OF GLUCAGON, G . I . P . HAVING A MOLECULAR WEIGHT OF 5 , 1 0 5 AND GLUCAGON, 3 , 4 8 5 . THE R E S U L T S PRESENTED INDICATED THAT 1 0 . 0 / J G / K G OF GLUCAGON Y I E L D E D 7 0 - 1 0 0 $ I N C R E A S E S IN BLOOD SUGAR L E V E L S ( F l G . 3 8 , T A B L E S X X X AND X X X I ) . R E S U L T S THEREFORE INDICATE THAT IN DOSES UP TO 1 4 TIMES THOSE AT WHICH G . I . P . IS AN E F F E C T I V E INHIBITOR OF ACID S E C R E T I O N , IT Y I E L D S NO HYPERGLYCAEM I C NOR P A N C R E A T I C INHIBITORY E F F E C T S D E S P I T E STRUCTURAL S I M I L A R I T I E S TO GLUCAGON. E X P E R I M E N T S IN WHICH THE E F F E C T S OF G . I . P . ON P E P S I N OUTPUT WERE MONITORED HAD INVOLVED THE ST IMULAT ION OF H + - 1 4 9 -S E C R E T I ON AND MOTOR A C T I V I T Y . T H E A C T I O N OF S E C R E T I N AS A S T I M U L A N T OF P E P S I N S E C R E T I O N IS D I F F E R E N T TO I T S O T H E R G A S T R I C E F F E C T S , I . E . I N H I B I T I O N OF G A S T R I C H + S E C R E T I O N AND MOTOR A C T I V I T Y . S E C R E T I N T H U S P R O V I D E D A M E A N S OF S T I M U L A T I N G P E P S I N W I T H O U T S T I M U L A T I N G H + S E C R E T I O N OR G A S T R I C MOTOR A C T I V I T Y . T H E DOSE OF S E C R E T I N U S E D WAS SHOWN BY JO H N S O N AND GROSSMAN (1968) TO BE S U B M A X I M A L FOR P A N C R E A T I C S T I M U L A T I O N IN T H E D O G , B U T S T I L L P R O D U C E D P O T E N T I N H I B I T I O N OF G A S T R I N — S T I M U L A T E D H + S E C R E T I O N . G . I . P . IN A D O S E S U F F I C I E N T TO P R O D U C E 85$ I N H I B I T I O N OF P E P S I N O U T P U T S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E P R O D U C E D NO S I G N I F -I C A N T I N H I B I T I O N O F S E C R E T I N - S T I M U L A T E D P E P S I N L E V E L S ( T A B L E X X X I I ) . NO E X P L A N A T I O N FOR T H I S O B S E R V A T I O N WAS R E A D I L Y A V A I L A B L E , B U T S E V E R A L P O S S I B I L I T I E S E X I S T E O . I T WAS P O S S I B L E T H A T S E C R E T I N S T I M U L A T E D P E P S I N O U T P U T BY A D I F F E R E N T M E C H A N I S M THAN G A S T R I N OR H I S T A M I N E , WHICH WAS R E S I S T A N T TO T H E A C T I O N OF G . I . P . , OR SOME O T H E R A C T I O N ( S ) O F S E C R E T I N MAY H A V E B E E N I N T E R F E R I N G WITH T H E I N H I B I T O R Y A C T I O N OF G . I . P . ON P E P S I N S E C R E T I O N . TH E A D V A N T A G E S AND MORE S P E C I F I C A L L Y T H E N E C E S S I T Y OF H A V I N G P H Y S I O L O G I C A L G A S T R I C I N H I B I T O R Y M E C H A N I S M S HAVE B E E N O U T L I N E D . T E L E O L O G I C A L L Y , ONE C O U L D S P E C U L A T E AS TO WHAT AN E F F E C T I V E G A S T R I C I N H I B I T O R Y M E C H A N I S M S H O U L D E N T A I L . C L I N I C A L AND E X P E R I M E N T A L E V I D E N C E S U P P O R T E D T H E S T A T E M E N T T H A T T H E MUCOSA OF T H E S M A L L I N T E S T I N E IS MUCH L E S S R E S I S T A N T TO C H E M I C A L AND M E C H A N I C A L S T R E S S THAN T H A T OF T H E S T O M A C H . E V E N S O , G A S T R I C J U I C E OF LOW P H AND H I G H - 1 5 0 -C O N C E N T R A T I O N OF P E P S I N , I F IN C O N T A C T WITH T H E G A S T R I C MUCOSA FOR P R O L O N G E D P E R I O O S OF T I M E , CAN SE F A T A L L Y U L C E R -O G E N I C , E . G . T H E SHAY RAT P R E P A R A T I O N (SH A Y , SUN AND G R U E N S T E I N , 1954). IN A D D I T I O N , T H E R E IS T H E F A C T T H A T A N E U T R A L M E D I U M W I L L P R O V I D E O P T I M U M C O N D I T I O N S FOR D I G E S T I V E A C T I V I T Y IN T H E D U O D E N U M . T H U S AS A S A F E T Y F A C T O R AND TO C R E A T E O P T I M U M D I G E S T I V E C O N O I T I O N S , AN I N H I B I T O R Y M E C H A N I S M I D E A L L Y S H O U L D I N H I B I T H + AND P E P S I N S E C R E T I O N , D E C R E A S E T H E R A T E OF G A S T R I C E M P T Y I N G AND N E U T R A L I Z E H +. G . I . P . MAY C O N T R I B U T E TO T H E N E U T R A L I Z A T I O N OF H + IN T H E S M A L L BOWEL BY T H E S T I M U L A T I O N OF J E J U N A L S E C R E T I O N . A L T H O U G H G . I . P . HAS SO FAR B E E N SHOWN TO P O S S E S S NO G L U C A G 0 N - L I KE H Y P E R — G L Y C A E M I C OR P A N C R E A T I C E F F E C T S , IT HAS B E E N SHOWN BY GROSSMAN ( P E R S O N A L C O M M U N I C A T I O N ) TO S T I M U L A T E I N T E S T I N A L S E C R E T I O N IN DOGS P R E P A R E D WITH J E J U N A L L O O P S AT A D O S E OF 1 5 0 J U G/15 M I N . IN A P R E V I O U S S