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Fundic inhibition of acid secretion and gastrin release Soon-Shiong, Patrick 1979

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FUNDIC  INHIBITION OF ACID SECRETION AND GASTRIN RELEASE by PATRICK {SOON-SHIONG o f W i t w a t e r s t r a n d , 1975  M.B.,B.Ch., U n i v e r s i t y  A THESIS SUBMITTED  IN PARTIAL FULFILMENT OF  THE REQUIREMENTS OF THE DEGREE OF MASTER OF SCIENCE INi THE FACULTY OP GRADUATE STUDIES (Department of Surgery)  We a c c e p t t h i s required  thesis  as c o n f o r m i n g t o t h e  standard  THE UNIVERSITY OF BRITISH COLUMBIA O c t o b e r , 1979 ||)  Patrick Soon-Shiong, 1979  In p r e s e n t i n g t h i s  thesis  in p a r t i a l  f u l f i l m e n t o f the requirements f o r  an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, the I  Library shall  make i t  freely available  f u r t h e r agree t h a t p e r m i s s i o n  for  f o r e x t e n s i v e copying o f  this  representatives. thesis  It  this  study. thesis  is understood that copying or p u b l i c a t i o n  f o r f i n a n c i a l gain s h a l l  written permission.  Department of The  r e f e r e n c e and  that  s c h o l a r l y purposes may be granted by the Head of my Department or  by h i s of  for  I agree  University of B r i t i s h  2075 W e s b r o o k P l a c e V a n c o u v e r , Canada V6T 1W5  Columbia  not be allowed without my  -  i i -  ABSTRACT  Despite e a r l i e r exists,  no such  Recently,  indirect  inhibitor  interest  caused  studies  that  by a n t r a l  b o t h the i n n e r v a t e d and d e n e r v a t e d v a g a l d e n e r v a t i o n o f the antrum.  the s o u r c e f o r t h i s  The  initial  as a p o s s i b l e  initiated  While  inhibitor  vagotomy on The  mechanism was  Once the fundus  of  was  shown t o be  i n the f u n d i c mucosa.  Four  f u n d i c pouch  of by  a  Subsequent the  CNS  inhibitory  fundus  indication  the f u n d u s ;  indeed,  that the  one.  the s o u r c e o f the this  of  mechanism  inhibitor  inhibitor,  did in fact  dogs were p r e p a r e d w i t h a  (or H e i d e n h a i n pouch, HP),  the main, i n n e r v a t e d stomach ( g a s t r i c r e s p o n s e s o f b o t h the HP  the  s t u d y i n g the e f f e c t  in r e a l i t y a fundic  whether  secretory  study suggested  gave c l e a r  from  n e c e s s a r y to e s t a b l i s h  denervated  enhanced  the antrum nor  by  results  antral  reside  the r e s p o n s e  to i n v e s t i g a t e  the a n t r a l  indeed r e l e a s e d  was  this  for a given  i n h i b i t o r y mechanism, i t  s t u d y was  the i n h i b i t o r was  it  showed t h a t  distension,  that neither  aim o f t h i s  by d i s t e n s i o n .  inhibitory  inhibitory  inhibitor.  s o u r c e o f the  proximal g a s t r i c  extract.  as t o the s o u r c e o f the i n h i b i t o r .  s t u d i e s , however, s u g g e s t e d was  chalone  stomach i s g r e a t l y  neuro-humoral c h a r a c t e r o f the a n t r a l indication  in antral  i n the q u e s t i o n o f an a n t r a l  i n serum g a s t r i n  gave no  t h a t an a n t r a l  has been found  mechanism has been r e v i v e d by rise  evidence  and GF  fistula,  and GF).  t o graded  a  fistula The  doses  of  acid  - i i i-  pentagastrin  and  histamine  s e c r e t i o n o f a c i d and the  blood  studied.  response of  i n r e s p o n s e to a s t a n d a r d  studied. the  the  was  I n a d d i t i o n both  immunoreactive g a s t r i n i n  meal o f 15%  A l l t h e s e e x p e r i m e n t s were r e p e a t e d  f u n d i c mucosa o f the main stomach.  e x c i s i o n of stimuli  the  f u n d i c mucosa reduced  by 85-100%  increased  by  247%  to histamine.  .  By  increase  output  i n the  the GF  even g r e a t e r .  36±3 t o 248±37 pg/ml) and  (from  168±12 p r e o p e r a t i v e l y  Since  the  intragastric  t e s t s both before response could by  and  not  e x c i s i o n o f the  be  pH  the  releases  indicating parietal  was  an  i t can  held  be  inhibitor  constant  increase  at 5.5 the  concluded  30  418%. i n both response  during  the  meal  augmented g a s t r i n  a c i d s e c r e t i o n caused  from the  that:  (1)  antral  fundus;  (2)  e x c i s i o n of  r e s p o n s e of the HP  maximal d o s e s o f p e n t a g a s t r i n  mass has  sensitivity  increased; basal  r e s p o n s e i n d e p e n d e n t o f the pH inhibitor  by  peak  of  f u n d i c mucosa.  mucosa r e s u l t s i n i n c r e a s e d  an  i n response  t o 392±49 pg/ml p o s t o p e r a t i v e l y ) .  a t t r i b u t e d to reduced  t h a t b o t h the  cell  200%  food-stimulated  f u n d i c mucosa r e s u l t s i n i n c r e a s e d  submaximal and  and  the  acid secretion  increased  a f t e r the o p e r a t i o n ,  From t h e s e s t u d i e s distension  a c i d s e c r e t i o n to  S i m i l a r l y , the  F u n d i c mucosal e x c i s i o n a l s o r e s u l t e d i n the (from  was  r e s p o n s e t o submaximal doses  i n r e s p o n s e to f e e d i n g  basal  extract  r e s u l t s show t h a t  c o n t r a s t , the maximal HP  t h e s e exogenous s t i m u l i was m i n u t e s HP  The  liver  a f t e r e x c i s i o n of  i n r e s p o n s e to p e n t a g a s t r i n  The  the  of  of g a s t r i n r e l e a s e .  of  (3) and  the  and  to  both  histamine  oxyntic  cell  e x c i s i o n of the  and  fundic  food-stimulated  gastrin  the meal s u g g e s t i n g  removal  of  -  Further  studies  inhibitor(s). that  the  excision  of  the  in  could  be r e v e r s e d  fundic  not  peptides  inhibitor,  vagotomy  has  no e f f e c t  inhibitory  are  atropine-sensitive  f i b e r s which  we h a v e  the  the  role  s t a t e was  does not  in  of of  the  HP  of  gastrin  vagal  action  supply  with  is  the  fibers  which  mediated antrum.  These acid  rise  mucosal  on  the  release  atropine  serum that  mediated  supply  the  by a t r o p i n e  of  show further  meal.  i n HP a c i d in  and  response  studies  the  or  mucosa.  secretion  to  rise  is  shown  exogenous VIP  fundic  the hypothesis  release  have  a n d HP a c i d  response  on t h e p o s t f u n d u s e c t o m y consistent  of  parenteral  increase  fundic  fundic  the vagus  studied.  gastrin  by  infusion  to e x i s t  the  performed  caused  the postfundusectomy  mechanism  stimulatory  identify  response by  -  on m e a l - s t i m u l a t e d g a s t r i n  abolishes  results  to  the e f f e c t  s i g n i f i c a n t l y decreases  These  the  known  further  t r u n c a l vagotomy  Atropine but  studies  secretory  the postfundusectomy  that but  Additional  investigate  truncal  necessary  increased  somatostatin,  To  are  iv  secretion gastrin.  the  by  fundus  resistant  and  that  vagal  - v -  TABLE OF CONTENTS  PART I ;  PYLORO-OXYNTIC  NEUROHUMORAL INHIBITORY REFLEX  1  OF ACID SECRETION  Introduction  2  Purpose  5  Material  and Methods  Animal  7  Preparation  Experimental  Design  Determinations  PART I I ;  Results  12  Discussion  19  . FUNDIC INHIBITION OF ACID SECRETION AND  22  GASTRIN RELEASE  Introduction  23  Purpose  24  Material  and Methods  Animal  25  Preparation  Experimental  Design  Determinations Results  36  Discussion  47  - vi-  PART I I I :  ANATOMY OF VAGAL INHIBITION OF GASTRIN RELEASE  51  Introduction  52  Purpose  54  M a t e r i a l and Methods  55  Animal Preparations Experimental Design Determinations Results  58  Discussion  66  SUMMARY AND CONCLUSIONS  71  REFERENCES  74  CURRICULUM VITAE  - v i i-  TABLE LEGEND  TABLE I :  Mean ( ± S E ) Serum G a s t r i n C o n c e n t r a t i o n Pentagastrin-Infusion  Experiments  (pg/ml) During  -  Vlll  -  FIGURE LEGENDS PART I :  PYLORO-OXYNTIC NEUROHUMRAL INHIBITORY REFLEX OF ACID SECRETION  FIGURE 1:  Animal p r e p a r a t i o n showing a n t r a l pouch and g a s t r i c f i s t u l a before and after proximal g a s t r i c vagotomy.  FIGURE 2:  The e f f e c t of graded doses of histamine d i h y d r o c h l o r i d e on GF acid s e c r e t i o n prePGV (closed c i r c l e s ) and postPGV (open c i r c l e s ) . In t h i s and each of the following f i g u r e s each p o i n t represents the mean (±SE) of two experiments i n each of four dogs.  FIGURE 3:  The e f f e c t of IV bolus i n j e c t i o n of regular i n s u l i n (0.5 U k g ) on GF a c i d output ( l e f t panel) and g a s t r i n response ( r i g h t p a n e l ) , prePGV (closed c i r c l e s ) and postPGV (open c i r c l e s ) . - 1  FIGURE 4:  GF a c i d response to constant IV perfusion of pentagastrin (4.0 ug kg "- h r ) under c o n t r o l c o n d i d i t i o n s , i . e . no d i s t e n s i o n (closed c i r c l e s ) and during a n t r a l pouch d i s t e n s i o n with 0.1 M HC1 (open c i r c l e s ) i n the prePGV stage. -  FIGURE 5:  - 1  GF a c i d response to constant IV p e r f u s i o n of p e n t a g a s t r i n (4.0 yg kg "- h r ) under c o n t r o l c o n d i t i o n s , i . e . no d i s t e n s i o n (closed c i r c l e ) and during a n t r a l pouch d i s t e n s i o n with 0.1 M HC1 (open c i r c l e s ) i n the postPGV stage. -  - 1  PART I I :  FUNDIC INHIBITION OF ACID SECRETION AND GASTRIN RELEASE  FIGURE 1:  Animal p r e p a r a t i o n demonstrating the g a s t r i c f i s t u l a (GF) of the innervated stomach and a v a g a l l y denervated fundic or Heidenhain pouch (HP).  FIGURE 2a&b:  Operative procedure demonstrating e x c i s i o n of the oxyntic c e l l mucosa s u p e r f i c i a l to the muscularis mucosa.  FIGURE 3:  PHOTO MICROGRAPHS TAKEN AT VARIOUS MAGNIFICATIONS OF A SECTION OF THE FUNDUS OF THE STOMACH OF THE DOG  3a:  Normal fundic mucosa removed at o p e r a t i o n . Note the muscularis mucosa and submucosa ( l l x m a g n i f i c a t i o n , H + E stain)  3b:  High power view of surface e p i t h e l i a l c e l l s l i n i n g p i t of fundic gland (175x m a g n i f i c a t i o n ; H + E stain)  - ix -  H i g h power v i e w o f f u n d i c mucosa s h o w i n g the e o s i n o p h i l i c round to p y r a m i d a l shaped o x y n t i c ( p a r i e t a l ) c e l l , as w e l l as t h e more b a s o p h i l i c z y m o g e n i c c e l l ( 1 7 5 x , H + E) H i g h power v i e w o f f u n d i c base s h o w i n g the b a s o p h i l i c zymogenic c e l l s . The v a c u o l a t e d and r e t i c u l a r appearance i n the c y t o p l a s m r e p r e s e n t e s the poor u p t a k e by the s e c r e t i o n g r a n u l e s o f the H + E s t a i n (175x) Normal  f u n d i c mucosa  removed  Granulation tissue lining absence of p a r i e t a l c e l l s  at  fundus (llx)  operation  at  (llx)  autopsy.  