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Reflex cardiovascular and renal responses from the pulmonary arteries of the anesthetized dog Kan, Wai-On 1977

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REFLEX CARDIOVASCULAR AND RENAL RESPONSES FROM THE PULMONARY ARTERIES OP THE ANESTHETIZED DOG BY WAI-ON KAN B.Sc. (DISTINCTION), WASHINGTON STATE UNIVERSITY, 1970 M . S c , UNIVERSITY OP SOUTHERN CALIFORNIA, 1973 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY IN THE DEPARTMENT OF PHYSIOLOGY FACULTY OF MEDICINE We  accept  this  thesis  the r e q u i r e d  as conforming  to  standard  THE UNIVERSITY OF BRITISH COLUMBIA NOVEMBER, 1976  ©  Wai-On Kan, 1977  In  presenting  an  advanced  the I  Library  this  degree shall  f u r t h e r agree  for  scholarly  by h i s of  this  written  at  that  it  purposes  for  may It  is  British  April  6,  1977  of  Columbia,  British  by  for  gain  Columbia  shall  the  that  not  requirements I agree  r e f e r e n c e and copying  t h e Head o f  understood  Physiology of  of  for extensive  permission.  University  fulfilment  available  be g r a n t e d  financial  2075 Wesbrook Place Vancouver, Canada V6T 1WS  Date  freely  permission  representatives. thesis  in p a r t i a l  the U n i v e r s i t y  make  Department o f The  thesis  of  this  be a l l o w e d  or  that  study. thesis  my D e p a r t m e n t  copying  for  or  publication  without  my  ii ABSTRACT A preparation i s described u t i l i z i n g a  constant  flow, right-heart bypass f o r perfusion of the i s o l a t e d main pulmonary a r t e r i e s at c o n t r o l l e d pressures.  I t i s demons-  t r a t e d that stepwise increments of pressure  i n the pulmon-  ary a r t e r i e s are accompanied by increases i n systemic vascular resistance and i n hind-limb vascular r e s i s t a n c e . These changes were demonstrated over the whole range of 5-120 cm ILjO pressure  i n the pulmonary a r t e r i e s .  In contrast  there were no s i g n i f i c a n t changes i n renal vascular r e s i s tance or heart r a t e .  I t i s .also shown that changing the  temperature of the perfusate  i n the pulmonary a r t e r y from  37°C to 30°C i s associated with a decrease i n systemic vascular r e s i s t a n c e .  The e f f e c t s of r a i s i n g the pulmonary  a r t e r i a l pressure and of cooling the pulmonary a r t e r y were abolished by c e r v i c a l vagotomy.  I t i s suggested that there  i s a t o n i c r e f l e x vasoconstrictor tone generated by a c t i v i t y of receptors l y i n g i n or close to the walls of the pulmonary artery.  I t i s f u r t h e r suggested that the d i f f e r e n t i a l  e f f e c t s on systemic vascular resistance and r e n a l resistance may d i s t r i b u t e cardiac output p r e f e r e n t i a l l y to the kidney providing one mechanism by which changes i n blood may l e a d to appropriate  volume  changes i n renal solute excretion.  The l a t e r hypothesis was put to t e s t by c o l l e c t i n g urine from the i n t a c t kidneys of animals with i s o l a t e d pulmonary pouch preparation.  A step increase i n the pouch  pressure  evoked a corresponding r i s e i n the urinary volume, osmolar  iii clearance, sodium excretion r a t e , but not the free water clearance and the potassium excretion r a t e .  The response  may be caused by renal hemodynamic changes as a r e s u l t of the r e f l e x increase i n systemic a r t e r i a l pressure.  