E R I E S OF E X P E R I M E N T S GROSSMAN ( P E R S O N A L C O M M U N I C A T I O N ) R E P O R T E D T H A T G L U C A G O N WAS SHOWN TO E X E R T T H E S A M E E F F E C T AT A S I M I L A R D O S E . T H E DOSE OF G . I . P . U S E D WAS A B O U T 2 0 T I M E S H I G H E R THAN T H A T R E Q U I R E D TO P R O O U C E 7 5 $ I N H I B I T I O N OF G A S T R I N P E N T A P E P T I D E - S T I M U L A T E D H + S E C R E T I O N FROM F U N D I C P O U C H E S IN D O G S , AND T H E D O S E OF G L U C A G O N FAR A B O V E L E V E L S T H A T W I L L P R O D U C E P H Y S I O L O G I C A L C H A N G E S IN B L O O D SUGAR L E V E L S . T H E S I G N I F I C A N C E OF T H I S MUST A W A I T F U R T H E R S T U D Y , P A R T I C U L A R L Y TO D E T E R M I N E I F G . I . P . IS E F F E C T I V E AS A S T I M U L A N T OF I N T E S T I N A L S E C R E T I O N IN D O S E S C O M P A R A B L E TO T H O S E WHICH P R O D U C E I N H I B I T I O N OF G A S T R I C S E C R E T I O N . - 1 5 1 -T H E G A S T R O I N T E S T I N A L H O R M O N E S S E C R E T I N AND C C K - P Z H A V E B E E N C L A S S I F I E D A S E N T E R O G A S T R O N E S B E C A U S E O F T H E I R A B I L I T Y TO I N H I B I T G A S T R I N - S T I M U L A T E D H + S E C R E T I O N . S E C R E T I N , T H E E N T E R O G A S T R O N E W H I C H I S P R O B A B L Y R E L E A S E D BY T H E P R E S E N C E O F H CL IN T H E D U O D E N U M ( J O H N S O N AND G R O S S M A N , 1 9 6 8 ) , I N H I B I T E D G A S T R I C A C I D S E C R E T I O N AND MOTOR A C T I V I T Y B U T S T I M U L A T E D P E P S I N O U T P U T ( N A K A J I M A AND M A G E E , 1 9 7 0 ) . S l N C E T H E S T R U C T U R E O F C C K - P Z HAS NOT B E E N C O M P L E T E L Y E L U C I D A T E D , T H E A C T I O N S O F T H E P U R E M A T E R I A L ON T H E S T O M A C H C A N N O T B E S T A T E D W I T H C O M P L E T E A S S U R A N C E . T H I S I S P A R T I C U L A R L Y T R U E W I T H R E S P E C T TO S T U D I E S I N V O L V I N G T H E U S E O F T H E 1 0 $ P U R E C C K - P Z , I N T H A T T H I S M A T E R I A L A C T E D AS T H E S T A R T I N G M A T E R I A L FOR T H E P U R I F I C A T I O N O F G . I . P . T H E L A S T P O I N T I S G I V E N C R E D E N C E BY T H E WORK OF S P I N G O L A AND G R O S S M A N ( 1 9 7 1 ) WHO F O U N D T H A T E N D O G E N O U S L Y R E L E A S E D C C K - P Z IN T H E DOG WOULD NOT I N H I B I T H E I D E N H A I N P O U C H S E C R E T I O N S T I M U L A T E D BY G A S T R I N P E N -T A P E P T I D E , A L T H O U G H T H E P A N C R E A T I C R E S P O N S E C H A R A C T E R I S T I C O F C C K - P Z WAS E L I C I T E D . T H E F A C T T H A T AN E X O G E N O U S P O R C I N E C C K - P Z P R E P A R A T I O N ( 2 5 0 I . D . U . / M G ) WOULD I N H I B I T G A S T R I N P E N T A P E P T I D E - S T I M U L A T E D H + S E C R E T I O N WAS A T T R I B U T E D BY T H E M TO BE D U E TO E I T H E R T H E P R E S E N C E O F G A S T R I C I N H I B I T O R Y P O L Y P E P T I D E OR A D I F F E R E N C E IN C A N I N E AS O P P O S E D TO P O R C I N E C C K - P Z IN T E R M S O F I T S A B I L I T Y TO I N H I B I T G A S T R I N P E N T A -P E P T I D E - S T I M UL A T E D H + S E C R E T I O N IN T H E DOG. IN A D D I T I O N TO NOT I N H I B I T I N G A L L O F T H E G A S T R I C P A R A M E T E R S M E N T I O N E D , S E C R E T I N AND C C K - P Z F A L L S H O R T OF C O M P L E T E L Y F U L F I L L I N G T H E R O L E O F E N T E R O G A S T R O N E BY NOT I N H I B I T I N G H I S T A M I N E -- 152 -S T I M U L A T E D G A S T R I C S E C R E T I ON ( J O H N S O N AND G R O S S M A N , 19^9)» A R E S P O N S E E L I C I T E D BY P L A C I N G F A T IN T H E D U O D E N U M . G . I . P . HAS B E E N SHOWN IN T H E S T U D I E S OF T H I S T H E S I S TO I N H I B I T G A S T R I C H , P E P S I N AND MOTOR A C T I V I T Y S T I M U L A T E D BY G A S T R I N P E N T A P E P T I D E , G A S T R I N , I N S U L I N H Y P0G L Y C A E M I A AND H I S T A M I N E . T H U S IT F U L F I L L S T H E P H Y S I O L O G I C A L R E Q U I R E -M E N T S D E S C R I B E D A B O V E FOR AN E F F I C I E N T G A S T R I C I N H I B I T O R Y M E C H A N I S M AND M I M I C S T H E A C T I O N S P R O D U C E D BY T H E P R E S E N C E OF F A T IN T H E D U O D E N U M . FOR T H E S E R E A S O N S IT IS F E L T T H A T G . I . P . IS AN E X C E L L E N T C A N D I D A T E FOR T H E HUMORAL A G E N T R E L E A S E D FROM T H E DUODENUM BY F A T AND P E R H A P S BY HYORO— C H L O R