Total  A r e a o f r e g e n e r a t i o n o f f u n d i c mucosa w i t h absence of p a r i e t a l c e l l s . Note d i f f e r e n c e i n height b e t w e e n m u c o s a i n F i g u r e s 4 a & 4c ( l l x ) Meal  test  by the  method  of  intragastric  titration.  GF r e s p o n s e t o 15% l i v e r e x t r a c t m e a l b y i n t r a g a s t r i c t i t r a t i o n (pH 5 . 5 ) b o t h p r e o p e r a t i v e l y ( c l o s e d c i r c l e s ) and p o s t f u n d u s e c t o m y (open circles). I n t h i s and i n each s u b s e q u e n t f i g u r e , e a c h p o i n t r e p r e s e n t s t h e mean ( ± S E ) o f t w o experiments i n each of four dogs. The e f f e c t o f g r a d e d d o s e s o f h i s t a m i n e ( l e f t p a n e l ) a n d p e n t a g a s t r i n ( r i g h t p a n e l ) o n GF a c i d response b e f o r e ( c l o s e d c i r c l e s ) and a f t e r e x c i s i o n o f t h e o x y n t i c c e l l mucosa (open c i r c l e s ) . H e i d e n h a i n p o u c h r e s p o n s e t o a 15% l i v e r extract meal. T h e pH i s m a i n t a i n e d c o n s t a n t a t pH 5 . 5 t h r o u g h o u t t h e t e s t by i n t r a g a s t r i c t i t r a t i o n . A s i g n i f i c a n t i n c r e a s e i n b o t h b a s a l and m e a l s t i m u l a t e d response i s seen i n the fundusectomized a n i m a l s ( o p e n c i r c l e s ) as c o m p a r e d t o t h e preoperative controls (closed c i r c l e s ) . Heidenhain pouch response to graded doses o f p e n t a g a s t r i n i n f u s i o n both before (closed c i r c l e s ) and a f t e r e x c i s i o n o f the o x y n t i c mucosa (open circles) HP r e s p o n s e t o g r a d e d d o s e s o f h i s t a m i n e d i h y d r o c h l o r i d e both p r e o p e r a t i v e l y (closed c i r c l e s ) and a f t e r e x c i s i o n o f the o x y n t i c mucosa (open circles).  L e f t Panel: G a s t r i n response to a 15% l i v e r e x t r a c t meal both p r e o p e r a t i v e l y (closed c i r c l e s ) and f o l l o w i n g e x c i s i o n of the oxyntic mucosa (open circles). pH was maintained constant (5.5) throughout a l l meal t e s t s by the method of intragastric titration Right Panel: G a s t r i n increment over basal during the 15% l i v e r e x t r a c t meal p r e o p e r a t i v e l y (closed c i r c l e s ) and p o s t o p e r a t i v e l y (open c i r c l e s ) . Heidenhain pouch ( l e f t panel) and serum g a s t r i n response ( r i g h t panel) to a 15% l i v e r e x t r a c t meal i n fundusectomized animals with (open c i r c l e s ) and without (closed c i r c l e s ) i n f u s i o n of 0.5 u g kg~l h r ~ l somatostatin. Heidenhain pouch ( l e f t panel) and serum g a s t r i n response ( r i g h t panel) to a 15% l i v e r e x t r a c t meal i n fundusectomized with (open c i r c l e s ) and without (closed c i r c l e s ) i n f u s i o n of 1.0 u g kg~l h r ~ l VIP. THE ANATOMY OF VAGAL INHIBITION OF GASTRIN RELEASE Heidenhain pouch acid output ( l e f t panel) and g a s t r i n response ( r i g h t panel) a f t e r a 15% l i v e r e x t r a c t meal by i n t r a g a s t r i c t i t r a t i o n . Each p o i n t represents the mean±SE of two experiments i n three dogs before (closed c i r c l e s ) and a f t e r (open c i r c l e s ) fundic mucosal e x c i s i o n . E f f e c t of graded doses of pentagastrin on HP a c i d response i n c o n t r o l studies (closed c i r c l e s ) , i n fundusectomized animals (open c i r c l e s ) and f o l l o w i n g t r u n c a l vagotomy i n fundusectomized animals (open squares). E f f e c t of graded doses of histamine d i h y d r o c h l o r i d e on HP a c i d response i n c o n t r o l studies (closed c i r c l e s ) , fundusectomized animals (open c i r c l e s ) and f o l l o w i n g t r u n c a l vagotomy i n fundusectomized animals (open squares). Heidenhain pouch acid output ( l e f t panel) and g a s t r i n response ( r i g h t panel) a f t e r a 15% l i v e r e x t r a c t meal i n c o n t r o l studies (closed c i r c l e s ) , f o l l o w i n g fundic mucosal e x c i s i o n (open c i r c l e s ) and f o l l o w i n g atropine i n j e c t i o n i n postfundusectomy dogs (open c i r c l e s ) . Heidenhain pouch (HP) ( l e f t panel) and g a s t r i n response ( r i g h t panel) to a 15% l i v e r e x t r a c t meal in c o n t r o l studies (closed c i r c l e s ) , f o l l o w i n g fundic mucosal e x c i s i o n (open c i r c l e s ) and following t r u n c a l vagotomy a f t e r fundusectomy (closed squares).  - xi -  FIGURE 6:  Vagal c o n t r o l of g a s t r i n  release.  - xii  -  ACKNOWLEDGEMENT  Doctor H a i l e Debas who d i r e c t e d t h i s study has been a constant source of i n s p i r a t i o n and encouragement.  I am indebted  to him f o r h i s advice and guidance. I thank Gayle Henderson and Diane S t e e l f o r t h e i r extreme patience and s k i l l  i n the production of t h i s  manuscript.  I wish to thank the members of the Department of General Surgery, e s p e c i a l l y Doctor W.B. Chung and Doctor A.D. Forward f o r the guidance, encouragement and support they have given me. Expert t e c h n i c a l a s s i s t a n c e has been given to me by the f o l l o w i n g people: Mr. Kwok-Lam Leung and Mr. Peter Cheung - t h e i r i n v a l u a b l e a s s i s t a n c e i n the animal l a b o r a t o r y has made t h i s study p o s s i b l e ; Mrs. E i l e e n Bonagura and Mrs. Nancy Tronsgard  performed  the serum g a s t r i n assays; Miss Marie K e n d a l l was r e s p o n s i b l e f o r the superb h i s t o l o g i c a l s e c t i o n i n g and s t a i n i n g ; Mr. N i z a r A l l a d i n a and Margaret McKinney have been of much a s s i s t a n c e . I am g r a t e f u l to the graphic and photographic s e c t i o n s of the Department of Biomedical Communications f o r t h e i r outstanding q u a l i t y of work. Last but not l e a s t , a thank you to my wife, M i c h e l l e , f o r her understanding and encouragement.  - 1 -  PART I ;  PYLORO-OXYNTIC NEUROHUMORAL INHIBITORY REFLEX OF ACID SECRETION  - 2 -  INTRODUCTION  D i s t e n s i o n of the p y l o r i c and  i n h i b i t i o n of g a s t r i c  acid  Stimulation of g a s t r i c i s mediated both,by g a s t r i n pyloro-oxyntic  The  acid  secretion  release  distension  and by a g a s t r i n - i n d e p e n d e n t  secretion  by a n t r a l  c l e a r l y understood.  o f t h e antrum f a c i l i t a t e d ulcer.  H i s t o r i c a l l y , the first  antrum onto t h e c o l o n other h a l f  i n 1956.  i n i t s normal l o c a t i o n ,  location  suggesting had r e l e a s e d  that  acid  when the p o r t i o n acid  bathing  7  irrigation  this." '**  secretion  t h e antrum  c h a l o n e was thus  t h e n e x t decade c o n t r o v e r s y  showing a n t r a l  half  of the  released  i n i t s normal  it.  The  born.  r a g e d , some  investigators  an i n h i b i t o r , ' w h i l e  others  the c u r r e n t  c h a l o n e h y p o t h e s i s and c o n c l u d e d  evidence f o r  o f t h e antrum  from the pouch  secretion.  i n 1974 J . C . Thompson^ r e v i e w e d  o f the a n t r a l  convincing  They t r a n s p l a n t e d  an i n h i b i t o r o f a c i d  h y p o t h e s i s o f an a n t r a l  During  the p r o d u c t i o n o f  i n dogs w i t h H e i d e n h a i n pouches l e a v i n g t h e  i t s normal l o c a t i o n was e x c i s e d ,  increased  that  T h i s c o n c e p t was g i v e n s u p p o r t by  H a r r i s o n and c o - w o r k e r s ^  status  antral  the antrum may p l a y an i n h i b i t o r y r o l e was  histamine-induced  refuted  after  by S t a t e and c o - w o r k e r s ^ i s 1955, when t h e y showed  resection  in  stimulation  reflex.  however, i s l e s s  concept that  i n both  secretion.  i n h i b i t o r y mechanism o f a c i d  distension  raised  antrum r e s u l t s  t h e r e was no  - 3 -  Indirect supplied  evidence  for  an a n t r a l  b y D e b a s e t a l * when  denervation of the g a s t r i c  inhibitor  the a n t r a l pouch  occurred during  was to  activity.  i t was an  unexpectedly noted  increase  f i s t u l a and H e i d e n h a i n p o u c h  serum g a s t r i n hypothesis  i n h i b i t o r y mechanism  t h u s made  acid  Since  that  response  to a given  of  increment  antral distension  released  required vagal  as w e l l  as  pouch  and  after  both  with a l k a l i .  the Heidenhain  were a f f e c t e d , a humoral  that  antral distension  s e c r e t i o n which both  in  was  tone  The  an  for  its  the g a s t r i c  a n e u r a l mechanism  of  fistula  is  implicated.  Direct  evidence  confirming  inhibitory  m e c h a n i s m was  distension  of  the  s u p p l i e d when  antrum s i g n i f i c a n t l y  pentagastrin-stimulated fistula.•'-O  Recently,  gastric  The the  for  of  antrum c o u l d  antral  the  distension  elsewhere,  fundus of  the  communication other no  longer  s u c h as  stomach, t h e CNS only  abdominal causes  from the  in duodenal  i n h i b i t o r now  requires  source,  are  it  is  i n t e s t i n e or  the source  b e t w e e n t h e CNS  organs being  i n h i b i t i o n of  acid  since,  and a n t r u m  vagally  acid  gastric the  same  a defective ulcer  patients.  l o c a l i z a t i o n . While equally possible  the c e n t r a l nervous  the s m a l l  antral  shown t h a t  i n i t i a t e d a r e f l e x mechanism which  inhibitor  t h e antrum nor  this  inhibited  interestingly,  i t s e l f be t h e  of  al-'--'- d e m o n s t r a t e d  antral distension  source  i t was  secretion  Schoon et  p h e n o m e n o n i n h e a l t h y man a n d inhibition  the existence  releases  system,  pancreas. when is  denervated, secretion.10  that the  the Neither  vagal preserved, antral  all  distension  - 4 -  This study sought to i n v e s t i g a t e the e f f e c t of vagal denervation of the oxyntic mucosa or proximal g a s t r i c vagotomy (PGV) on the i n h i b i t i o n of pentagastrin-stimulated caused by a n t r a l d i s t e n s i o n . abolishes  acid  The r e s u l t s show that PGV  secretion completely  the i n h i b i t o r y e f f e c t of a n t r a l d i s t e n s i o n and suggests  that the fundus i s the source of the i n h i b i t o r y substance(s) released  by a n t r a l  distension.  - 5 -  PURPOSE  To mucosa  investigate ie.,  proximal  the  gastric  pentagastrin-stimulated distension.  effect  acid  of vagal denervation  vagotomy secretion  ( P G V ) on t h e caused  by  of  the  oxyntic  inhibition  antral  of  FIGURE 1:  A n i m a l p r e p a r a t i o n showing a n t r a l f i s t u l a b e f o r e and a f t e r p r o x i m a l  pouch and g a s t r i c g a s t r i c vagotomy.  - 7 -  M A T E R I A L AND METHODS  ANIMAL  PREPARATION:  Four with  stomach  pouch of  by d i v i d i n g except  for  the  ensured  antrum.  