The  r i s e i n sodium excretion rate continued even a f t e r the release of the pressure i n the pulmonary artery pouch thus the r o l e of a n a t r i u r e t i c hormone i n the r e f l e x was suspected.  A s e r i e s of animals with one kidney i n t a c t and one  kidney i s o l a t e d and perfused with constant pressure was used i n attempt to demonstrate the n a t r i u r e t i c  action.  These r e s u l t s confirmed the hemodynamic e f f e c t on the urinary f u n c t i o n of the i n t a c t kidney.  In the i s o l a t e d kidney there  was no s t a t i s t i c a l l y s i g n i f i c a n t increase i n sodium excreti o n r a t e , therefore the r o l e of a n a t r i u r e t i c agent i n the r e f l e x response to distension still  uncertain.  of the pulmonary artery i s  iv ACKNOWLEDGEMENTS I would l i k e to thank my supervisor, Dr. J.R. Ledsome, f o r h i s continuous support and encouragement throughout the course of t h i s study, e s p e c i a l l y during the preparation of t h i s t h e s i s . I would also l i k e to thank Mrs. L. Punnell, Mrs. R. Anderson and Ms. K. Kason f o r t h e i r excellent t e c h n i c a l a s s i s t a n c e . I am also g r a t e f u l to Dr. C P . B o l t e r f o r the i n t e r e s t he showed i n my work and h i s u s e f u l advice. S p e c i a l thanks are due to Mr. K. Henze and Mr. R. Assinna f o r arranging the supply of experimental animals and producing the i l l u s t r a t i o n s . Thanks to my wife, Joyce, f o r her patient and understanding during t h i s study. F i n a l l y I'd l i k e to dedicate t h i s t h e s i s to my l a t e grand-mother.  Her support, i n s p i r a t i o n and love to  her grand-children made t h i s p o s s i b l e .  V  TABLE OF CONTENTS PAGE INTRODUCTION  1  METHODS  5  A. ANESTHESIA AND GENERAL PREPARATION  6  B. RIGHT-HEART BYPASS AND PULMONARY ARTERY POUCH PREPARATION  7  C. HIND-LIMB AND KIDNEY PERFUSION  11  a) HIND-LIMBS  11.  b) KIDNEYS  13  D. COOLING  15  E. URINE COLLECTION-KIDNEYS INTACT  16  F. URINE COLLECTION-INTACT AND ISOLATED KIDNEYS  18  EXPERIMENTAL PROTOCOL  24  A. LIMB AND KIDNEY PERFUSION B. COOLING  25 ....  26  C. URINE COLLECTION  27  D. COMPARISON OF INTACT AND ISOLATED KIDNEYS,:.  29  EVALUATION OF EXPERIMENTAL TECHNIQUES  30  A. CONSTANT FLOW/PRESSURE PREPARATION  30  B. HEART RATE CALCULATION .  32  C. PRESSURE AND FLOW RECORDINGS  33  D. URINE AND PLASMA ANALYSIS  34-  E. FEEDBACK CONTROL CIRCUITS  36  F. MATHEMATICAL METHODS  ..  38  a) CORRECTION TO ABSOLUTE ZERO PRESSURE ..  38  v i  b) t-TEST  38  c) WLLCOXON TWO SAMPLE. RANK TEST  39  RESULTS  41  A. CARDIOVASCULAR EFFECTS OF GRADED PULMONARY ARTERY DISTENSION  41  a) SYSTEMIC PRESSURE AND HEART RATE CHANGES  41  b) CHANGE IN LIMB RESISTANCE  43  c) CHANGES IN KIDNEY VASCULAR RESISTANCE .  47  d) PERFUSION WITH SALINE AT DIFFERENT' TEMPERATURES  48  B. DISTENSION OF THE PULMONARY ARTERY WITH 30°C SALINE  50  C. EFFECT OF VAGAL SECTION  52  D. URINE COLLECTION EXPERIMENTS  54  a) CARDIOVASCULAR EFFECTS  54-  b) EFFECT ON URINE VOLUME  63  c) EFFECT ON OSMOLAR CLEARANCE  65  d) EFFECT ON SODIUM EXCRETION  68  e) EFFECT ON POTASSIUM EXCRETION  70  f ) EFFECT ON FREE WATER CLEARANCE  72  E. URINE COLLECTION WITH ONE KIDNEY ISOLATED AND PERFUSED  . 75  a) INTACT KIDNEY  75  b) ISOLATED KIDNEY  80  vii DISCUSSION A. REVIEW a) EMBRYOLOGICAL EVIDENCE b) HISTOLOGICAL STUDIES  8  6 86 86 '87  c) INNERVATION OP THE PULMONARY ARTERY . . .  