I C A C I D AND H Y P E R T O N I C S O L U T I O N S WHICH I N H I B I T S G A S T R I C S E C R E T I O N AND MOTOR A C T I V I T Y . GA S T R I N IS T H E ONLY ONE OF T H E C H E M I C A L L Y I D E N T I F I E D G A S T R O I N T E S T I N A L HORMONES FOR WHICH T H E R E IS A S P E C I F I C A S S A Y A L L O W I N G I T S D E T E C T I O N IN B L O O D ANO T I S S U E S . I F T H E D E T E C T I O N O F S E C R E T I O N AND C H A N G E S O F BLOOD L E V E L S OF A HUMORAL A G E N T A R E R E Q U I R E D AS F I N A L P R O O F OF HORMONAL S T A T U S , T H E N S E C R E T I N AND C C K - P Z F A L L S H O R T O F A C H I E V I N G T H I S S T A T U S . IN T H A T T H E S A M E C O N D I T I O N S H A V E B E E N M E T FOR G . I . P . AS HAVE B E E N F U L F I L L E D FOR S E C R E T I N AND C C K - P Z , N A M E L Y T H E M I M I C K I N G OF T H E E F F E C T S OF AN E N D O G E N O U S L Y R E L E A S E D HORMONE BY AN E X O G E N O U S M A T E R I A L , G . I . P . HAS M E T T H E S A M E R E Q U I R E M E N T S FOR HORMONAL S T A T U S AS S E C R E T I N AND C C K - P Z . H O W E V E R , T H E E S T A B L I S H M E N T O F G . I . P . AS A HORMONE P A R T I C I P A T I N G IN A P H Y S I O L O G I C A L G A S T R I C I N H I B I T O R Y M E C H A N I S M MUST A W A I T I T S D E T E C T I O N IN B L O O D AND T I S S U E S . B I B L I O G R A P H Y 1. A L L E Y , A. AND M A C K E N Z I E , D.W. D I S S O C I A T I O N OF T H E F U N C -T I O N A L P R O P E R T I E S OF G A S T R I C G L A N D S U N D E R T H E I N F L U E N C E O F F A T . AM . J . D I G . D I S . ANO NU T . 1_, 333 (1934-35). 2. AN D E R S S O N , S. IN H I B I T O R Y E F F E C T S OF A C I D IN A N T R U M -DUODENUM ON F A S T I N G G A S T R I C S E C R E T I O N IN P A V L O V AND H E I D E N H A I N P O U C H D O G S . A C T A . P H Y S I O L . S C A N D . 49, 42 (1960A) . — 3. AN D E R S S O N , S. IN H I B I T O R Y E F F E C T S OF H Y D R O C H L O R I C A C I D IN A N T R U M AND DUODENUM ON G A S T R I C S E C R E T O R Y R E S P O N S E S TO T E S T M E A L IN P A V L O V AND H E I D E N H A I N P O U C H D O G S . A C T A . P H Y S I O L . S C A N D . 49, 231 (1960B) . 4. AN D E R S S O N , S. IN H I B I T O R Y E F F E C T S OF H Y D R O C H L O R I C A C I D IN A N T R U M AND DUOOENUM ON H I S T A M I N E S T I M U L A T E D G A S T R I C S E C R E T I O N IN PA V L O V AND H E I D E N H A I N P O U C H D O G S . A C T A . P H Y S I O L . S C A N D . 50, 186 (1960c). 5. AN D E R S S O N , S. AND GR O S S M A N , M . I . E F F E C T O F D E N E R V A T I O N AND S U B S E Q U E N T R E S E C T I O N OF A N T R A L P O U C H E S ON S E C R E T I O N FROM H E I D E N H A I N P O U C H E S IN R E S P O N S E TO G A S T R I N AND H I S T A M I N E . GA S T R O E N T E R O L O G Y 5__, 4 (1965). 6. AN D E R S S O N , S. , N I L S S O N , G. AND UV NHS , B. IN H I B I T I O N OF G A S T R I C S E C R E T I O N BY A C I D IN P R O X I M A L AND D I S T A L D U O D E N A L P O U C H E S . A C T A . PH Y S I O L . S C A N D . 6j>, 191 (1965). 7. AN S O N , M.L. AND M I R S K Y , A.E. TH E E S T I M A T I O N O F P E P S I N FROM H E M O G L O B I N . J . G E N . P H Y S I O L . 1j5, 59 (1932). 8. B A Y L I S S , W.M. AND S T A R L I N G , E.N. TH E M E C H A N I S M O F P A N C R E A T I C S E C R E T I O N . J . P H Y S I O L . 28, 325 (1902). 9. B E A U M O N T , W. E X P E R I M E N T S AND O B S E R V A T I O N S ON T H E GA S T R I C  J U I C E AND T H E PH Y S I O L O G Y O F D I G E S T I O N . ( P L A T T S B U R G , NEW YO R K , 1833). 10. B I B L E R , D.D., H A R K I N S , H.N. AND N Y H U S , L.M. IN H I B I T I O N OF E X O G E N O U S G A S T R I N S T I M U L A T E D S E C R E T I O N BY F A T IN T H E DUOD,ENUM. R E V . S U R G . 22, 455 (1965). 11. B L A I R , E . L . , H A R P E R , A.A., P E A R S O N , J.A. AND R E E D , J.D. S T I M U L A T I O N OF P E P S I N S E C R E T I O N BY E X T R A C T S OF I N T E S T I N A L M U C O S A . J . P H Y S I O L . 175, 60 (1964). 12. BO D A N S K Y , M., O N D E T T I , M.A. AND L E V I N E , S.D. S Y N T H E S I S OF A H E P T A C O S A P E P T I D E A M I D E WITH T H E HORMONAL A C T I V I T Y OF S E C R E T I N . CH E M . IN D U S T R . 42, 1757 (1966). - 153 -- 1 5 4 -1 3 . BROWN, J.C. A G A S T R I C INHIBITORY P O L Y P E P T I D E . I. THE A M I N O ACID COMPOSITION AND THE T R Y P T I C P E P T I D E S . C A N . J . B I O C H E M . 4 9 , 2 5 5 ( 1 9 7 1 ) . 