body o f  restored  by a n a s t o m o s i n g  A Thomas c a n n u l a was  A small the  to  this  amount  antral  (Figure  1,  inserted  acid  pouch  to  Stage  I)  the  second  operation,  prevent  a n i m a l s were  neurovascular  intact  the  antrum. all  The l a s t  nerve  Stage  anterior  II)  fibers  into to  the  to  body o f as  the  basal  to  to  cannula  continuity  to  the  the  lesser  stomach fistula  the  left  In  the  the from  the  leaving  of Laterjet also  with  performed  junction  e s o p h a g u s was  completeness  all  (GF).  secretion.  were  curvature  nerves  was  duodenum.  operation.  by d i v i d i n g  and p o s t e r i o r  ensure  innervation  gastrin  a second  only  This  the  studies  the  created.  a gastric  gastro-esophageal  of  body o f  m u c o s a was d e l i b e r a t e l y  excessive  along  T h e AP w a s  a Gregory  stomach  prepared  c u r v e where  septum  and  the  serve  subjected  2 inches  lesser  of vagal  pre-PGV c o n t r o l  connections  j u n c t i o n to  the  the  Gastrointestinal  PGV was p e r f o r m e d  antrum-body both  AP.  secreting  recovery,  before  2 cm a t  body o f  anastomosis  of  Following  the  (AP).  c o m p l e t e l y from  transected  the  surgically  antrum  preservation  The p y l o r u s was the  were  a double-mucosal  complete  into  proximal  of  kg)  pyloric  antrum  and  inserted  (20-26  the  a bridge  m u c o s a was d i v i d e d  procedure the  mongrel dogs  an i n n e r v a t e d  prepared  the  female  to  denuded  of PGV. (Figure  1,  the of  - 8 -  EXPERIMENTAL  DESIGN;  No e x p e r i m e n t s were p e r f o r m e d operation.  The a n i m a l s were f a s t e d o f f o o d  18 h o u r s b e f o r e each o t h e r  The  i n a given  each  b u t not o f water f o r  No t e s t s were done w i t h i n 2 days o f  animal.  and a f t e r  Proximal  Vagotomy:  H i s t a m i n e D o s e - r e s p o n s e t o c h a r a c t e r i z e GF Response: was p e r f o r m e d by c o n s t a n t  intravenous  histamine-dihydrochloride  i n doses d o u b l i n g  160 u g  (2)  each t e s t .  3 weeks a f t e r  f o l l o w i n g e x p e r i m e n t s were p e r f o r m e d b e f o r e  Gastric  (1)  f o r at l e a s t  kg-1 h r  I n s u l i n Test secretion IV b o l u s  - 1  This  infusion of from 5 t o  .  F o r C o m p l e t e n e s s o f Vagotomy:  and serum g a s t r i n c o n c e n t r a t i o n i n j e c t i o n of regular  insulin  Both GF a c i d i n response  t o an  -  (0.5 U kg "-) was  studied.  (3)  Control Pentagastrin Plateau response to a continuous  of S e c r e t i o n :  -  s t u d i e s , t h e AP was  d i s t e n s i o n was p r e v e n t e d from which t h e AP was  secretion in  i n f u s i o n of pentagastrin  hr "-) was d e t e r m i n e d over a 3 hour p e r i o d . control  Acid  filled  by k e e p i n g  filled  with  During  -  (4 y g k g l these  0.1 M HC1 b u t  the l e v e l  a t the l e v e l  of the b a r o s t a t  o f the pouch.  - 9 -  (4)  E f f e c t of A n t r a l D i s t e n s i o n on P e n t a g a s t r i n P l a t e a u :  These  experiments were s i m i l a r to the c o n t r o l pentagastrin plateau experiments except the AP was  distended  by l i f t i n g  the  barostat to 40 cm during the second hour of the pentagastrin infusion. HC1  In these t e s t , the AP was  i n the f i r s t  d i s t e n s i o n was of  AP.  and  kept f i l l e d with 0.1  t h i r d hours of i n f u s i o n but  prevented  M  AP  by keeping the barostat at the  level  - 10  -  DETERMINATIONS  ACID OUTPUT;  GF  s e c r e t i o n was  divided before  collected  i n t o 15 minute samples.  continuously Two  by g r a v i t y  and  basal  samples were  obtained  The  volume o f each  sample  a d m i n i s t r a t i o n of a s t i m u l u s .  t-  was  measured  to the  d e t e r m i n e d by NaOH on output  an was  nearest  titrating  0.5  0.1 ml  automatic t i t r a t o r  ml  and  acid  concentration  of each sample to pH  7.0  ( R a d i o m e t e r , Copenhagen).  c a l c u l a t e d by m u l t i p l y i n g the volume by  with  0.1  M  Acid  the  concentration.  SERUM GASTRIN CONCENTRATION:  Venous b l o o d the  start  Serum was until  was  separated  every  by  Walsh from the C e n t e r The  c o l d c e n t r i f u g a t i o n and  antibody  (the kind g i f t  f o r U l c e r R e s e a r c h and  a s s a y was  concentration  1296  30 m i n u t e s  and  Serum g a s t r i n c o n c e n t r a t i o n was  immunoassay u s i n g  total  b a s a l l y and  of s t i m u l a t i o n i n a l l p e n t a g a s t r i n  assayed.  Angeles).  obtained  insulin  after  tests. >  s t o r e d at -40°C measured by o f Dr.  John  Education,  s e n s i t i v e to 5 pg/ml and  radioH.  Los  measured  the  of immunoreactive g a s t r i n .  STATISTICAL ANALYSIS;  The during  s i g n i f i c a n c e o f the d i f f e r e n c e o f the mean a c i d s e c r e t i o n  the c o n t r o l and  d i s t e n s i o n e x p e r i m e n t s was  analysed  using  - 11 -  t-test  for paired values.  considered  significant.  A p-value of l e s s  than 0.05  was  - 12 -  RESULTS  EFFECT OF PGV ON GF RESPONSES  (1)  H i s t a m i n e Dose-Response;  F i g u r e 2 shows t h a t the e f f e c t dose-response to histamine  i s small.  maximal r e s p o n s e s a r e a f f e c t e d . only  (2)  seen a t t h e 20 yg k g  o f PGV  - 1  on t h e  Submaximal  A significant  but not  decrease  was  h r ~ l dose.  Insulin Test:  PGV  completely  hypoglycemia  ( F i g u r e 3, l e f t  response to i n s u l i n was  abolished  panel).  occurred  not s t a t i s t i c a l l y  the GF a c i d r e s p o n s e t o i n s u l i n An i n c r e a s e  f o l l o w i n g PGV,  significant  in gastrin  but t h i s  ( F i g u r e 3, r i g h t  change  panel).  EFFECT OF ANTRAL DISTENSION ON PENTAGASTRIN BEFORE PGV  Antral inhibition applied  distension with  0.1 M HCI caused  of a c i d response during  (Figure 4).  control values  responses during  infusion f e l l  o f 15.2±1.1 and 14.8 mEq  r e s p e c t i v e l y with discontinued,  t h e time t h e d i s t e n s i o n was  The two h a l f h o u r l y  second hour o f p e n t a g a s t r i n  significant  significantly  recovery  i n acid  from the  t o 9.9±1.2 and 8.5±1.4  d i s t e n s i o n . Once a n t r a l d i s t e n s i o n was  t h e r e was  the  response.  mEq  - 13  PGV hr~l)  lowered  only  the  slightly,  non-significant.  plateau the  -  response to p e n t a g a s t r i n  change b e i n g  However, f o l l o w i n g  r e s p o n s e to p e n t a g a s t r i n ,  by  antral  (4  ug  kg~l  statistically PGV,  i n h i b i t i o n of  distension,  was  GF  abolished.  5)  (Figure  SERUM GASTRIN RESPONSES;  The  e f f e c t of  antral distension  r e s p o n s e s both b e f o r e and  a f t e r PGV  m i g h t be  distension  effect  on  expected, a n t r a l gastrin  release,  and  are  given  gastrin  in Table I .  i n f a c t , serum g a s t r i n  l e v e l s were  distension  serum g a s t r i n  c o n c e n t r a t i o n were of  no  acid  was  had  As  stimulatory  lower when a c i d  with  on  no  significantly  shown above.  with acid  applied.  consequence  Changes i n  i n the  results  - 14 -  EC  • mmm  8000  E  T  I/  jo LU D Q. D  O o  6000-  f  4000 2000 -l/ 0  L  * p < 0.05  ....  r  <  L  B 5  10 20  40  Histamine (jug kg"^  FIGURE 2:  ^1—* Control 7 T PGV  80 160 hH)  The e f f e c t o f g r a d e d d o s e s o f h i s t a m i n e d i h y d r o c h l o r i d e on GF a c i d s e c r e t i o n prePGV ( c l o s e d c i r c l e s ) and postPGV (open c i r c l e s ) . I n t h i s and each o f t h e f o l l o w i n g f i g u r e s each p o i n t r e p r e s e n t s the mean (±SE) o f two e x p e r i m e n t s i n each o f f o u r dogs.  - 15 -  ACID O" LI r1 1 1  4000 r  |  n s u l i n  •  GASTRIN • — • Pre PGV U o o Post PGV ^ 200 T * < 0.05 3: p  "5 3000 -  g 150 o  u  Q_ D  o  2000 -  o  i  •E ioo  I  y,* 'I  </>  <  LL.  *  Insulin  O  1000-  4-1 o * * Q'...a.%.n...rS  B 1  3  5  15 min Periods  FIGURE 3:  O E  50  D  0)  CO  0  B  1  2  3  30 min Periods  The e f f e c t o f IV b o l u s i n j e c t i o n o f r e g u l a r i n s u l i n (0.5 U k g " ) on GF a c i d o u t p u t ( l e f t p a n e l ) and g a s t r i n r e s p o n s e ( r i g h t p a n e l ) j prePGV ( c l o s e d c i r c l e s ) and postPGV (open c i r c l e s ) . 1  - 16 -  { 20  Pentagastrin 4.0 ;ug kg-1 hrl  f  Distension ?  Pre PGVl  c  E o co  16 -  cr LU J .  "5 a "5 O  12  •"ft  -T  T  X  8  Control o»»o Distension  <  * p < 0.05 0  B  L 1  J  2  3  4  5  30 min Intervals  FIGURE 4: GF a c i d response t o constant IV p e r f u s i o n o f p e n t a g a s t r i n (4.0 yg k g h r " ) under c o n t r o l c o n d i d i t i o n s , i . e . no d i s t e n s i o n ( c l o s e d c i r c l e s ) and d u r i n g a n t r a l pouch d i s t e n s i o n w i t h 0.1 M HC1 (open c i r c l e s ) i n the prePGV stage. - 1  1  - 17 -  J  Pentagastrin 4.0//g kg"l hr'l J distension  Post PGV  I  d 12 CO  —I I  cr  3  XV  J  9  a  8  6  <  J  • - • Control 0"«o Distension  0' B  1 30 min Intervals  FIGURE 5:  GF a c i d r e s p o n s e t o c o n s t a n t IV p e r f u s i o n o f p e n t a g a s t r i n (4.0 yg k g h r " ) under c o n t r o l c o n d i t i o n s , i . e . no d i s t e n s i o n ( c l o s e d c i r c l e ) and d u r i n g a n t r a l pouch d i s t e n s i o n w i t h 0.1 M HCI (open c i r c l e s ) i n t h e postPGV s t a g e . - 1  1  - 18 -  TABLE I :  Mean (±SE) Serum G a s t r i n C o n c e n t r a t i o n Pentagastrin-Infusion  EFFECT OF DISTENSION  (pg/ml) D u r i n g  Experiments  (PRE PGV): BASAL  PRE-DIST  DISTENSION  POST-DIST  CONTROL (0 DISTENSION)  71±17  46±9  44±8  54±12  40 cm DISTENSION  47±4  51±8  38±3  32±3*  DISTENSION  POST-DIST  EFFECT OF VAGOTOMY: BASAL  PRE-DIST  PRE-PGV (DISTENSION)  47±4  52±8  38±3  32±3  POST-PGV  69±13  58±12  46±4  41±5  (DISTENSION)  * p < 0.05  - 19  -  DISCUSSION  The  impetus f o r t h i s  observation denervated  that  vagal  following  also  that vagal  the  inhibitor  was  the  source of  not  sites.  These o t h e r  inhibitor  was  recent  the  CNS  inhibitor  are  was  the  reflexly  c e l l mucosa m i g h t be  the  antral  i m p l i c a t i o n was  that  not  only  but  to the  of g a s t r i n  a c t i o n of g a s t r i n  i t was  the  c e r t a i n the  of  antrum  determine  from the  antrum or  the  the  CNS,  release  extra-antral  o x y n t i c mucosa,  or  inhibitor,suggesting  from the  the  oxyntic  the  the  other  the  mucosa may  completely abolished  the  be  that  the  vagally-innervated  possibility  source of  antrum  that  the  inhibitor the  Indeed, t h i s  and  that  effector study  inhibitory action  has of  distension.  The was  The  s t u d y would not  neuro-hormonal pathway.  shown t h a t PGV  increased  evidence that neither  study explored  b r a n c h e s t o the  and  organs.  