89  d) ELECTROPHYSIOLOGICAL STUDIES -  91  e) DRUG STIMULATION STUDIES  94  f ) PULMONARY-ARTERY DISTENSION STUDIES . . .  96  g) SUMMARY  99  B. CARDIOVASCULAR EFFECT OF PULMONARY ARTERY DISTENSION  102  C. URINE EXCRETION FROM THE INTACT KIDNEYS IN RESPONSE TO PULMONARY ARTERY DISTENSION . . .  109  D. A POSSIBLE PHYSIOLOGICAL ROLE OF THE REFLEX RESPONSE TO PULMONARY ARTERIAL DISTENSION .  142  SUMMARY  155  REFERENCES  157  viii LIST OF FIGURES FIGURE  PAGE  1  R i g h t - h e a r t bypass p r e p a r a t i o n  9  2  Hind-limb p e r f u s i o n p r e p a r a t i o n  12  3  Kidney p e r f u s i o n p r e p a r a t i o n  14  4  Feedback c o n t r o l c i r c u i t  37  5  Systemic pressure and heart r a t e changes v s . pulmonary a r t e r i a l pressure (pulmona r y a r t e r y perfused w i t h 37°C blood) . . . .  42  6  Changes i n h i n d - l i m b and r e n a l v a s c u l a r r e s i s t a n c e v s . pulmonary a r t e r i a l p r e s sure (pulmonary a r t e r y * p e r f u s e d w i t h 37°C blood)  ...  45  7  Tape playback of a h i n d - l i m b p e r f u s i o n experiment  46  8  Tape playback r e c o r d of a pulmonary a r t ery c o o l i n g experiment  49  9  Changes i n systemic a r t e r i a l pressure and heart r a t e v s . pulmonary a r t e r i a l pressure (pulmonary a r t e r y perfused w i t h 30°C s a l i n e )  51  Systemic a r t e r i a l pressure and heart r a t e responses a f t e r c u t t i n g the vagus nerves  53  Urine e x c r e t i o n responses from the i n t a c t kidneys ( c o n t r o l experiments)  56  Urine e x c r e t i o n responses from the i n t a c t kidneys (pulmonary a r t e r y distended to 40 cm H~0)  58  10  11 12  ix FIGURE 13  PAGE Urine e x c r e t i o n responses from the i n t a c t kidneys (pulmonary a r t e r y distended t o 80 cm H 0)  60  Systemic a r t e r i a l pressure responses pulmonary a r t e r y d i s t e n s i o n  62  2  14 15 16 17 18 19 20  21  to  U r i n a r y volume responses to pulmonary artery distension U r i n a r y osmolar clearance responses pulmonary a r t e r y d i s t e n s i o n U r i n a r y sodium e x c r e t i o n responses pulmonary a r t e r y d i s t e n s i o n  •  64  to 67 to  U r i n a r y potassium e x c r e t i o n responses pulmonary a r t e r y d i s t e n s i o n U r i n a r y f r e e water clearance responses pulmonary a r t e r y d i s t e n s i o n  69 to 71 to •  73  Systemic a r t e r i a l pressure and u r i n a r y f u n c t i o n responses of the i n t a c t kidneys t o pulmonary a r t e r y d i s t e n s i o n . . . . . . . . . .  77  Renal blood f l o w and u r i n a r y f u n c t i o n responses of the i s o l a t e d kidneys to pulmonary a r t e r y d i s t e n s i o n  81  X  LIST OF TABLES TABLE 1  PAGE Experiments performed  21 22 23  2  R e s u l t s from the c o n t r o l u r i n e c o l l e c t i o n experiments  3  57  R e s u l t s from the u r i n e c o l l e c t i o n e x p e r i ments (pulmonary a r t e r y distended to 40 cm H 0) 59 2  4  R e s u l t s from the u r i n e c o l l e c t i o n e x p e r i ments (pulmonary a r t e r y distended to 80 cm H 0)  61  5  S t a t i s t i c a l r e s u l t s of the u r i n e c o l l e c t i o n experiments  74  6  R e s u l t s from the i n t a c t kidney p e r f u s i o n experiments  78  7  R e s u l t s from the i s o l a t e d kidney p e r f u s i o n experiments  82  8  S t a t i s t i c a l r e s u l t s from the i n t a c t  2  and i s o l a t e d kidney experiments  85  1  INTRODUCTION J . P. P e t e r s (1935) f i r s t proposed a p r i n c i p l e of c i r c u l a t o r y blood volume c o n t r o l .  