1 4 . BROWN, J.C. AND DRYBURGH, J . R . A GASTRIC INHIBITORY P O L Y P E P T I D E . I I . TH E COMPLETE AMINO ACID S E Q U E N C E . C A N . J . B I O C H E M . IN P R E S S . 1 5 . BROWN, J.C. AND MA G E E , D . F . INHIBITORY ACTION OF CHOLECYSTOK I N I N ON ACID S E C R E T I O N FROM HEIDENHAIN POUCHES INDUCED BY ENDOGENOUS G A S T R I N . GUT 8 , 2 9 ( 1 9 6 7 ) . 1 6 . BROWN, J . C , MU T T , V . AND P E D E R S O N , R . A . FURTHER P U R I F I -CATION OF A P O L Y P E P T I D E DEMONSTRATING ENTEROGASTRONE A C T I V I T Y . J . P H Y S I O L . 2 0 9 , 5 7 ( 1 9 7 0 ) . 1 7 . BROWN, J.C. AND P E D E R S O N , R . A . A MULT IPARAMETER STUDY ON THE ACT ION OF P R E P A R A T I O N S CONTAINING C H O L E C Y S T O K I N I N -PANCREOZYM I N. S C A N D . J . G A S T R O E N T . j), 5 3 7 ( 1 9 7 0 ) . 1 8 . BROWN, J . C , P E D E R S O N , R . A . , J O R P E S , E . AND MU T T , V . P R E P A R A T I O N OF HIGHLY A C T I V E ENTEROGASTRONE . C A N . J . P H Y S I O L . PH A R M A C . 4 7 , 1 1 3 ( 1 9 6 9 ) . 1 9 . CANNON, W.B. THE MECHANICAL FACTORS OF D I G E S T I O N . (LO N G M A N S , GREEN & Co., NEW YO R K , 1 9 1 1 ) . "~ 2 0 . C O D E , C . F . AND WA T K I N S O N , G . IMPORTANCE OF VAGAL INNER-VATION IN THE REGULATORY E F F E C T OF ACID IN THE DUODENUM ON G A S T R I C S E C R E T I O N OF A C I D . J . P H Y S I O L . 1 3 0 » 2 3 3 ( 1 9 5 5 ) . 2 1 . DA Y , J . J . AND KOMAROV, S . A . GLUCOSE AND GASTRIC S E C R E -T I O N . AM E R . J . D I G . D I S . 6 , 169 ( 1 9 3 9 ) . 2 2 . D A Y , J . J . ANO WE B S T E R , D . R . THE AUTO REGULATION OF THE G A S T R I C S E C R E T I O N . AMER. J . D I G E S T . D l S . NUTR. 2 , 5 2 7 ( 1 9 3 5 ) . 2 3 . DUBOWSKI , K . M . AN 0 - T O L U I D I N E METHOD FOR B O D Y - F L U I D GLUCOSE D E T E R M I N A T I O N . J . C L I N . CHEM. 8 , 2 1 5 ( 1 9 6 2 ) . 2 4 . D Y C K , W . P . , R U D I C K , J . , HO E X T E R , B . AND J A N O W I T Z , H . D . IN F L U E N C E OF GLUCAGON ON P A N C R E A T I C EXOCRINE S E C R E T I O N . GASTROENTEROLOGY 5.6, 5 3 1 ( 1 9 6 9 ) . 2 5 . EWALD, C A . AND BO A S , J . VIRCHOWS A R C H . 1 0 4 , 2 7 1 ( 1 8 8 6 ) . C I T E D BY GREGORY, R . A . SECRETORY MECHANISMS OF THE  G A S T R O - I N T E S T I N A L T R A C T F 1 1 8 (EDWARD ARNOLD L T D . , NEW Y O R K , 1 9 6 2 ) . 2 6 . F A R R E L L , J . E . AND IVY , A . C S T U D I E S ON THE MOT IL ITY OF THE TRANSPLANTED G A S T R I C POUCH. AMER. J . P H Y S I O L . 7 6 , 2 2 7 ( 1 9 2 6 ) . - 1 5 5 -2 7 . F E N G , T . P . , Hou, H .C. AND L I M , R . K . S . ON THE MECHANISM OF THE INH IB IT ION OF GASTRIC SECRET ION BY F A T . CHINESE J . P H Y S I O L . 3 , 371 ( 1 9 2 9 ) . 2 8 . G I L L E S P I E , I . E . AND GROSSMAN, M . I . INHIBITORY E F F E C T OF S E C R E T I N AND C H O L E C Y S T0K I N I N ON HEIDENHAIN POUCH RESPONSES TO GASTRIN EXTRACT AND H I S T A M I N E . G U T J ) , 342 ( 1 9 - 4 ) . 2 9 . G R A Y , J . S . , B R A O L E Y , W . B . ANO IVY , A . C . ON THE P R E P A R -AT ION AND B I O L O G I C A L ASSAY OF ENTEROGASTRONE. A M . J . P H Y S I O L . J J _ S , 463 ( 1 9 3 7 ) . 3 0 . GR E E N G A R D , H . A . , A T K I N S O N , A . J . , GROSSMAN, M . I . AND I V Y , A . D . T H E E F F E C T I V E N E S S OF P A R E N T E R A L L Y ADMINISTERED ENTEROGASTRONE IN THE P R O P H Y L A X I S OF RECURRENCES OF E X P E R I M E N T A L AND C L I N I C A L P E P T I C U L C E R . GASTROENTEROLOGY 7 , 6 2 5 ( 1 9 4 6 ) . 3 1 . G R E E N L E E , H . B . , L O N G H I , E . H . , GUERRERO, J . D . , N E L S O N , T . S . , E L - B E D R I , A . L . , AND D R A G S T E D T , L . R . INHIBITORY E F F E C T OF P A N C R E A T I C S E C R E T I N ON GASTRIC S E C R E T I O N . A M . J . P H Y S I O L . J _ 9 0 , 396 ( 1 9 5 7 ) . 3 2 . GREGORY, R . A . ENTEROGASTRONE - A R E A P P R A I S A L OF THE P R O B L E M . IN GA S T R I C S E C R E T I O N , 4 7 7 , S H N I T K A , T . K . , G I L B E R T , J . A . AND H A R R I S O N , R . C , E D . (PERGAMON P R E S S , NEW YO R K , 1 9 6 7 ) . 3 3 . GREGORY, R . A . AND T R A C Y , H . J . CO N S T I T U T I O N AND P R O P E R -T I E S OF TWO GASTRINS EXTRACTED FROM HOG ANTRAL MUCOSA. GUT 5 , 1 0 3 ( 1 9 6 4 ) . 3 4 . G R I F F I T H S , W . J . THE DUODENUM AND THE AUTOMATIC CONTROL OF GASTRIC A C I D I T Y . J . P H Y S I O L . 8 7 , 34 ( 1 9 3 6 ) . 3 5 . GROSSMAN, M . I . GA S T R I N AND ITS A C T I V I T I E S . NATURE 2 2 8 , 1 1 4 7 ( 1 9 7 0 ) . 3 6 . HA L V O R S O N , H . C , M I D D L E T O N , M . D . , B I B L E R , D . D . , H A R K I N S , H .N. AND NY H U S , L . M . INFLUENCE OF THE VAGUS NERVE ON THE INHIBITORY E F F E C T OF FAT IN THE OUODENUM. A M . J . D I G . D I S . 