provided  oxyntic  f i b e r s of  present  be  abdominal  The  vagal  While  s o u r c e o f the  released  greatly  antrum a b o l i s h e d  released  sites.  the  the  s i t e s could  s t u d y has  1  inhibitor  of g a s t r i n .  vagally-supplied  A  of  innervated  i n serum g a s t r i n  release  the g a s t r i n , t h a t  the  other  antrum.  i s an  denervation but  the  r e s u l t s i n the  whether  nor  of  of a s u b s t a n c e t h a t  and  increment  a n t r a l d i s t e n s i o n was  denervation  antral distension  unexpected  r e s p o n s i v e n e s s o f b o t h the  stomach to a g i v e n  concentration after  the  s t u d y came from the  choice  based on  to d i s t e n d  earlier  the  antrum w i t h a c i d  demonstration that  rather  than  a c i d d i s t e n s i o n was  alkali more  - 20 -  effective  than a l k a l i  distension.  these d i f f e r e n c e s might gastrin  thus adding  inhibitor  minimize  result  Denervated sake  a g a i n s t which t h e  acid  response  i n order to  i n serum g a s t r i n c o n c e n t r a t i o n  distension  pouches were n o t used and t h e s t a t e m e n t  o f t h e antrum.  i n the p r e s e n t s t u d y f o r t h e t h a t a humoral agent i s 1  i s based  on p r e v i o u s s t u d i e s o f t h i s m e c h a n i s m . '  now know t h a t v a r i o u s i n h i b i t o r y p e p t i d e s a r e found fibers  and i n e n d o c r i n e c e l l s w i t h i n  Substance vagal  1  endings. 2,13,14,15,19  found  1  The i n h i b i t i o n  be m e d i a t e d substances. mentioned  suggests that  the c i r c u l a t i o n .  by a n t r a l d i s t e n s i o n c o u l d  The f a c t  than  those  that a Heidenhain  the i n h i b i t o r  can be t r a n s m i t t e d  S i n c e s u b s t a n c e P and s o m a t o s t a t i n do n o t  Further studies are required  inhibitor(s)  endocrine  substance  t o have p e r s i s t e n c e i n the c i r c u l a t i o n ,  candidates. the  caused  be i n v o l v e d .  i n the  o f the o x y n t i c  Of c o u r s e , an e n t i r e l y d i f f e r e n t  pouch i s i n h i b i t e d  appear  i n the v a g a l  v i P , s o m a t o s t a t i n and g l u c a g o n  by r e l e a s e o f t h e s e n e u r o c r i n e and/or  above might  We  t h e o x y n t i c mucosa.  i n the endocrine c e l l s  mucosa. ^  via  1 0  P, V I P , and s o m a t o s t a t i n have been shown t o e x i s t  nerve  are also  releases  I n t h e p r e s e n t s t u d y a dose o f p e n t a g a s t r i n  o f any d e c r e a s e  from  of s i m p l i c i t y  released  be t h a t a l k a l i n e d i s t e n s i o n  t h a t gave near maximal a c i d  the e f f e c t  t h a t might  explanationfor  to the stimulus of s e c r e t i o n  has t o a c t .  was s e l e c t e d  A possible  involved  in this  antral  t h e y a r e weak  to d e f i n e the nature of neuro-humoral  inhibitory  mechanism.  The  q u e s t i o n o f whether an a n t r a l  s u b j e c t o f much h e a t e d  debate  chalone  e x i s t s has been t h e  s i n c e H a r r i s o n e t a l ^ suggested i t s  - 21 -  existence.  Some i n v e s t i g a t o r s have been a b l e  acidification is  likely  control  that  inhibits  acid secretion,4,5,6  these d i s c r e p a n t  indicate release  others  f i n d i n g s were due  study along  to f a i l u r e  others  previously  antral acidification  an a n t r a l c h a l o n e , and t h a t  mechanism i s i n r e a l i t y  to  those  who  the antrum had p o s i t i v e r e s u l t s . The  with several  that neither  antral  have not.7'8  the element o f a n t r a l d i s t e n s i o n , so t h a t o n l y  inadvertently distended present  to show t h a t  a fundic  nor a n t r a l d i s t e n s i o n  the a n t r a l i n h i b i t o r y  one.  1  published »!0  I  t  - 22 -  PART I I :  FUNDIC INHIBITION OF ACID SECRETION AND GASTRIN RELEASE  - 23 -  INTRODUCTION:  This proof of a p y l o r o - o x y n t i c neurohumoral i n h i b i t o r y strengthens  the hypothesis  reflex  that i n h i b i t o r y mechanism(s) of a c i d  s e c r e t i o n reside i n the fundus.  In a d d i t i o n three types of evidence point to the fundus as a p o s s i b l e source of an i n h i b i t o r of a c i d s e c r e t i o n and/or g a s t r i n release.  F i r s t , proximal  and proximal  gastrectomy, fundic mucosal s t r i p p i n g ^  g a s t r i c vagotomy-^! a l l r e s u l t i n a marked increase i n  24 hour Heidenhain pouch (HP) a c i d s e c r e t i o n i n dogs.  This  increase had been a t t r i b u t e d to the r i s e i n pH f o l l o w i n g l o s s of parietal cell activity.  Second, vagal denervation  of the oxyntic  mucosa r e s u l t s i n increases i n basal,22,23,24,25 food-24,25 i n s u l i n - s t i m u l a t e d 2 3 g a s t r i n release i n man. hypergastrinaemia and dog.26  occurs  n  (  j  This postvagotomy  independent of change i n pH i n both man25  T h i r d , endocrine c e l l s containing peptides  inhibitory  to a c i d s e c r e t i o n and g a s t r i n release have been i d e n t i f i e d mucosa of the proximal  a  i n the  stomach.1^,17,18  This study aimed to define the i n h i b i t o r y r o l e of the fundus by i n v e s t i g a t i n g the e f f e c t of fundic (oxyntic c e l l ) mucosal e x c i s i o n on a c i d s e c r e t i o n and g a s t r i n release i n response to endogenous and exogenous s t i m u l i .  The r e s u l t s i n d i c a t e that  removal of the fundic mucosa may r e s u l t i n the withdrawal of inhibitory  substance(s).  - 24 -  PURPOSE  To d e f i n e the  t h e i n h i b i t o r y r o l e o f the fundus by  e f f e c t of fundic  secretion  and g a s t r i n  exogenous  stimuli.  (oxyntic  c e l l ) mucosa  release  i n response  excision  investigating on  t o endogenous  acid and  -  25  -  HP  GF  FIGURE  1:  Animal p r e p a r a t i o n demonstrating the g a s t r i c f i s t u l a (GF) o f t h e i n n e r v a t e d stomach and a v a g a l l y d e n e r v a t e d f u n d i c o r H e i d e n h a i n pouch (HP).  - 26 -  METHODS AND  MATERIAL  ANIMAL PREPARATIONS  Four fistula  female dogs (15-20 kg) were p r o v i d e d w i t h a g a s t r i c  (GF) and a v a g a l l y d e n e r v a t e d H e i d e n h a i n pouch  ( F i g u r e 1)  Following  completion of c o n t r o l  underwent a second o p e r a t i o n gastrostomy, superficial mucosa was  the o x y n t i c c e l l  removed  and  The  a t the m a r g i n s  at a plane  entire  oxyntic r i m near  cell the  Figure 3 i s a  F i g u r e 4 shows the  fundusectomy,  demonstrating  excision.  dogs t o l e r a t e d  normal d i e t w i t h i n 5-6  anterior  o f the GF.  f u n d i c mucosa.  o f mucosa b e f o r e and a f t e r  e x t e n t o f mucosal  The  excised  ( F i g u r e 2) e x c e p t f o r a s m a l l  p h o t o m i c r o g r a p h o f normal  the  e x p e r i m e n t s the dogs  t h r o u g h an  mucosa was  t o the m u s c u l a r i s mucosa.  esophageal j u n c t i o n  specimens  i n which,  (HP).  the p r o c e d u r e r e m a r k a b l y w e l l  and  resumed  days.  EXPERIMENTAL DESIGN  T h r e e weeks were a l l o w e d f o r r e c o v e r y from the 1 s t o p e r a t i o n , and  two weeks from t h e 2nd.  b e f o r e each t e s t . other. the (1)  The  fundic  No  following  The  dogs were f a s t e d  hours  t e s t s were done w i t h i n 48 h o u r s o f each t e s t s were done b e f o r e and  after  excision  mucosa:  Meal T e s t by I n t r a g a s t r i c T i t r a t i o n : cork  f o r 18  from the GF,  After  the i n s i d e o f the stomach  removal o f the was  rinsed with  of  - 27 -  tap water. obtained  Two 15 m i n u t e  from  t h e GF a n d H P .  w e r e made u s i n g each  the  15 m i n u t e s .  extract  (w/v) then  titration  sytem.  extract  Phoenix, was  10 s t r o k e s  assembly  end-point  Dickinson,  per  Intragastric  0.5  minute,  adjusted  to  from  M NaHCC>3 u s e d  During  -15,  0,  clotting  s e r u m was  at  -40°C  Pentagastrin infusion  o f 0.15 a rate  periods  of  M NaCl  the  infusate  at  SBR2C,  (Brewer, adjusted  at  titrant.  two h o u r s w i t h for  each  30  recorded  test  pH a t  the  minutes  the  venous  amount  5.5. blood  was  After  centrifugation  A continuous  After  and  0.5  intravenous peristaltic  t w o 15 m i n u t e  o f GF a n d HP s e c r e t i o n , starting  and  gastrin.  Studies;  hour.  2 7  Titrator  speed  intragastric  by c o l d  dried  titration  90 a n d 120 m i n u t e s .  for  was  Recorder  is given using a Harvard  o f 28 m l p e r  collection  output  titration  assayed  Dose Response  pump a t  to  60,  separated  until  the  t i t r i g r a p h which  to m a i n t a i n  30,  GK3221C,  for  liver  t h e GF  o f F o r d t r a n and W a l s h  M NaHCC»3 a s  Acid  saline  Company,  intragastric  Maryland) with  intragastric  at  stored  of  25 m l . b u r e t t e ,  each  obtained  used  D e n m a r k ) , a p i s t o n pump  5.5.  were  intragastric  extract  (electrode  and 0.5  the  into  (Reheck C h e m i c a l  t i t r a t i o n was p e r f o r m e d  was c a l c u l a t e d  added  method  A u t o b u r e t t ABV13 w i t h  60453,  introduced  The l i v e r  The t e c h n i q u e  Copenhagen,  was  50 m l  15% s o l u t i o n o f  an a u t o m a t i c  o f mammalian l i v e r  a pH s t a t  Radiometer, Model  to  the  i r r i g a t i o n with  300 m l . o f  ( F i g u r e 5)  a m o d i f i c a t i o n of  TTTll,  of  t o pH 5 . 5  connected  Arizona).  employed  of  A meal of  secretion  A l l c o l l e c t i o n s o f HP s e c r e t i o n  technique  adjusted  w h i c h was  water  c o l l e c t i o n s of basal  yg k g  -  basal  pentagastrin 1  hr  - 1  and  is  - 28 -  doubling hr  - 1  .  the dose  The  s t e p w i s e e v e r y 30 m i n u t e s  l o w e s t dose was  c o l l e c t i o n was  infused  done by g r a v i t y  f o r 45 m i n u t e s .  and HP  ml  and  using  10 ml  ml,  and  acid  samples  and HP  an a u t o m a t i c t i t r a t o r  volume by the c o n c e n t r a t i o n . collection  s i z e , HP  o u t p u t was  histamine. (3)  HP  calculated The  employed  kg  - 1  hr  - 1  .  the  15  t a k e n as the r e s p o n s e f o r i n HP  e x p r e s s e d as % o f the maximal r e s p o n s e t o  These  t o the p e n t g a s t r i n  starting  s t e p w i s e e v e r y 30 m i n u t e s 160 y g  o u t p u t i n the l a s t  (Sigma C h e m i c a l Co.,  a t doses  respectively  To m i n i m i z e d i f f e r e n c e s  H i s t a m i n e Dose-Response S t u d i e s ;  dihydrochloride  i n 0.5  by m u l t i p l y i n g  r e s p o n s e t o meal were h a n d l e d  i n a manner s i m i l a r  to the  determined  collections  a t each dose was  t h a t dose o f p e n t a g a s t r i n .  