He reasoned t h a t the f u l l -  ness of the blood stream may provoke d i u r e t i c response on the p a r t of the k i d n e y .  Many groups of i n v e s t i g a t o r s have  v e r i f i e d t h i s concept e x p e r i m e n t a l l y by i s o s m o t i c  expansion  of b l o o d volume, among them B o r s t (1948), Zuidema, C l a r k e , Reeves, Gauer and Henry (1956) recorded an i n c r e a s e i n u r i n e f l o w a f t e r the expansion.  A n a l y s i n g the d i s t e n s i b i -  l i t y p r o p e r t i e s throughout the c i r c u l a t i o n Gauer and Henry (1963) adapted the terms l o w - and high-pressure systems t o d i s t i n g u i s h the pulmonary c i r c u l a t i o n , r i g h t heart and capacitance v e s s e l s from the systemic a r t e r i a l c i r c u l a t i o n . Because of the e l a s t i c r e s i s t a n c e of the low-pressure  cir-  c u i t i s 100 t o 200 lower than the high-pressure c i r c u i t they reasoned t h a t d u r i n g a b l o o d volume expansion the majori t y of the e x t r a volume would go t o the low-pressure  circuit.  Prom a p h y s i c a l p o i n t of view b i o l o g i c a l r e c e p t o r s r e g i s t e r i n g v a s c u l a r bed t e n s i o n a t a n y i r e g i o n throughout^the l o w pressure system c o u l d sense the " f u l l n e s s of the blood s t r e a m " , and f u n c t i o n as "volume r e c e p t o r s " . E f f o r t s to l o c a t e the r e c e p t o r s i n the low-pressure system have r e s u l t e d i n f u r t h e r f u n c t i o n a l s u b d i v i s i o n i n t o i n t r a t h o r a c i c and capacitance v e s s e l compartments.  Differ-  ent types of maneuvers t o a l t e r the i n t r a t h o r a c i c blood volume such as h i g h p o s i t i v e pressure b r e a t h i n g  (Drury,  2  Henry and Goodman, 194-7; Murdaugh, S i e k e r and M a n f r e d i , 1959)» negative pressure b r e a t h i n g ( S i e k e r , Gauer and Henry, 1954-; Pabst and Gauer, 1959)» water immersion ( A r b o r e l i u s , B a l l d i n , L i l l e t and Lundgren, 1972; Lange, Lange, Echt and Gauer, 1974-) and s a l i n e i n f u s i o n ( S t r a u s s , D a v i s , Rosenbaum and R o s s m e i s l , 1951; L e v i n s k y and L a l o n e , 1963) were employed t o i n v e s t i g a t e the i n t r a t h o r a c i c a r e a . The general r e s u l t of a l l these d i f f e r e n t experiments was t h a t an expanded i n t r a t h o r a c i c volume would b r i n g on a d i u r e s i s and n a t r i u r e s i s , w h i l e a decreased i n t r a t h o r a c i c volume i s f o l l o w e d by o l i g u r i a .  Since there are no proven  r e f l e x a c t i v i t i e s o r i g i n a t i n g from the capacitance v e s s e l s i t i s w i d e l y accepted t h a t the i n t r a t h o r a c i c compartment i s a ref1exogenic area which r e g u l a t e s b l o o d volume. E l e c t r o p h y s i o l o g i c a l r e c o r d i n g s of the rhythmic a c t i v i t y i n vagal a f f e r e n t s from the heart have shown a p o p u l a t i o n of nerve endings on the low-pressure s i d e of the c i r c u l a t i o n f u n c t i o n i n g as r e c e p t o r s ( P a i n t a l , 1953)•  In  the case of some l e f t a t r i a l r e c e p t o r s the stimulus appears t o be r e l a t e d t o the degree of s t r e t c h of the a t r i a l muscle f i b e r s thus the i n t r a t h o r a c i c blood volume.  