1_1_, 911 ( 1 9 6 6 ) . 3 7 . HA R P E R , A . A . AND R A P E R , H .S. PA N C R E O Z Y M I N , A ST IMULANT OF THE S E C R E T I O N OF P A N C R E A T I C ENZYMES IN E X T R A C T S OF THE SMALL I N T E S T I N E . J . P H Y S I O L . 1 0 2 , 115 ( 1 9 4 3 ) . 3 8 . H I R S C H O W I T Z , B . l . THE S E C R E T I O N OF P E P S I N O G E N . HANDBOOK  OF P H Y S I O L O G Y , AL IMENTARY C A N A L , V O L . I I , CHAPTER 50 (AM E R I C A N P H Y S I O L O G I C A L S O C I E T Y HANDBOOK S E R I E S , WASHINGTON D . C , 1 9 6 7 ) . 3 9 . H I R S C H O W I T Z , B . l . GA S T R I N I, PENTAGASTRIN AND HISTAMINE IN THE F I S T U L A DOG. F E D . P R O C 2 7 , 1 3 1 8 ( 1 9 6 8 ) . - 1 5 6 -40. H lRSCHOWITZ , B . I . AND S A C H S , G. ATROPINE INHIBIT ION OF I N S U L I N - , HISTAMINE— AND P E N T A G A S T R I N - S T I M U L A T E D GASTRIC ELECTROLYTE AND PEPSIN SECRETION IN THE DOG. GASTRO-ENTEROLOGY 56, 693 (1969). 41. HO N G , S.S., M A G E E , D.F. AND CR E W D S O N , J . F . TH E P H Y S I O -L O G I C A L REGULATION OF GALL BLADDER EVACUAT ION. GASTRO-ENTEROLOGY 3 0 , 6 2 5 ( 1 9 5 6 ) . 4 2 . I V Y , A.C. PH Y S I O L O G Y OF T H E G A L L B L A D D E R . P H Y S I O L . R E V . U , 1 (1934). 43. I V Y , A.C. AND O L D B E R G , E. A HORMONE M E C H A N I S M FOR G A L L BLADDER CONTRACTION AND E V A C U A T I O N . AMER. J . P H Y S I O L . 8 6 , 5 9 9 ( 1 9 2 8 ) . 4 4 . J A C O B Y , H . I . AND M A R S H A L L , C H . GA S T R I C M O T O R - S T I M U L A -T I N G A C T I V I T Y OF GASTRIN TE TRAPEPT I DE IN OOGS. G A S T R O -ENTEROLOGY .56, 8 0 ( 1 9 6 9 ) . 4 5 . J O H N S T O N , D. AND D U T H I E , H.L. E F F E C T O F F A T IN T H E DUODENUM ON GASTRIC ACID SECRETION BEFORE AND AFTER VAGOTOMY IN MAN. SCAND. J . GASTROENT. 4, 561 ( 1 9 6 9 ) . 46. JO H N S O N , L . P . , BR O W N , J . C . AND M A G E E , D.F. E F F E C T OF SECRET IN AND C H O L E C Y S T0K I N I N - P A N C R E0Z Y M I N EXTRACTS ON GASTRIC MOTIL ITY IN MAN. GUT 7, 52 ( 1 9 6 6 ) . 47. J O H N S O N , L . P . AND M A G E E , D.R. C H O L E C Y S T O K I N I N - P A N C R E O -ZYMIN EXTRACTS AND GASTRIC MOTOR I N H I B I T I O N . SURG. G Y N E C . O B S T E T . V21_, 5 5 7 ( 1 9 6 5 ) . 4 8 . J O H N S O N , L.R. AND GR O S S M A N , M. I . S E C R E T I N : T H E E N T E R O -G A S T R O N E R E L E A S E D BY A C I D IN T H E D U O D E N U M . AM E R . J . P H Y S I O L . 21_5, 8 8 5 ( 1 9 6 8 ) . 49. J O H N S O N , L.R. AND GR O S S M A N , M . I . E F F E C T S OF F A T , SECRET IN AND CHOLECYSTOKININ ON HI STAM I N E - S T I M U L A T E D G A S T R I C S E C R E T I O N . AM E R . J . P H Y S I O L . 2 1 6 , 1 1 7 6 (I969). 5 0 . J O H N S O N , L.R. AND GR O S S M A N , M . I . A N A L Y S I S OF I N H I B I T I O N OF ACID SECRETION BY CHOLECYST0KIN IN IN DOGS. AMER. J . P H Y S I O L . 21J3, 5 5 0 ( 1 9 7 0 ) . 5 1 . J O R P E S , J . E . TH E I S O L A T I O N AND C H E M I S T R Y OF S E C R E T I N AND CHOLECYSTOK I N I N. GA S T R 0 E N TE R 0 L 0 G Y _55 , 1 5 7 ( 1 9 6 8 ) . 5 2 . J O R P E S , J . E . AND MU T T , V. G A S T R O I N T E S T I N A L H O R M O N E S , S E C R E T I N AND C H O L E C Y S T 0 K I N I N - P A N C R E 0 Z Y M I N . A N N . I N T E R N . ME D . 5 5 , 3 9 5 ( 1 9 6 1 ) . 5 3 . J O R P E S , J . E . AND MU T T , V. CH O L E C Y S T O K I N I N AND P A N C R E O -Z Y M I N , ONE SINGLE HORMONE? A C T A . P H Y S I O L . SCAND. 6 6 , 19 6 ( 1 9 6 6 ) . - 157 -J O R P E S , J.E., M U T T , V., MA G N U S S O N , S . ANO S T E E L E , B.B. AMINO A C I D C O M P O S I T I O N AND T E R M I N A L A M I N O A C I D S E Q U E N C E O F P O R C I N E S E C R E T I N . B L O C H E M . B L O P H Y S . R E S . C O M M . 9 , 275 (1962) . J O R P E S , J.E., M U T T , V. AND TO C Z K O , K. FU R T H E R P U R I F I -C A T I O N OF C H O L E C Y S T O K l N I N AND P A N C R E O Z Y M I N . A C T A . C H E M . S C A N D . J_8, 2408 (1964). K A L K , H. AND M E Y E R , P.F. B L U T Z U C K E R S P I E G E L UND M A G E N -S E K R E T 1 O N . Z. K L I N . M E D . J_20, 693 (1932) . K A S A N S K I , P. J A H R E S B E R . FO R T S C H R . T I E R C H E M . J53, 552 (1903) . C I T E O IN I V Y , A.D. AND GR A Y , J . S . E N T E R O G A S T R O N E , COLO S P R I N G HARBOR S Y M P . QU A N T . B I O L . 