collected  ( A u t o b u r e t t e , Radiometer,  Copenhagen). A c i d o u t p u t was  minutes  measured  c o n c e n t r a t i o n was  o f GF  - 1  above.  volume o f each c o l l e c t i o n was  n e a r e s t 0.1  kg  GF  s e c r e t i o n was  by an i r r i g a t i o n method as d e s c r i b e d The  t o 16 u g  similarly.  t e s t s were tests.  performed  Histamine  S t . L o u i s , MO)  a t 5 pg k g ~ l h r  - 1  t o the h i g h e s t dose  A g a i n the l o w e s t dose was  was  and d o u b l i n g used which infused  was  f o r 45  minutes.  DETERMINATION OF  SERUM GASTRIN CONCENTRATION:  Serum g a s t r i n c o n c e n t r a t i o n s were d e t e r m i n e d radioimmunoassay  using  a n t i b o d y 1296  which was  Dr. J . Walsh from the C e n t e r f o r U l c e r (CURE),  Los A n g e l e s , C a l i f o r n i a .  Research  by  the k i n d g i f t  of  and E d u c a t i o n  This antibody cross-reacts with  - 29 -  both  t h e G-17  gastrin.  ( l i t t l e ) and the G-34  The a s s a y was  sensitive  SOMATOSTATIN AND VASOACTIVE  (large molecular  forms of  t o 5 pg/ml.  INTESTINE POLYPEPTIDE  (VIP) INFUSION  STUDIES ON MEAL TEST  In a d d i t i o n f o l l o w i n g e x c i s i o n o f f u n d i c mucosa, the e f f e c t s of VIP  infusion  of e i t h e r  somatostatin  ( P e n i n s u l a Lab, San C a r l o s ) o r  ( P e n i n s u l a L a b , San C a r l o s ) on a c i d  r e l e a s e were s t u d i e d .  The meal t e s t  s e c r e t i o n and g a s t r i n  by i n t r a g a s t r i c  titration  p e r f o r m e d as d e s c r i b e d above b u t i n a d d i t i o n i n t r a v e n o u s of  somatostatin  (0.5 yg k g  - 1  hr  - 1  ) or VIP  (1.0 yg k g ~ l h r  commenced 10 m i n u t e s p r i o r  t o the i n s t i l l a t i o n  e x t r a c t meal and c o n t i n u e d  throughout  peptide  i s p e r f o r m e d on s e p a r a t e  test  the t e s t . days.  o f the  is  infusion - 1  ) is  liver  I n f u s i o n o f each  - 30 -  FIGURE 2a&b:  Operative procedure demonstrating e x c i s i o n of the oxyntic c e l l mucosa s u p e r f i c i a l to the mucularis mucosa.  FIGURE  FIGURE  2a  2b  - 32 -  FIGURE 3:  PHOTO MICROGRAPHS TAKEN AT VARIOUS MAGNIFICATIONS OF A SECTION OF THE FUNDUS OF THE STOMACH OF THE DOG  3a:  Normal f u n d i c mucosa removed a t o p e r a t i o n . Note t h e m u s c u l a r i s mucosa and submucosa ( l l x m a g n i f i c a t i o n , H + E stain)  3b:  H i g h power view o f s u r f a c e e p i t h e l i a l c e l l s l i n i n g p i t o f f u n d i c g l a n d (175x m a g n i f i c a t i o n ; H + E stain)  3c:  H i g h power view o f f u n d i c mucosa showing t h e e o s i n o p h i l i c round t o p y r a m i d a l shaped o x y n t i c ( p a r i e t a l ) c e l l , as w e l l as t h e more b a s o p h i l i c zymogenic c e l l (175x, H + E)  3d:  H i g h power view o f f u n d i c base showing t h e b a s o p h i l i c zymogenic c e l l s . The v a c u o l a t e d and r e t i c u l a r appearance i n t h e c y t o p l a s m r e p r e s e n t e s the poor uptake by t h e s e c r e t i o n g r a n u l e s o f t h e H + E s t a i n (175x)  1  -34-  FIGURE 4a:  N o r m a l f u n d i c mucosa removed a t operation ( l l x )  FIGURE 4b:  Granulation tissue lining fundus at autopsy. Total absence of p a r i e t a l c e l l s ( l l x )  FIGURE 4c:  Area of r e g e n e r a t i o n of f u n d i c mucosa w i t h a b s e n c e o f p a r i e t a l cells. Note d i f f e r e n c e i n h e i g h t between mucosa i n F i g u r e s 4a & 4c ( 1 1 c )  - 35 -  FIGURE 5:  Meal t e s t by the method of i n t r a g a s t r i c  titration.  - 36 -  RESULTS  EFFECT OF FUNDIC MUCOSAL EXCISION ON GF RESPONSES:  E x c i s i o n o f t h e f u n d i c mucosa from the main stomach by  t h e GF a b o l i s h e d  The  a c i d r e s p o n s e t o meal c o m p l e t e l y  maximal r e s p o n s e t o p e n t a g a s t r i n  to histamine  by 8 4% i n d i c a t i n g t h a t  left  ( F i g u r e 7)  behind.  drained  (Figure 6 ) .  was reduced by 83% and  some a c i d s e c r e t i n g mucosa was  EFFECT OF FUNDIC MUCOSAL EXCISION ON HP RESPONSES  Basal  HP S e c r e t i o n :  significant  E x c i s i o n o f t h e f u n d i c mucosa r e s u l t e d i n  increases  the mean o f a l l b a s a l mean b a s a l histamine increase  i n basal  a c i d s e c r e t i o n from t h e HP.  collection  15 minute o u t p u t response before  taken before  increased  from 5.5±1.6% o f the maximal  e x c i s i o n t o 50.1±4.6% a f t e r e x c i s i o n , an  (Figure 8 ) :  Following  e x c i s i o n o f t h e f u n d i c mucosa  from the main stomach, a s i g n i f i c a n t the meal o c c u r r e d ,  (p < 0.05)  from 38% o f maximal h i s t a m i n e This  Pentagastrin all  each e x p e r i m e n t t h e  o f 909%.  Meal T e s t  after.  Taking  represents  increase  i n HP r e s p o n s e t o  The peak 30 m i n u t e o u t p u t output before  increased  e x c i s i o n t o 159%  a r i s e o f 418%.  Dose Response  doses o f p e n t a g a s t r i n  (Figure 9 ) : significantly  S i m i l a r l y , HP r e s p o n s e t o increased,  (p < 0.05)  The  - 37  i n c r e a s e s were more marked w i t h 0.5  yg  dose i n c r e a s e d by  increased  by  only  response to histamine  the h i g h e r  doses.  16.0  yg  EFFECT OF  (Figure 10):  was  similar  yg  dose was  The  increased,  dose by  only  concentration  but  over 10  the  dose  of  the  pentagastrin.  r e s p o n s e to to the  times w h i l e  response  the  to  the  response  to  GASTRIN RELEASE:  ( F i g u r e 11,  increased  left  e x p e r i m e n t s done 2 weeks a f t e r  panel):  from a mean o f 36±3  i n b a s a l g a s t r i n was  d i d not  the  doubled.  The  evident  an  The  basal  before  i n c r e a s e of  even w i t h  the o p e r a t i o n .  appear t o r i s e w i t h  the  688%.  first  Basal g a s t r i n  time a f t e r  e x c i s i o n of  f u n d i c mucosa.  G a s t r i n Response t o Meal meal was The  the  compared  t o a mean o f 248±47 pg/ml a f t e r ,  the  yg  exaggeration  fundusectomy  concentration  16  t o t h a t seen w i t h  FUNDIC MUCOSAL EXCISION ON  increase  r e s p o n s e to  Thus, f u n d i c mucosal e x c i s i o n i n c r e a s e d  Basal Gastrin Concentration gastrin  The  t h a t to the  more m a r k e d l y e l e v a t e d  r e s p o n s e to the 0.5 the  while  r e s p o n s e t o a l l doses was  lower doses was  lower d o s e s .  247%.  H i s t a m i n e Dose-Response  The  558%  -  significantly  peak r e s p o n s e was  Since  intragastric  postoperative decreased  pH  ( F i g u r e 11):  elevated  after  The  g a s t r i n response  to  f u n d i c mucosal e x c i s i o n .  168±12 pg/ml b e f o r e  and  was  i n the p r e o p e r a t i v e  identical  experiments, t h i s  a c i d response during  rise  (5.5)  c o u l d not  the meal  39 2±49 pg/ml  be  after. and  a t t r i b u t e d to  i n the e x p e r i m e n t s  after  - 38 -  f u n d i c mucosal e x c i s i o n .  T e s t s were commenced 14 d a y s  o p e r a t i o n and a l l meal t e s t s  completed w i t h i n 23 days  after after  operation. Although higher of  after  t h e a b s o l u t e serum g a s t r i n fundusectomy,  serum g a s t r i n  basal gastrin  r e s p o n s e t o t h e meal was  ( F i g u r e 11, l e f t  p a n e l ) the i n c r e m e n t  o v e r b a s a l was n o t changed because o f t h e h i g h  concentration  after  the o p e r a t i o n .  (Figure  11, r i g h t  panel).  EFFECT OF SOMATOSTATIN AND VIP INFUSION ON MEAL TEST RESPONSE;  Acid  Secretion;  infusion  d i d not r e v e r t  prefundusectomy difference  Gastrin  Both s o m a t o s t a t i n  Release:  release after  the meal s t i m u l a t e d HP r e s p o n s e t o  levels.  was n o t e d  ( F i g u r e 12) and VIP ( F i g u r e 13)  W i t h b o t h p e p t i d e s no s i g n i f i c a n t  from the c o n t r o l  (postfundusectomy)  S i m i l a r l y VIP i n f u s i o n  a meal t e s t when compared  (postfundusectomy) l e v e l s however r e s u l t e d  i n s i g n i f i c a n t lowering  s i g n i f i c a n t l y higher  response.  than t h a t  on  gastrin  to c o n t r o l  ( F i g u r e 13, r i g h t p a n e l ) .  ( F i g u r e 12, r i g h t p a n e l ) . D e s p i t e t h i s , still  had noH e f f e c t  levels.  Somatostatin  of the g a s t r i n the g a s t r i n  levels  r e s p o n s e was  o f t h e p r e f u n d u s e c t o m y meal  - 39 -  15% LE IGT (pH 5.5)  f  *  8000 r GF Response LU 51  a o  -g <  Pre-op 6000 4000 -  * p < 0.05  2000 -  * * * * * * Q I vOiiiiMin,.....ir>.......n i F  B1  2  3  4  p  .n.i.n'O  5  ocf  rOM-op  6  20 min Intervals FIGURE 6:  GF r e s p o n s e t o 15% l i v e r e x t r a c t meal by i n t r a g a s t r i c t i t r a t i o n (pH 5.5) b o t h p r e o p e r a t i v e l y ( c l o s e d c i r c l e s ) and p o s t f u n d u s e c t o m y (open c i r c l e s ) . I n t h i s and i n each s u b s e q u e n t f i g u r e , each p o i n t r e p r e s e n t s t h e mean (±SE) o f two e x p e r i m e n t s i n each o f f o u r dogs.  - 40 -  GF  GF "?  E  Pre-op  6000  I  Pre-op  jo 4000  /  3  a 2000  6 -a  i/  < 0  J  L  B  5  10  1  I  20  40  Histamine (fxg kg"^  L  80 160 hH)  * * » B 0.5 1.0  .  >  s  . . . " t " " *  P  o  s  ,  ? :• 2.0 4.0  8.0 16.0  Pentagastrin (/ugkg^hr" ) 1  FIGURE 7:  The e f f e c t o f g r a d e d d o s e s o f h i s t a m i n e ( l e f t p a n e l ) and p e n t a g a s t r i n ( r i g h t p a n e l ) on GF a c i d r e s p o n s e b e f o r e ( c l o s e d c i r c l e s ) and a f t e r e x c i s i o n o f t h e o x y n t i c c e l l mucosa (open c i r c l e s ) .  o  p  - 41 -  15%LE IGT (pH 5.5) | HP RESPONSE 200 r C  E o  i  J Post Op  X  o *p<0.05 3 Q.  "5 O  I  Pre Op  *G <  B  1  2  3  4  30 min Intervals  FIGURE 8:  H e i d e n h a i n pouch r e s p o n s e t o a 15% l i v e r e x t r a c t meal. The pH i s m a i n t a i n e d c o n s t a n t a t pH 5.5 t h r o u g h o u t t h e t e s t by i n t r a g a s t r i c t i t r a t i o n . A s i g n i f i c a n t i n c r e a s e i n b o t h b a s a l and meal s t i m u l a t e d r e s p o n s e i s seen i n the f u n d u s e c t o m i z e d a n i m a l s (open c i r c l e s ) as compared to t h e p r e o p e r a t i v e c o n t r o l s ( c l o s e d c i r c l e s ) .  - 42 -  HP  150 r  so  *o Post Op  1 2 0  a  *0'  fl>  2- * O  90  i 60 -  <  3:  x o  i  J*  Pre Op  30 p<0.05  5-  B0.5 1.0  2.0  4.0  8.0 16.0  Pentagastrin (jug kg~^ hr"^)  FIGURE 9 :  H e i d e n h a i n pouch r e s p o n s e t o g r a d e d doses o f p e n t a g a s t r i n i n f u s i o n b o t h b e f o r e ( c l o s e d c i r c l e s ) and a f t e r e x c i s i o n o f t h e o x y n t i c mucosa (open c i r c l e s ) *  - 43 -  T  to O  .o^Post Op  a C£  3  Q. D  o  c  'e ,§ Pre Op  o  <  *± x'  o *p<0.05  B 5  10  20  40  80  160  Histamine ( fig kg"^ hr"^)  FIGURE 10:  HP r e s p o n s e t o g r a d e d d o s e s o f h i s t a m i n e d i h y d r o c h l o r i d e both p r e o p e r a t i v e l y ( c l o s e d c i r c l e s ) and a f t e r e x c i s i o n o f t h e o x y n t i c mucosa (open circles).  - 44 -  15% LE (IGT pH 5.5 )  15% LE (IGT: pH 5.5)  1  f  400  ''ft  375 -  "<i  175 5  Post op  300 O)  c o  U  o  150  6 Post-op  E  u>125  225  J.  150  </) D  *  200  Pre-op  75  B  <  *p<0.05  ft  0  100 o O  I  I  I  I  1  2  3  4  30 min Intervals  75 50 B  1  2  3  4  30 min Intervals  FIGURE 11: L e f t P a n e l : G a s t r i n r e s p o n s e t o a 15% l i v e r e x t r a c t meal b o t h p r e o p e r a t i v e l y ( c l o s e d c i r c l e s ) and f o l l o w i n g e x c i s i o n o f t h e o x y n t i c mucosa (open c i r c l e s ) . pH was m a i n t a i n e d c o n s t a n t (5.5) t h r o u g h o u t a l l meal t e s t s by the method o f i n t r a g a s t r i c t i t r a t i o n Right Panel: G a s t r i n i n c r e m e n t over b a s a l d u r i n g the 15% l i v e r e x t r a c t meal p r e o p e r a t i v e l y ( c l o s e d c i r c l e s ) and p o s t o p e r a t i v e l y (open c i r c l e s ) .  - 45 -  %  M  A  O  15% LE IGT ( H5.5) P  rmpi  ,  ,  I  200 200  ,  15% LE IGT ( H5.5)  p y / mL  P  r  I  400  40Q  rr^ASTRiN]  160  350  a 120  300  3  O '9  80  h°  K^i""*  40hj°  QL I Bl  CO  •—•Control o o Somatostatin i  >1 I I  5  j  i  200 -  0L  L  * P <  0.05  l  l  Bl  30 min Periods  FIGURE 12: H e i d e n h a i n pouch ( l e f t p a n e l ) and serum g a s t r i n r e s p o n s e ( r i g h t p a n e l ) t o a 15% l i v e r e x t r a c t meal i n f u n d u s e c t o m i z e d a n i m a l s w i t h (open c i r c l e s ) and w i t h o u t ( c l o s e d c i r c l e s ) i n f u s i o n o f 0.5 y g k g ~ l h r ~ l somatostatin.  46  -  r 200  r  15% LE IGT (pH5.5)  HP >  160  I  120  O  3  x  h  . , 15% LE IGT (pH5.5) pg/mL r — — 400 " GASTRIN I c  If-  350  $ 300 E S 250  80 6*  L  200  L  BI  e - « Control o-o VIP  CO  40 h J 0  -  0  2  3  30 min Intervals  4  L  L  BI  2  3  4  30 min Intervals  FIGURE 13: H e i d e n h a i n pouch ( l e f t p a n e l ) and serum g a s t r i n r e s p o n s e ( r i g h t p a n e l ) t o a 15% l i v e r e x t r a c t meal i n f u n d u s e c t o m i z e d w i t h (open c i r c l e s ) and w i t h o u t ( c l o s e d c i r c l e s ) i n f u s i o n o f 1.0 yg k g h r VIP. - 1  -  1  - 47  -  DISCUSSION;  This  s t u d y has  shown t h a t e x c i s i o n of  the  oxyntic  o f the main stomach c a u s e s marked e l e v a t i o n s b o t h gastrin  and  b a s a l HP  enhancement i n the histamine. tonic  and  gastrin  These r e s u l t s are phasic  fundic  cell  to e l e v a t i o n s  i n pH  by  postulated  inhibitor  (parietal release  fundic  i n that  the method of  i n h i b i t o r ) or  (G-cell  inhibitor)?  to d e f i n i t i v e l y  significant  the  increase  the  increment  elevation parietal  on  indirectly, design  o f our  find  no  This  o f l o s s of  in be  changes were this  cell,  inhibiting  gastrin  s t u d y does However,  in gastrin concentration  i s as a r e s u l t  increase  Is  the p a r i e t a l by  the  response cannot  titration.  answer t h i s q u e s t i o n .  i n g a s t r i n over b a s a l .  i n the HP cell  elevated  intragastric  The  f o r the  i n t r a d i g e s t i v e pH  acting d i r e c t l y  cell  us  f o l l o w i n g e x c i s i o n of  This  meal i n the p o s t f u n d u s e c t o m y dogs, we in  of  of a c i d s e c r e t i o n and/or  inhibition  f o l l o w i n g a meal.  eliminated  the  and  the p r e s e n c e  mucosa i s a p o s s i b l e e x p l a n a t i o n  a c i d output  allow  serum  release.  oxyntic  due  mucosa  i s marked  to p e n t a g a s t r i n  consistent with  inhibition  in basal  In a d d i t i o n , t h e r e  r e s p o n s e t o meal, and  L o s s of p h a s i c  HP  acid secretion.  cell  not despite  following  significant  the  change  suggests that  the  inhibition  the  of  directly.  E v i d e n c e f o r removal o f a t o n i c f u n d i c  inhibitory  s u b s t a n c e ( s ) o f a c i d s e c r e t i o n and  gastrin release  i s supported  the  a c i d o u t p u t and  basal g a s t r i n  significant  elevation in basal  by  - 48  l e v e l s noted  f o l l o w i n g e x c i s i o n of  second e x p l a n a t i o n hypochlorhydria negative  -  for this  the  f i n d i n g could  that follows  and  B o t h mechanisms may  subsequently  be  involved.  within  increase  i n b a s a l g a s t r i n and  output  i s unknown.  G-cell  turnover  To  date there  The and  increased  histamine  time was  sensitivity  remove  output.  gastrin  levels  - whether G - c e l l  increase  in basal  studies  reported  on  Williams^**  reported  that  for HP  in  2 t o 4 months.  of the HP  a l s o suggests that  the  of time to a c c o u n t  909%  are no  i n dogs, but Lehy and  mice the G - c e l l t u r n o v e r  may  b a s a l HP  operation  this period  A  the  However a l l b a s a l  hyperplasia  occur  mucosa.  r e s u l t i n g in basal  increased  d a y s of the  could  cell  that  these o p e r a t i o n s  were measured w i t h i n 23  688%  be  f e e d b a c k c o n t r o l of g a s t r i n r e l e a s e  hypergastrinaemia  the  oxyntic  fundic  t o exogenous inhibition  pentagastrin  requires  tonic  activity.  The  observation  pentagastrin sensitivity While  the  and  that  the HP  histamine  o f the  oxyntic  increased  r e s p o n s e to submaximal doses  i s increased, cell  sensitivity  to t h e s e s t i m u l i  is  to h i s t a m i n e  be  the p r e s e n c e of b a s a l h y p e r g a s t r i n a e m i a f u n d i c mucosa, the explained  on  the  increased  same b a s i s .  suggests that  sensitivity The  can  somatostatin  and VIP  inhibitors  unlikely  e x c i s i o n of  that  the  candidate  the  oxyntic  removal o f the  explained  r e s u l t s suggest that been removed.  removed by  increased.  to p e n t a g a s t r i n  o f a c i d s e c r e t i o n has are  cell  latter  the  f o l l o w i n g e x c i s i o n of  inhibitor(s)  two  by the  cannot  an  Glucagon,  t h a t may  mucosa.  of  have been  I t appears  peptides  can  explain  be  - 49 -  the l o s s of in  inhibition  h i g h doses  d i d not  gastrin  levels  a meal.  While  remains  that  responsible  The  f o r these  and  glucagon,  hormone, y e t t o be  that  the maximal h i s t a m i n e the p a r i e t a l  i s compatible important  cell  i n the t r o p h i c  a marked t r o p h i c  effect  evidence  t h a t g a s t r i n has  such  identified,  response  population,29,30  on  the HP.  a trophic  a n a  i  -  n  m  results a  n  #  f a c t o r s ma;y  be  in  v a g a l nerve  inhibitory  substance  paracrine), or  is this  endings.  and  v a g a l ending  fundic  this  the mass.^l these  study  i s the  inhibitory  the f u n d i c mucosa  i s vagal a c t i v i t y  s u p p l y i n g the fundus  has  to choose between  s u b s t a n c e P have been  substance(s)  parietal  growing  cell  q u e s t i o n thus a r i s e s :  r e l e a s e d by  i f so,  inhibitory  The  a  important.  r o l e o f the vagus i n the r e l e a s e of t h i s s o m a t o s t a t i n and  is  p a t i e n t s with  i m p o r t a n t q u e s t i o n as y e t unanswered by  substance. VIP,  has  in increased  s t u d y does not a l l o w us  An  is  action - chronic  The  both  of the  There  syndrome have a h i g h e r p a r i e t a l  Indeed,  to  is  mass i n the HP  Zollinger-Ellison  factors.  i n response  hypergastrinaemia  of p e n t a g a s t r i n t o r a t s  d e s i g n o f our  serum  possibility  regulation  been removed or the r e s u l t a n t  cell  the  w i t h the h y p o t h e s i s t h a t e i t h e r  produced  parietal  nor  changes.  observation that  administration  output  the  have not e x c l u d e d  a c o m p l e t e l y new  factor  acid  we  increased  has  the HP  state  indicates  cell  revert  of t h e s e p e p t i d e s  t o t h a t o f the p r e f u n d u s e c t o m y  increased  fundic  s i n c e exogenous i n f u s i o n  Is  identified this  (endo or  required for i t s release  released d i r e c t l y (neurocrine).  With  from  the  regard to  - 50 -  fundic fact  inhibition  that  endocrine  the HP  of a c i d s e c r e t i o n ,  (parietal  i s a f f e c t e d suggests  (humoral) r a t h e r  that  In  of g a s t r i n r e l e a s e  summary, we  from  s e c r e t i o n and  inhibitor  the antrum  tonically  gastrin release.  (G-cell  that  n e i t h e r VIP  nor  is study  fundic  inhibitor).  the f u n d i c mucosa  and  phasically  G l u c a g o n , VIP  s o m a t o s t a t i n are c a n d i d a t e s f o r these substances. suggests  Our  the same f o r the  have shown t h a t w i t h i n  r e s i d e s u b s t a n c e ( s ) which both acid  i n h i b i t o r ) the  t h a n p a r a or n e u r o c r i n e .  however does not e n a b l e us t o c o n c l u d e inhibitor  this  cell  s o m a t o s t a t i n subserve  inhibit  and Our  study  this  i n h i b i t o r y mechanism, b u t does not e x c l u d e the p o s s i b i l i t y glucagon involved. fundic mucosa.  or a n o t h e r  as y e t u n i d e n t i f i e d s u b s t a n c e ( s ) may  I n a d d i t i o n t o i t s r o l e as i n h i b i t o r  s u b s t a n c e ( s ) may  a l s o be t r o p h i c  may  that  be  of s e c r e t i o n ,  t o the p a r i e t a l  cell  this  - 51 -  PART I I I ;  THE ANATOMY OF VAGAL INHIBITION OF GASTRIN RELEASE  INTRODUCTION  We have p r o v i d e d acid  evidence that  inhibitory  s e c r e t i o n and g a s t r i n r e l e a s e r e s i d e  o f the vagus  substance(s) of  i n the f u n d u s .  The r o l e  i n the r e l e a s e of these substances r e q u i r e s c l e a r e r  definition.  The vagus b o t h s t i m u l a t e s Evidence f o r vagal  inhibitory  and i n h i b i t s g a s t r i n r e l e a s e . f i b r e s was p r o v i d e d  Walsh32 h o showed t h a t a t r o p i n e  enhanced  w  hypoglycaemia constant,  stimulated  by food.33,34  vagi  stimulated increases gastrin  could  enhances g a s t r i n r e l e a s e  Further  evidence  r e s u l t s i n increased sham f e e d i n g  release.  0 0  d,  inhibitory  distribution the  truncal  vagotomy 2  occurs  i n pH i n b o t h man^S and dog.  a b a l a n c e between fibers.  ; that  ' 2 5 and i n s u l i n - s t i m u l a t e d 3  The r e l e a s e o f g a s t r i n by v a g a l therefore  a n c  pentagastrin-  T h i s postvagotomy h y p e r g a s t r i n e m i a  i n d e p e n d e n t o f change  inhibitory  s e l e c t i v e c o o l i n g of the  inhibits  2 4  f o r these  g a s t r i n response to i n s u l i n  a c i d s e c r e t i o n i n dogs,36 basal,22,23,24,25 f  held  n o t have been promoted by  by t h e f i n d i n g s t h a t  hypoglycemia,35 t h a t  the g a s t r i n r e s p o n s e t o  the pH i n the stomach was  S i m i l a r l y , atropine  i s provided  cervical  Since  t h i s enhancement  alkalinity.  