D i s t e n s i o n of  the l e f t a t r i u m by i n f l a t i n g a b a l l o o n has produced an unequivocal d i u r e t i c response (Ledsome, Linden and O'Connor, 1961; Shu'ayb, Moran and Zimmermann, 1965; Johnson, Moore and Segar, 1969).  The d i u r e s i s although challenged by some  i n v e s t i g a t o r s has been shown by good evidence t o be mediated  3  through the c o n t r o l of ADH r e l e a s e (Ledsome and Mason, 1972; De T o r r e n t e , Robertson, McDonald and S c h r i e r , 1975).  The  ADH mechanism e x p l a i n e d the i n c r e a s e i n f r e e water clearance a s s o c i a t e d w i t h an expanded i n t r a t h o r a c i c blood volume but i t can not account f o r the accompanying s m a l l n a t r i u r e s i s . Other s i t e s i n the i n t r a t h o r a c i c area have a l s o been examined for possible reflexogenic e f f e c t s . The main pulmonary a r t e r y and i t s b i f u r c a t i o n s r i c h l y s u p p l i e d w i t h sensory nervous endings.  is  I t i s developed  from the VI embryonic v i s c e r a l a r c h (Koch, 1931) and s t r u c t u r a l l y s i m i l a r t o the c a r o t i d sinus and a o r t i c a r c h b a r o receptor s i t e s .  Since the f i r s t h i s t o l o g i c a l study by  D o g i e l (1898) nervous endings i n conspicuous r i n g s , w i t h branching c o i l s and f i b e r s w i t h bushy endings have been r e p o r t e d by many i n v e s t i g a t o r s (Nonidez, 1937; C o l e r i d g e , K i d d and Sharp, 1961; G r i g o r ' e v a , 1962), they are thought t o be b a r o r e c e p t o r s .  Both sympathetic and parasympathetic  i n n e r v a t i o n s have been t r a c e d t o the pulmonary a r t e r y r e c e p t o r s ( C o l e r i d g e , Kidd and Sharp, 1961; Edgeworth,  1892;  G r i g o r ' e v a , 1962) and the nervous connections can e i t h e r be f a s t conducting l a r g e diameter myelinated A f i b e r s o r s m a l l myelinated or unmyelinated C f i b e r s ( C o l e r i d g e , C o l e r i d g e , Dangel, K i d d , Luck and S l e i g h t , 1973)•  The l a r g e myelinated  v a g a l f i b e r s discharge a c t i v e l y a t pressures normally present i n the pulmonary a r t e r y .  Besides these nervous  endings  Nonidez (1937) d e s c r i b e d some glomus t i s s u e i n the pulmonary a r t e r y a d v e n t i t i a which might f u n c t i o n as chemoreceptors.  4 Attempts t o s t i m u l a t e the pulmonary a r t e r y r e c e p t o r s w i t h h y d r a u l i c pressure have produced i n c o n s i s t e n t r e s u l t s ( C h u r c h i l l and Cope, 1929} S c h w e i t z e r , 1936; P a r i n , 194-7) •  P a r t of the i n c o n s i s t e n c y may be caused by pressure  changes i n the lungs when the pulmonary a r t e r i a l was i n c r e a s e d .  pressure  Improved techniques developed by Osorio  and Russek (1962), C o l e r i d g e and K i d d (1963) allowed the pulmonary a r t e r i a l pressure t o be i n c r e a s e d l o c a l l y without impairment to the c a r d i a c output. of responses.  