5, 405 (1937) . K E N N E D Y , J.A. AND H A L L E N B E C K , G.A. TH E P A N C R E A S ANO G A S T R I C S E C R E T I O N . F A I L U R E OF P A N C R E A T E C T O M Y TO P R E V E N T I N H I B I T I O N OF G A S T R I C S E C R E T I O N BY S E C R E T I N . GUT 4 , 58 (1963) . K O N T U R E K , S . J . , G A 8 R Y S , B. ANO D U B I E L , J . E F F E C T OF E X O G E N O U S AND E N D O G E N O U S S E C R E T I N ON G A S T R I C ANO P A N C R E A T I C S E C R E T I O N IN C A T S . A M E R . J . P H Y S I O L . 217, 1110 (1969) . K O S A K A , T. AND L l M , R . K . S . ON T H E M E C H A N I S M O F T H E I N H I B I T I O N OF G A S T R I C S E C R E T I O N BY F A T . T H E R O L E OF B I L E AND C Y S T O K | N I N . C H I N E S E J . P H Y S I O L . 4 , 213 0 9 3 0 A ) . K O S A K A , T. AND L l M , R . K . S . D E M O N S T R A T I O N OF T H E HUMORAL A G E N T IN F A T I N H I B I T I O N OF G A S T R I C S E C R E T I O N . P R O C . Soc. E X P . B I O L . M E D . 2 7 , 890 (1930s) . KO S A K A , T., L I M , R . K . S . , L I N G , S.M. AND L I U , A.C. ON T H E M E C H A N I S M OF T H E I N H I B I T I O N OF G A S T R I C S E C R E T I O N BY F A T . A G A S T R I C I N H I B I T O R Y A G E N T O B T A I N E D FROM T H E I N T E S T I N A L M U C O S A . CH I N E S E J . P H Y S I O L . 6, 107 (1932) . L E C O N T E , P. F O N C T I O N S G A S T R 0 - I N T E S T I N A L E S . LA C E L L U L E 17, 307 (1900) . C I T E D BY B A B K I N , B.P. IN TH E S E C R E T O R Y  M E C H A N I S M S OF T H E D I G E S T I V E G L A N D S , 2ND E D . , 651 ( P A U L B. HO E B E R I N C . , NEW YO R K , 1950) . L I M , R . K . S . , Loo, C T . AND L I U , A . C O B S E R V A T I O N S ON T H E S E C R E T I O N OF T H E T R A N S P L A N T E D S T O M A C H . C H I N E S E J . P H Y S I O L . 1_, 51 (1927) . L I N , T.M. AND S P R A Y , G.F. E F F E C T OF G L U C A G O N ON G A S T R I C HCL S E C R E T I O N ( A B S T R . ) . G A S T R O E N T E R O L O G Y ^ , 1254 (1968) . L I N T W A R E V , I . B I O C H E M . C E N T R . 1_, 96 (1903) . C I T E D IN I V Y , A.D. AND GR A Y , J . S . EN T E R O G A S T R O N E , COLD S P R I N G HARBOR S Y M P . QU A N T . B I O L . 5, 405 (1937) . - 1 5 8 -6 6 A . L J U N G B E R G , S . B l O L O G I S K S T Y R K E B E S T A M N I N G AV C H O L E C Y S T O -K I N I N . S V E N S K . FARM. T I D S K R . 6 8 , 351 ( 1 9 6 4 ) . 67. L O B A S O V , 1 . 0 . T H E S I S . S T . P E T E R S B U R G ( 1 8 9 6 ) . C I T E D B Y B A B K I N , B . P . I N T H E S E C R E T O R Y M E C H A N I S M S O F T H E O I G E S T I V E G L A N D S , 2ND E D . , 5 3 6 (PAUL B. H O E B E R INC., NEW YORK, 1 9 5 0 ) . 6 8 . L U C I E N , H . W . , ITOH, Z . , SUN, D . C . H . , M E Y E R , J . , C A R L T O N , N. AND S C H A L L Y , A . V . T H E P U R I F I C A T I O N O F E N T E R O G A S T R O N E FROM P O R C I N E G U T . A R C H . B I O C H E M . B I O P H Y S . 1 3 4 , 1 8 0 (1969). 69. L U C I E N , H . W . , ITOH, Z. AND S C H A L L Y , A . V . I N H I B I T O R Y E F F E C T S O F A P U R I F I E D E N T E R O G A S T R O N E , S E C R E T I N , AND C H O L E C Y S T O K I N I N ON H I S T A M I N E — S T I M U L A T E D G A S T R I C A C I D S E C R E T I O N . G A S T R O E N T E R O L O G Y 59, 7 0 7 ( 1 9 7 0 ) . 7 0 . M A G E E , O . F . ANO NAKAMURA, M . A C T I O N O F P A N C R E O Z Y M I N P R E -P A R A T I O N S ON G A S T R I C S E C R E T I O N . N A T U R E 2 1 2 , 1 4 8 7 ( 1 9 6 6 ) . 7 1 . M A R B A I X , 0 . L E P A S S A G E P Y L O R I Q U E . LA C E L L U L E 1 4 , 2 4 9 ( 1 8 9 8 ) . — 7 2 . M E N G U Y , R. S T U D I E S ON T H E R O L E O F P A N C R E A T I C AND B I L I A R Y S E C R E T I O N S I N T H E M E C H A N I S M O F G A S T R I C I N H I B I T I O N BY F A T . S U R G E R Y 4 8 , 1 9 5 ( 1 9 6 0 ) . 7 3 . M O R R I S , T . Q . , S A R O I , G . AND B R A D L E Y , S . E . C H A R A C T E R O F G L U C A G O N - I N D U C E D C H O L E R E S I S . F E D . P R O C . 2 6 , 7 7 4 ( 1 9 6 7 ) . 7 4 . M U R A T , J . E . AND W H I T E , T . T . S T I M U L A T I O N O F G A S T R I C S E C R E T I O N BY C O M M E R C I A L C H O L E C Y S T O K I N I N E X T R A C T S . P R O C . S O C . E X P T L . B I O L . M E D . 1_23, 5 9 3 ( 1 9 6 6 ) . 7 5 . M U T T , V . AND J O R P E S , J . E . S E C R E T I N I S O L A T I O N A N D D E T E R -M I N A T I O N O F S T R U C T U R E ( A B S T R . ) . P R O C E E D I N G S O F T H E F O U R T H I N T E R N A T I O N A L S Y M P O S I U M ON T H E C H E M I S T R Y O F N A T U R A L P R O O U C T S . S T O C K H O L M , SWEOEN ( 1 9 6 6 ) . 7 6 . M U T T , V . AND J O R P E S , J . E . S T R U C T U R E O F P O R C I N E C H O L E -C Y S T O K I N I N — P A N C R E O Z Y M I N . E U R O P E A N J . B l O C H E M . 