fibers  i n man.  by F a r o o q and  stimulation  represents  t h e e f f e c t s o f s t i m u l a t o r y and  A clearer definition  o f both the a n a t o m i c  and t h e p h y s i o l o g i c r o l e o f t h e vagus w i t h  control of g a s t r i n release  i s required.  t h i s by i n v e s t i g a t i n g the e f f e c t  of atropine  This  r e s p e c t to  s t u d y aims t o do  and t r u n c a l  vagotomy  - 53  on  the  o f our release the  secretory  patterns  study suggest that  i n fundusectomized the  i s m e d i a t e d by v a g a l  the  antrum.  f i b e r s supplying  The  stimulant  the  results  fundus and  i s m e d i a t e d by v a g a l  In a d d i t i o n evidence  presence of a n o n g a s t r i n  animals.  i n h i b i t o r y mechanism o f g a s t r i n  s t i m u l a t i o n of g a s t r i n r e l e a s e  supplying  -  i s supplied  of a c i d s e c r e t i o n  that  fibers for  the  i n dogs.  - 54 -  PURPOSE  To define the r o l e of the vagus i n the fundic mechanism by i n v e s t i g a t i n g  inhibitory  the e f f e c t of atropine and t r u n c a l  vagotomy i n fundusectomized animals, on acid s e c r e t i o n release  and g a s t r i n  i n response to endogenous and exogenous s t i m u l i .  - 55 -  MATERIAL AND METHODS  ANIMAL  PREPARATION;  T h r e e dogs each p r e p a r e d w i t h  a gastric  H e i d e n h a i n pouch  (HP) underwent  the  oxyntic  mucosa was p e r f o r m e d as d e s c r i b e d  The  s t u d i e s were r e p e a t e d  cell  In a d d i t i o n ,  the  r e s p o n s e was  studied.  bilateral  effect  control  fistula  following  of  atropine  s t u d i e s before  recovery on the  t r u n c a l vagotomy  excision  of  previously.  from the  operation.  postfundusectomy  Following completion  transthoracic  (GF) and  of  was  these  studies  performed.  EXPERIMENTAL DESIGN:  The before  dogs were f a s t e d  each  test.  of  food but not o f  water  No t e s t s were done w i t h i n  for  18  48 h o u r s of  hours each  other.  A.  CONTROL STUDIES;  (1)  Meal T e s t by I n t r a g a s t r i c and  the  inside  Two  15-minute  GF and the  of  the  basal  HP.  collections  The t e c h n i q u e s  of  described.  D u r i n g each  clotting  of  at - 1 5 ,  0,  same as  from  serum was  60,  the and  previously  titration 30,  opened,  water.  acid c o l l e c t i o n  intragastric  the  tap  were o b t a i n e d  a c i d o u t p u t were the  venous b l o o d was o b t a i n e d After  The GF was  stomach washed w i t h  calculation  minutes.  Titration;  test  90 and 120  separated  by  cold  - 56 -  c e n t r i f u g a t i o n and stored at -40°C u n t i l assayed f o r gastin. (2)  Pentagastrin Dose Response Study;  The a c i d response  from the GF and HP to graded doses of pentagastrin was studied as described (3)  before.  Histamine Dose Response Study; graded doses of histamine  S i m i l a r l y the e f f e c t s of  d i h y d r o c h l o r i d e was assessed  as described p r e v i o u s l y .  B.  THE EFFECT OF FUNDUSECTOMY:  Following e x c i s i o n of oxyntic c e l l mucosa, the c o n t r o l s t u d i e s above were repeated.  In a d d i t i o n the e f f e c t of  atropine on the meal t e s t was assessed.  E f f e c t of Atropine on Meal Test: c o l l e c t i o n s were obtained sulphate  Two 15-minute basal  from the GF and HP.  Atropine  (0.2 mg/kg) (Galaxo, Toronto) was then i n j e c t e d  subcutaneously.  T h i r t y minutes a f t e r atropine i n j e c t i o n the  meal t e s t was commenced.  Acid and blood c o l l e c t i o n s were  performed as i n the c o n t r o l study.  C.  THE EFFECT OF TRUNCAL VATOTOMY:  Following completion vagotomy was performed. recovery  from surgery.  performed:  of the above s t u d i e s , t r u n c a l Three weeks were allowed f o r  The f o l l o w i n g t e s t s were then  - 57 -  (1)  meal t e s t by i n t r a g a s t r i c  titration  (2)  pentagastrin dose response s t u d i e s  (3)  histamine  dose response s t u d i e s .  DETERMINATION OF SERUM GASTRIN CONCENTRATION;  This has been described i n d e t a i l p r e v i o u s l y .  STATISTICAL  SIGNIFICANCE  The s i g n i f i c a n c e of the d i f f e r e n c e of the mean a c i d output and g a s t r i n responses during the c o n t r o l and postoperative experiments was analysed p-values  using a t - t e s t f o r unpaired  of l e s s than 0.05 was considered  values.  significant.  A  - 58 -  RESULTS  A.  EFFECT OF FUNDUSECTOMYt  (1)  Meal Response:  HP Acid Output: significant  increase  acid secretion seen i n Part  Fundic mucosal e x c i s i o n  resulted in a  i n both basal and meal stimulated  from the HP (Figure 1,  l e f t panel),  as  II.  G a s t r i n Response:  Similarly a significant  increase  in  basal and meal stimulated g a s t r i n release occurred f o l l o w i n g the operation (Figure 1,  (2)  right panel).  P e n t a g a s t r i n and Histamine Dose Response S t u d i e s : HP a c i d output i n response histamine  The  to exogenous p e n t a g a s t r i n and  increased s i g n i f i c a n t l y after  e x c i s i o n of  the  oxyntic mucosa (Figures 2 and 3 ) .  B.  EFFECT OF ATROPINE SULPHATE ON MEAL RESPONSE AFTER FUNDUSECTOMY:  HP A c i d Output:  The response  HP response  i n the fundusectomized animals in  to a meal was s i g n i f i c a n t l y decreased  subcutaneous  atropine i n j e c t i o n .  The peak  (74%)  secretion  after  - 59 -  decreased output  4,  meal  (peak  an o u t p u t  (MAO) b e f o r e  (Figure the  from  left  Gastrin  output  elevated  fundusectomized injection.  C.  of  after  atropine  The e f f e c t  the  HP t o  the  of  acid  injection  atropine  was  prefundusectomy  to  return  level  46±10% M A O ) .  gastrin  animals persisted  No f u r t h e r  the  response  response  elevation  i n the  (Figure  4  right  after  meal  from  seen  atropine  by I n t r a g a s t r i c  atropine  those without  atropine  FUNDUSECTOMY  Titration:  No s i g n i f i c a n t d i f f e r e n c e  between  the  responses  meal  and a f t e r  (198±51% 198±48% In atropine  the  was  dogs w i t h  Output:  panel),  the  sulphate  response  HP A c i d  before  in  panel).  E F F E C T OF TRUNCAL VAGOTOMY A F T E R  Meal Test  the  fundusectomized  no s i g n i f i c a n t d i f f e r e n c e f  to  in gastrin  showing  (1)  maximal histamine  Release:  The  noted,  52±21%  panel).  response  acid  to  o f 198±51%  peak  of  the  t r u n c a l vagotomy response  acid  noted  fundusectomized (Figure 5,  being v i r t u a l l y  maximum h i s t a m i n e  was  output  dogs  left  identical  compared  to  respectively). the  fundusectomized  compared  to  the  animals,  effect  of  the  effect  truncal  of  vagotomy  - 60 -  differed and  signficantly,  the  peak  1 9 8 ± 4 9 % maximal h i s t a m i n e  G a s t r i n Release: fundusectomized significantly  elevation  lower  study  t r u n c a l vagotomy  ( F i g u r e 5,  42±17%  respectively.  in  response  when compared to  in g a s t r i n  than i n the  being  a c i d output  dogs the g a s t r i n  elevated  prefundusectomy this  After  response  the  was  still  the  right panel).  r e l e a s e was  fundusectomized  However  significantly  animals  before  truncal  vagotomy. T h i s d r o p i n serum g a s t r i n vagotomy  ( F i g u r e 5,  levels  r i g h t panel)  was not  a c o r r e s p o n d i n g d r o p i n HP o u t p u t panel),  suggesting  stimulant  of  acid  the p r e s e n c e  output  accompanied by  ( F i g u r e 5,  of  truncal  left  a nongastrin  secretion.  When compared to acid  after  the  and g a s t r i n  effect  release  of to  atropine, a meal  both HP  significantly  differed.  Pentagastrin  and H i s t a m i n e Dose Response  Both the p e n t a g a s t r i n studies change  i n the after  and h i s t a m i n e  fundusectomized  t r u n c a l vagotomy  Studies  dose  a n i m a l s d i d not  response not  ( F i g u r e 2 and F i g u r e  3).  - 61 -  15% LE IGT ( H5.5)  15% LE IGT ( H5.5)  f  f  P  EH  P  1  200  c E o  ^  ± X o  Q. D  o  40  <  0  400h  I"  o—o Post Op  120 80  I GASTRIN  500  160  300  3  c O  -!  = 200  -5. £  O 1001-  i  1  i  -1  * p<0.05  •-•Control B  }  0  L  B  1  30 min Intervals  FIGURE 1:  H e i d e n h a i n pouch a c i d o u t p u t ( l e f t p a n e l ) and g a s t r i n r e s p o n s e ( r i g h t p a n e l ) a f t e r a 15% l i v e r e x t r a c t meal by i n t r a g a s t r i c t i t r a t i o n . Each p o i n t r e p r e s e n t s t h e mean±SE o f two e x p e r i m e n t s i n t h r e e dogs b e f o r e ( c l o s e d c i r c l e s ) and a f t e r (open c i r c l e s ) f u n d i c mucosal excision.  - 62 -  150 r  HP  0)  <> / c  o a  0)  £ - a>  O  *6 Post Op  120 o  A  90  £  .— C O 60 u  Post Op + TV  * Pre Op  •-  < ^ o 65  30  A* .5T  T - i - ^  I--  *p<0.05  .5'  »-  0 L» . B0.5 1.0  2.0  4.0  8.0 16.0  Pentagastrin (jug kg"^ hr"^)  FIGURE 2:  E f f e c t o f g r a d e d d o s e s o f p e n t a g a s t r i n on HP a c i d response i n c o n t r o l s t u d i e s ( c l o s e d c i r c l e s ) , i n f u n d u s e c t o m i z e d a n i m a l s (open c i r c l e s ) and f o l l o w i n g t r u n c a l vagotomy i n f u n d u s e c t o m i z e d a n i m a l s (open squares).  -  63  -  T  * D Post Op + TV /.aPost  Op  O *n  0) 3  C  a. £ O  o .« Pre Op  < o  *p<0.05 B5  10 20 40 80 160  Histamine ( //gkg^hr" ) 1  F I G U R E 3:  E f f e c t o f g r a d e d d o s e s o f h i s t a m i n e d i h y d r o c h l o r i d e on HP a c i d r e s p o n s e i n c o n t r o l s t u d i e s ( c l o s e d c i r c l e s ) , f u n d u s e c t o m i z e d a n i m a l s (open c i r c l e s ) and f o l l o w i n g t r u n c a l vagotomy i n f u n d u s e c t o m i z e d a n i m a l s (open squares).  - 64 -  15% LE IGT ( H5.5)  15% LE IGT ( H5.5)  P  P  m  200 c E 5  500  r  120  *  o -o Post op +  4  Atropine  so  CL  L  401-  72  <  0  T  I"  o—o Post Op  z>  O  IO ASTRINlj  E 400  160  x  i  £  1  L  ...••2  5  B  1  .oO  1  I*  300 c O o  o*  200  S ioo  •-•Control  * P<0,05 OLB  1  30 min Intervals  FIGURE  4:  H e i d e n h a i n pouch a c i d o u t p u t ( l e f t p a n e l ) and g a s t r i n r e s p o n s e ( r i g h t p a n e l ) a f t e r a 15% l i v e r e x t r a c t m e a l in control studies (closed c i r c l e s ) , following fundic m u c o s a l e x c i s i o n (open c i r c l e s ) and f o l l o w i n g a t r o p i n e i n j e c t i o n i n postfundusectomy dogs (open c i r c l e s ) .  - 65 -  15% LE IGT ( H5.5)  15% LE IGT (pH5.5)  f  I  P  on  } * j * ,iii'*'B)* • u. o  160  400  x  § ~  IGASTRIN1  *i  .E  I  500  o - o Post O p  120  a-a Post op + TV  CO a. 300-  <J c o u  80  *  I'* * f T  *  5^  40  ~D  \)  <  I  200  a O  1  ~  0  o  1  100 * P<0.05  •-•Control  9  J  B 1  L_  1  0 B 1 30 min Intervals  FIGURE 5:  Heidenhain pouch (HP) ( l e f t panel) and g a s t r i n response ( r i g h t panel) t o a 1.5% l i v e r e x t r a c t meal i n c o n t r o l studies (closed c i r c l e s ) , following fundic mucosal e x c i s i o n (open c i r c l e s ) and f o l l o w i n g t r u n c a l vagotomy a f t e r fundusectomy ( c l o s e d s q u a r e s ) .  - 66  -  DISCUSSION  E x c i s i o n of the oxyntic mucosa r e s u l t e d i n increased Heidenhain pouch response to meal and exogenous pentagastrin histamine.  and  These r e s u l t s are the same as those seen i n Part I I .  S i m i l a r l y , an increased g a s t r i n response to the meal occurred. These f i n d i n g s confirm the presence of a fundic  inhibitory  mechanism of a c i d s e c r e t i o n and g a s t r i n r e l e a s e .  The  enhanced g a s t r i n response to a meal seen a f t e r e x c i s i o n  of the oxyntic c e l l mucosa was  neither decreased  further by systemic  This suggests that the enhancing  atropine.  nor  increased  e f f e c t of atropine on food stimulated g a s t r i n release noted by previous  i n v e s t i g a t o r s - ^ 134  m a  y  j-,  e t n e  r  e  s  u  i t  of l o s s of fundic  i n h i b i t o r y mechanisms r e q u i r i n g vagal, a t r o p i n e - s e n s i t i v e innervation.  Following fundusectomy atropine reverted the HP  a c i d response  to a meal to c o n t r o l l e v e l s but f a i l e d to a b o l i s h a c i d s e c r e t i o n completely.  This f i n d i n g i s at variance with previous work i n  which atropine was  found to a b o l i s h a c i d responses of g a s t r i c  pouches to feeding.34,40 discrepancy  & p o s s i b l e explanation for t h i s  i s the presence of a nongastrin  stimulator of a c i d  s e c r e t i o n , now  unmasked by fundusectomy, which i s atropine  resistant.  cannot exclude  We  stimulated HP  the p o s s i b i l i t y that t h i s meal  response a f t e r atropine r e f l e c t s an  p a r i e t a l c e l l mass.  increased  - 67  Our  studies  showed t h a t  t r u n c a l vagotomy does not  r e s p o n s e to meal, to p e n t a g a s t r i n f u n d u s e c t o m i z e d dogs. vagotomy  (TV)  i n mind t h a t  has  -  or  to h i s t a m i n e  been shown to enhance HP already  the  l a c k of f u r t h e r e f f e c t  denervation  the  fundus may  n o n f u n d u s e c t o m i z e d dogs.  cell  vagotomy on HP  confirm  be A  a c i d response.  responsible  s t u d y of the  effect  this hypothesis.  We  have shown t h a t  s e c r e t i o n from the main stomach caused by  with  acid i s abolished  by  unproven, t h a t the  be m e d i a t e d by  parietal  cell  a reflex  r e l e a s e of t h i s  of  of  TV  parietal to  inhibition  of  antral distension  vagotomy.  inhibitory effect  effect  i s required the  to  i n d i c a t e that  f o r the  r e s p o n s e to t h e s e s t i m u l i  Bearing  response  o f TV may  acid  but  in  enhanced HP  these s t i m u l i ,  in  HP  In n o n f u n d u s e c t o m i z e d dogs, t r u n c a l  fundusectomy has  of  change  It is possible,  of a n t r a l d i s t e n s i o n inhibitor  from the  may  fundic  mucosa.  The  g a s t r i n r e s p o n s e to a meal i n the  dropped s i g n i f i c a n t l y t h a t c u t t i n g the fibers This  to the  f o l l o w i n g t r u n c a l vagotomy.  vagus n e r v e s removes not  fundus but  s u p p o r t s the  also stimulatory  f i n d i n g s that  2  antrum. 9 in  That a t r o p i n e  r e s p o n s e to f o o d ,  release who  g r e a t l y decreased  to  suggest that This  fibers  implies  inhibitory  to the  antrum.  response  to  release  denervation the  dogs  of  of  the  stimulatory  fibers  the mechanism f o r g a s t r i n concurs with  showed t h a t g a s t r i n r e l e a s e by  atropine.34  inhibit  This  the  the v a g a l  after vagal  failed  is noncholinergic.  only  i n dogs the HP  2 - d e o x y - g l u c o s e , which p r e s u m a b l y a c t s g a s t r i n , was  fundusectomized  feeding  f i n d i n g s of  i s r e s i s t a n t to  Csendes  - 68 -  VAGAL  CONTROL  O F GASTRIN  RELEASE  agus  "*«»••«•»** P y l o r o - P y l o r i c Reflex  ,  =  =  •'• ) f+j  Atropine  Resistant  Atropine  Sensitive  Atropine  Sensitivity  Unknown  Inhibition Stimulation  Vagal c o n t r o l of g a s t r i n  release.  - 69  The  -  amount of g a s t r i n released by any mode of vagal  s t i m u l a t i o n i s s u b s t a n t i a l l y smaller than can be released by or t o p i c a l a c e t y l c h o l i n e i n the antrum.  food  This suggests that  g a s t r i n release represents a balance between the e f f e c t of stimulatory and  i n h i b i t o r y vagal f i b e r s .  G a s t r i n i s released by  d i r e c t vagal s t i m u l a t i o n during the c e p h a l i c phase^S and long and  short neural r e f l e x e s , 4 1 r 4 2  a s  w  e  n  a s  by both  by d i r e c t  chemical  a c t i o n of food on the G - c e l l durng the g a s t r i c phase.^7 atropine^3 » 3 4  a n (  j t r u n c a l vagotomy increases food  g a s t r i n release g i v i n g support  Both  stimulated  to the presence of vagal  inhibitory  fibers.  The  r e s u l t s of t h i s study  suggest that i n h i b i t o r y mechanism  of g a s t r i n release i s mediated by vagal f i b e r s which supply  the  fundus and  fibers  that the stimulatory a c t i o n i s mediated by vagal  which supply  the antrum.  The  l a t t e r atropine r e s i s t a n t .  former are atropine s e n s i t i v e , the  This hypothesis,  i n combination with  the known mechanisms of g a s t r i n release, allows the d e s c r i p t i o n of a model for the mechanism of g a s t r i n release (Figure 6 ) . model o f f e r s an explanation for several f i n d i n g s . vagotomy r e s u l t s i n hypergastrinemia cannot be explained by changes i n pH. that the PCV  Parietal  2  i n both man 5 n d a  cell  dog^G which  A p o s s i b l e explanation i s  removes i n h i b i t o r y f i b e r s which subserve a fundic  i n h i b i t o r y mechanism. same i n h i b i t o r y agent.  Fundic mucosal e x c i s i o n might remove the In man,  increase i n g a s t r i n release in  response to feeding i s greater i n proximal s e l e c t i v e vagotomy.24 hypothesis  This  vagotomy than i n  These f i n d i n g s can be explained by  the  that i n h i b i t o r y mechanisms of g a s t r i n release mediated  - 70  -  by vagal f i b e r which supply the fundus and f i b e r s of g a s t r i n release  Truncal  vagotomy i n the fundusectomized animal causes  A corresponding f a l l  i n HP  gastrin  release.  s e c r e t i o n does not occur.  acid output i s v i r t u a l l y i d e n t i c a l before and  vagotomy.  stimulatory  supply the antrum.  s i g n i f i c a n t decrease i n meal stimulated  HP  that the  These f i n d i n g s are  Indeed  the  after truncal  i n keeping with the hypothesis  that  removal of the fundic mucosa unmasks a nongastrin mechanism of stimulation  of acid s e c r e t i o n .  might be explained  that TV has  Alternatively, this interrupted  observation  extra-gastric  vagal  f i b e r s which subserve release of an i n t e s t i n a l i n h i b i t o r (vagogastrone)  In summary, these p h y s i o l o g i c a l observations have served to define  the anatomy of the d i s t r i b u t i o n of vagal f i b e r s to  stomach.  The  i n h i b i t o r y a c t i o n of the vagus i s mediated  atropine-sensitive stimulatory  f i b e r s that go to the fundus, while  a c t i o n i s mediated by atropine  go to the antrum.  the by  the  r e s i s t a n t f i b e r s that  - 71 -  SUMMARY AND  CONCLUSIONS  SUMMARY AND  This  study p r o v i d e s  between the that  fundus and  fundus a c t s as  The  r e s u l t s of t h i s  distention  inhibits  inhibition  i s abolished  a pyloro-oxyntic  evidence  the  the  CONCLUSIONS  an  for a servo  antrum.  c o n t r o l mechanism  I t s u p p o r t s the  inhibitory  hypothesis  organ.  s t u d y have shown t h a t a c i d a n t r a l  a c i d s e c r e t i o n from the main stomach.  vagal  by p a r i e t a l  cell  r e f l e x mechanism  vagotomy, s u g g e s t i n g i s involved.  antral  t h a t a neurohumoral mechanism  i n h i b i t o r y mechanism  Excison  o f the  fundic  and  HP  a c i d responses.  the p r e s e n c e o f s u b s t a n c e ( s ) and  phasically inhibit  release.  The  fact  the p a r i e t a l  cell  inhibitor  u n a b l e to d e f i n e whether paracrine  An  increased  i m p l i e s an due  or n e u r o c r i n e  HP  increased  the  These r e s u l t s are  consistent  oxyntic  cell  mucosa which  acid secretion i s affected implies i s humorally mediated.  both  is  This  that  study  is  endocrine,  nature.  parietal or  with  a c i d s e c r e t i o n and/or g a s t r i n  the G - c e l l i n h i b i t o r in  main  stimulated  r e s p o n s e to maximal h i s t a m i n e  to h y p e r g a s t r i n e m i a  removal o f  in basal  the  one.  and  i n the  tonically  t h a t HP  a fundic  Thus,  ( o x y n t i c c e l l ) mucosa of the  stomach c a u s e s marked e l e v a t i o n b o t h gastrin  responses  i s involved.  is in r e a l i t y  that  Previous  s t u d i e s have shown t h a t a n t r a l d i s t e n s i o n i n h i b i t s HP suggesting  This  cell  mass.  stimulation  Whether t h i s  increase  to l o s s o f a t r o p h i c s u b s t a n c e  f u n d i c mucusa remains t o be  answered.  with  is  - 73 -  The  r e s u l t s o f the e f f e c t  of atropine  f u n d u s e c t o m i z e d dogs s u p p o r t  the h y p o t h e s i s  mechanism o f g a s t r i n r e l e a s e  i s mediated  sensitive  f i b e r s which  action  i s mediated  supply  the antrum.  supply  by v a g a l ,  and  that  the  by v a g a l ,  the fundus and atropine  t r u n c a l vagotomy on  that  inhibitory  atropine the  stimulatory  resistant fibers  In a d d i t i o n , the f i n d i n g s s u g g e s t s  presence of a nongastrin  stimulatant  of acid s e c r e t i o n .  which the  - 74  -  REFERENCES  Debas HT,  Konturek SJ,  pyloro-oxyntic  reflex  Walsh JH, for  stimulation  G a s t r o e n t e r o l o g y 66:526-532,  S t a t e D, antrum  K a t z A,  K a p l a n RS,  in experimentally  Forum 5:278-280,  Lakey WH,  inhibitor  the  DuVal MK  of  49:569-572,  acid  of  secretion.  1974.  et  al:  The  role  induced u l c e r a t i o n  Hyde AA:  gastric  J r . , Fagella  regulation  of  Proof  of  the  pyloric  i n dogs.  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