They r e p o r t e d two types  Weak d i s t e n s i o n of the a r t e r y produced e i t h e r  no change or a f a l l i n systemic p r e s s u r e , w h i l e a s t r o n g e r d i s t e n s i o n always produced a r i s e . The e x i s t e n c e of a l a r g e p o p u l a t i o n of receptors i n the pulmonary a r t e r y has been proven beyond any doubt. T h e i r a f f e r e n t pathways and a c t i v i t i e s under d i f f e r e n t p u l monary a r t e r i a l pressures have a l s o been c l o s e l y examined, but so f a r t h e i r p h y s i o l o g i c a l f u n c t i o n i s s t i l l u n c e r t a i n . The only c o n s i s t e n t r e s u l t known i s an i n c r e a s e i n the systemic pressure when the pulmonary a r t e r y i s s u b j e c t e d t o pressure above 80 mm Hg. The f o l l o w i n g experiments were undertaken i n the hope t h a t a f u r t h e r improved experimental t e c h n i q u e , p r o v i d i n g b e t t e r c o n t r o l of the p h y s i o l o g i c a l v a r i a b l e s i n v o l v e d , would e l u c i d a t e the r e f l e x c a r d i o v a s c u l a r e f f e c t s of p u l monary a r t e r y pressure changes and t h e i r p o s s i b l e r o l e i n the r e g u l a t i o n of blood volume.  5 METHODS The experimental design allowed three major r e f l e x response p r o p e r t i e s o r i g i n a t i n g from the pulmonary a r t e r y t o be i n v e s t i g a t e d .  The f i r s t group of experiments  were designed t o demonstrate the changes i n the h i n d - l i m b , kidney and the general systemic v a s c u l a r r e s i s t a n c e as a r e s u l t of changes i n the pulmonary a r t e r y p r e s s u r e .  In  the second grdup the combined e f f e c t s of c o o l i n g and d i s t e n d i n g the pulmonary a r t e r y and the r o l e of the vagus nerves were i l l u s t r a t e d .  The l a s t group of experiments  showed the r e g u l a t i o n of u r i n e output when the pulmonary a r t e r y was subjected t o d i f f e r e n t s t a t i c pressure, and examined the behaviour of i n t a c t and i s o l a t e d kidneys response to the same pulmonary a r t e r y d i s t e n s i o n .  in  6 A.  Anesthesia and General P r e p a r a t i o n Mongrel dogs of 20 t o 35 kg were  subcutaneously  i n j e c t e d w i t h morphine sulphate (0.5 mg/kg).  One hour  l a t e r under l o c a l a n e s t h e s i a (mepivacaine h y d r o c h l o r i d e , 1$) a p o l y e t h y l e n e c a t h e t e r was i n s e r t e d through a saphenous v e i n i n t o the i n f e r i o r vena cava and each dog was anesthet i z e d by c h l o r a l o s e ( B r i t i s h Drug Houses).  (The c h l o r a l o s e  was prepared i n a s o l u t i o n of 0.9% NaCl at 60°C t o make a 1 gm chloralose/100 ml NaCl s o l u t i o n .  This s o l u t i o n was  f i l t e r e d t o remove u n d i s s o l v e d p a r t i c l e s p r i o r t o use. The c h l o r a l o s e was i n f u s e d through the saphenous cannula (0.1 gm/kg) to induce a n e s t h e s i a .  Subsequently, d u r i n g the  experimental procedures a steady s t a t e of l i g h t  anesthesia  and f l u i d input was maintained by the constant i n f u s i o n of a d d i t i o n a l c h l o r a l o s e s o l u t i o n i n t o the e x t e r n a l j u g u l a r v e i n d e l i v e r e d by a motor d r i v e n s y r i n g e pump (Harvard Apparatus Co. I n c . , Dover, Mass.).  The compositions  and  i n f u s i o n r a t e s of the a d d i t i o n a l c h l o r a l o s e s o l u t i o n s are l i s t e d under the i n d i v i d u a l groups of experiments. Body temperature of the animal was maintained around 37°C u s i n g a heated t a b l e c o n t r o l l e d by a t h e r m i s t o r probe i n s e r t e d i n t o the esophagus, a c t i v a t i n g a t e l e thermometer c o n t r o l u n i t (Yellow S p r i n g Instruments Inc.).  