6 , 1 5 6 ( 1 9 6 8 ) . 7 7 . N A K A J I M A , S . AND M A G E E , D . R . I N F L U E N C E S O F D U O D E N A L A C I D I F I C A T I O N ON A C I D ANO P E P S I N S E C R E T I O N O F T H E S T O M A C H I N D O G S . AMER. J . P H Y S I O L . __J_8, 5 4 5 ( 1 9 7 0 ) . 7 8 . NAKAMURA, M . , N A K A J I M A , S . AND M A G E E , D . F . A C T I O N O F P A N C R E O Z Y M I N P R E P A R A T I O N S ON G A S T R I C A C I D S E C R E T I O N . GUT 9 , 4 0 5 ( 1 9 6 8 ) . 79* OKAOA, S . , K U R A M O C H I , I., T S U K A H A R A , T . AND O O I N O U E , T . P A N C R E A T I C F U N C T I O N . IV . T H E H U M O N E U R A L R E G U L A T I O N O F T H E G A S T R I C , P A N C R E A T I C AND B I L I A R Y S E C R E T I O N S . A R C H . I N T E R N . M E D . 4 3 » 4 4 6 ( 1 9 2 9 ) . - 1 5 9 -8 0 . 81 . 8 2 . 8 3 . 8 4 . 8 5 . 8 6 . 8 7 . 8 8 . 8 9 . 9 0 . 9 1 . P A V L O V , I . P . T R A N S L A T E D B Y W . H . 1 9 1 0 ) . T H E WORK O F T H E D I G E S T I V E G L A N D S , 2 N D E D , T H O M P S O N ( C H A R L E S G R I F F I N , L O N D O N , P I N C U S , I . J . , T H O M A S , J . E . A N D R E H F U S S , M . E . A S T U D Y O F G A S T R I C S E C R E T I O N A S I N F L U E N C E D B Y C H A N G E S IN D U O D E N A L A C I D I T Y . P R O C . S o c . E x p . B l O L . N . Y . 51, 3 6 7 ( 1 9 4 2 ) . P R E S H A W , R . M . , C O O K , A . R . A N D G R O S S M A N , M . I . Q U A N T I T A -T I V E A S P E C T S O F R E S P O N S E O F C A N I N E P A N C R E A S T O D U O D E N A L A C I D I F I C A T I O N . A M E R . J . P H Y S I O L . 2 1 0 , 6 2 9 ( 1 9 6 6 ) . P R E S H A W , R . M . A N D G R O S S M A N , M . I . C O M P A R I S O N O F S U B C U -T A N E O U S A N D I N T R A V E N O U S A D M I N I S T R A T I O N O F P A N C R E A T I C S T I M U L A N T S . A M E R . J . P H Y S I O L . 2 0 9 , 8 0 3 ( 1 9 6 5 ) . Q U I G L E Y , J . P . A N D H A L L A R A N , W . R . T H E I N D E P E N D E N C E O F S P O N T A N E O U S G A S T R O - I N T E S T I N A L M O T I L I T Y A N D B L O O D S U G A R L E V E L S . A M E R . J . P H Y S I O L . 1 0 0 , 1 0 2 ( 1 9 3 2 ) . Q U I G L E Y , J . P . A N D M E S C H A N , I. T H E R O L E O F T H E V A G U S IN T H E R E G U L A T I O N O F T H E P Y L O R I C S P H I N C T E R A N D A D J A C E N T P O R T I O N S O F T H E G U T , W I T H S P E C I A L R E F E R E N C E T O T H E P R O C E S S O F G A S T R I C E V A C U A T I O N . A M E R . J . P H Y S I O L . 1 2 3 , 166 ( 1 9 3 8 ) . Q U I G L E Y , J . P . A N D P H E L P S , K . R . T H E M E C H A N I S M M O T O R I N H I B I T I O N F R O M I N G E S T E D C A R B O H Y D R A T E . P H Y S I O L . 1 0 9 , 1 3 3 ( 1 9 3 4 ) . O F G A S T R I C A M E R . J . Q U I G L E Y , J . P . , Z E T T L E M A N , H . J . A N D I V Y , A . D . A N A L Y S I S O F T H E F A C T O R S I N V O L V E D I N G A S T R I C M O T O R I N H I B I T I O N B Y F A T S . A M E R . J . P H Y S I O L . J _ 0 8 , 6 4 3 ( 1 9 3 4 ) . S A M O L S , E . , M A R R I , G . A N D M A R K S , V . P R O M O T I O N O F I N S U L I N S E C R E T I O N B Y G L U C A G O N . L A N C E T 2, 4 1 5 0 9 6 5 ) . S E R D I U K O V , A . S . , C I T E D IN P A V L O V , . . . T R A N S L A T E D D I G E S T I V E G L A N D S , 2 N D E D . T R A  ( C H A R L E S G R I F F I N , L O N D O N , 1 9 1 0 ) . I . P . T H E WORK O F T H E B Y W . H . T H O M P S O N S H A Y , H . A N D G E R S H O N - C O H E N , J . E X P E R I M E N T A L S T U D I E S IN G A S T R I C P H Y S I O L O G Y IN M A N . I I . A S T U D Y O F P Y L O R I C C O N T R O L . T H E R O L E S O F A C I D A N O A L K A L I . S U R G . G Y N E C . O B S T E T . 5 8 , 9 3 5 ( 1 9 3 4 ) . S H A Y , H . , G E R S H O N - C O H E N , J . A N D P E L S , S . S . T H E R O L E T H E U P P E R S M A L L I N T E S T I N E IN T H E C O N T R O L O F G A S T R I C S E C R E T I O N , T H E E F F E C T O F N E U T R A L F A T , F A T T Y A C I D A N D S O A P S : T H E P H A S E O F G A S T R I C S E C R E T I O N I N F L U E N C E D A N O T H E R E L A T I V E I M P O R T A N C E O F T H E P S Y C H I C A N D C H E M I C A L P H A S E S . A N N . I N T E R N . M E D . 1 3 , 2 9 4 ( 1 9 3 9 ) . O F - 160 -92. S H A Y , H., G E R S H O N - C O H E N , J . , F E L S , S.S. AND S I P L E T , H. CO N C E R N I N G T H E I N F L U E N C E OF G L U C O S E ON T H E R E S P O N S E OF T H E HUMAN S T O M A C H TO T E S T M E A L S . A M E R . J . D L G . D L S . 9, 363 ( 1 9 4 2 ) . 9 3 . SH A Y , H. , S U N , D.C.H. AND G R U E N S T E I N , M.A. Q U A N T I T A -T I V E METHOD FOR M E A S U R I N G S P O N T A N E O U S G A S T R I C S E C R E T I O N IN T H E R A T . G A S T R O E N T E R O L O G Y 2 6 , 906 ( 1 9 5 4 ) . 94. S I R C U S , W. S T U D I E S ON T H E M E C H A N I S M S IN T H E DUODENUM I N H I B I T I N G G A S T R I C S E C R E T I O N . Q U A R T . J . E X P . P H Y S I O L . 4 3 , 114 ( 1 9 5 8 ) . 9 5 . SO K O L O V , A.P. T H E S I S . S T . P E T E R S B U R G ( 1 9 0 4 ) . C I T E D BY B A B K I N , B.P. IN TH E S E C R E T O R Y ME C H A N I S M S OF T H E  D I G E S T I V E G L A N D S , 2ND E D . , 642 (PA U L B. HO E B E R I N C . , NEW YO R K , 1 9 5 0 ) . 9 6 . S P I N G O L A , L . J . AND GR O S S M A N , M . I . F A I L U R E O F E N D O G E N O U S C H O L E C Y S T O K I N I N TO I N H I B I T P E N T A G A S T R I N - S T I M U L A T E D A C I D S E C R E T I O N ( A B S T R . ) . G A S T R O E N T E R O L O G Y , IN P R E S S . 9 7 . S T E N I N G , G.F., JO H N S O N , L.R. AND GR O S S M A N , M . I . E F F E C T OF S E C R E T I N ON A C I D AND P E P S I N S E C R E T I O N IN C A T ANO D O G . GA S T R O E N T E R O L O G Y _5_6, 468 ( 1 9 6 9 A ) . 9 8 . S T E N I N G , G.F., JO H N S O N , L.R. AND GR O S S M A N , M . I . E F F E C T O F C H O L E C Y S T O K I N I N AND C A E R U L E I N ON G A S T R I N - AND H I S T A M I N E - E V O K E D G A S T R I C S E C R E T I O N . G A S T R O E N T E R O L O G Y 57, 44 ( 1 9 6 9 B ) . 9 9 . TH O M A S , J . E . TH E I N T E S T I N A L PH T H R E S H O L D FOR R E G U L A T I O N OF G A S T R I C E M P T Y I N G . F E D . P R O C . j5, 214 ( 1 9 4 7 ) . 1 0 0 . TH O M A S , J . E . , C R I D E R , J.O. AND MO G A N , J . C . A S T U D Y OF R E F L E X E S I N V O L V I N G T H E P Y L O R I C S P H I N C T E R AND ANTRUM AND T H E I R R O L E IN G A S T R I C E V A C U A T I O N . A M E R . J . P H Y S I O L . 1 0 8 , 683 ( 1 9 3 4 ) . 1 0 1 . TH O M A S , J . E . AND MO G A N , C . J . TH E E N T E R O G A S T R I C R E F L E X . P R O C . S O C . E X P . B I O L . N.Y. 2 8 , 968 (1931 ) . 102. T R A C Y , H . J . AND GR E G O R Y , R.A. PH Y S I O L O G I C A L P R O P E R T I E S OF A S E R I E S OF S Y N T H E T I C P E P T I D E S S T R U C T U R A L L Y R E L A T E D TO GA S T R I N I . NA T U R E 2 0 4 , 935 ( 1 9 6 4 ) . 1 0 3 . V A G N E , M., S T E N I N G , G.F., BR O O K S , F.P. AND GR O S S M A N , M . I . S Y N T H E T I C S E C R E T I N : C O M P A R I S O N WITH N A T U R A L S E C R E T I N FOR P O T E N C Y AND S P E C T R U M OF P H Y S I O L O G I C A L A C T I O N S . GA S T R O E N T E R O L O G Y j j 5 , 2 6 0 ( 1 9 6 8 ) . 1 0 4 . WA D D E L L , W.R. AND WANG, C C . TH E E F F E C T OF V A G O T O M Y ON G A S T R I C E V A C U A T I O N OF H I G H F A T M E A L S . J . A P P . P H Y S I O L . 5, 705 ( 1 9 5 3 ) . - 1 6 1 -1 0 5 . W A L A W S K I , J . L E S B I O O I A L Y S A T E S I N T E S T I N A U X A G E N T S I N H I B I T E U R S DE LA S E C R E T I O N G A S T R I Q U E . C R . S O C . BlOL. P A R I S 9 9 , 1 1 6 9 ( 1 9 2 8 ) . C I T E D BY B A B K I N , B.P. IN TH E S E C R E T O R Y M E C H A N I S M S OF T H E D I G E S T I V E G L A N D S , 2ND E D . , 6 3 5 ( P A U L B . HO E B E R I N C . , NEW YO R K , 1 9 5 0 ) . 1 0 6 . W A N G , C C AND GR O S S M A N , M . I . PH Y S I O L O G I C A L D E T E R -M I N A T I O N OF T H E R E L E A S E OF S E C R E T I N AND P A N C R E O Z Y M I N FROM T H E I N T E S T I N E OF DOGS WITH T R A N S P L A N T E D P A N C R E A S . AM E R . J . P H Y S I O L . __54, 5 2 7 ( 1 9 5 1 ) . 1 0 7 . W A Y , L . W . E F F E C T OF S E C R E T I N ON G A S T R I C A C I D S E C R E T I O N IN R E S P O N S E TO C H O L I N E R G I C S T I M U L I . GA S T R O E N T E R O L O G Y 5 9 , 5 1 0 ( 1 9 7 0 ) . 1 0 8 . W I R S C H U B S K I , I. J A H R E S B E R . FO R T S C H R . T I E R C H E M . 3 0 , 374 ( 1 9 0 0 ) . C I T E D IN I V Y , A.D. AND GR A Y , J . S . E N T E R O -G A S T R O N E , COLD S P R I N G HARBOR S Y M P . QU A N T . B I O L . 5, 4 0 5 ( 1 9 3 7 ) . 1 0 9 . WOODWARD, E . R . , L Y O N , E.S., LA N D O R , J . AND DR A G S T E D T , L . R . TH E P H Y S I O L O G Y OF T H E G A S T R I C A N T R U M . G A S T R O -E N T E R O L O G Y 2 7 , 7 6 6 ( 1 9 5 4 ) . 1 1 0 . W O R M S L E Y , K . C AND G R O S S M A N , M . I . I N H I B I T I O N OF G A S T R I C A C I D S E C R E T I O N BY S E C R E T I N AND BY E X O G E N O U S A C I D IN T H E D U O D E N U M . G A S T R O E N T E R O L O G Y 4 7 , 72 ( 1 9 6 4 ) . 

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