Co.,  Systemic a r t e r i a l pressure was recorded through a  8 cm l e n g t h of t e f l o n t u b i n g (1 mm bore) from e i t h e r the r i g h t femoral a r t e r y o r the r i g h t b r a c h i a l a r t e r y .  Elec-  7  trocardiogram was recorded from leads placed i n the r i g h t l e g and chest r e g i o n .  The s i g n a l was a m p l i f i e d by a p r e -  a m p l i f i e r (Grass Instruments, Quincy, Mass., P15) and d i s p l a y e d on an u l t r a v i o l e t r e c o r d e r .  Heart r a t e was  c a l c u l a t e d by counting the e l e c t r o c a r d i o g r a m r e c o r d over p e r i o d s of t h i r t y seconds. B.  Right-Heart Bypass And Pulmonary A r t e r y Pouch P r e p a r a t i o n As soon as p o s s i b l e a f t e r the i n d u c t i o n of anes-  t h e s i a a r t i f i c a l r e s p i r a t i o n was s t a r t e d v i a a t r a c h e a l cannula w i t h a mixture of 40$ oxygen i n a i r , s u p p l i e d from a r e s p i r a t i o n pump (Harvard Model 614) a t a r a t e of 14 s t r o k e s per minutes and a stroke volume of approximately 13 ml/kg body weight.  End t i d a l C0 $ was  monitored at the t r a c h e a l cannula by a C 0 M e d i c a l gas a n a l y z e r , Model L B - 1 ) .  continuously  2  2  analyser  (Beckman,  When the chest was  opened a r e s i s t a n c e t o e x p i r a t i o n equivalent t o 3 cm H 0 2  was p r o v i d e d by an e x h a l a t i o n v a l v e (Ohio Chemical C o . ) . During the s u r g i c a l procedures, the dogs r e c e i v e d a slow i n f u s i o n of 100 ml of Dextran (6$ Dextran 75 i n 0.9$ NaCl Travenol Inc.)  f o r each 13 kg body weight  (approximately  10$ o f t h e i r estimated blood volume). Thoracotomy was performed by s p l i t t i n g the sternum i n the m i d l i n e .  S u e c i n y l c h o l i n e c h l o r i d e (Squibb L a b o r a -  t o r i e s , 0.5 mg/kg) was given t o the animals before the thoracotomy to e l i m i n a t e muscular t w i t c h i n g which i n t e r -  8 f e r e d w i t h the surgery.  The s k i n and muscle were d i v i d e d  u s i n g e l e c t r o c a u t e r y ( B i r t c h e r model 755 E l e c t r o - s u r g i c a l u n i t ) , an e l e c t r i c s u r g i c a l saw (Styker Corp. model 8381210) was used t o s p l i t the sternum.  Hemostasis was a c h i e -  ved by t y i n g and c u t t i n g the i n t e r n a l mammary a r t e r i e s and v e i n s , c a u t e r i z i n g and bone waxing the cut surfaces of the bone. The l e f t pulmonary a r t e r y was d i s s e c t e d f r e e c l o s e t o i t s p o i n t of b i f u r c a t i o n o u t s i d e the p e r i c a r d i u m at the r o o t of the l e f t l u n g s .  A double lumen s t a i n l e s s s t e e l  cannula w i t h an i n n e r tube of 0.5 mm bore f o r pressure r e c o r d i n g and an outer tube of 5 nun bore f o r p e r f u s i o n was i n s e r t e d i n t o the l e f t pulmonary a r t e r y .  Right heart bypass was  e s t a b l i s h e d by i n s e r t i n g a 1 cm bore p o l y e t h y l e n e t u b i n g i n t o the r i g h t a t r i a l appendage and advancing i t i n t o the right ventricle.  Blood d r a i n e d through the t u b i n g i n t o a  constant temperature r e s e r v o i r which was maintained a t 37°C. From the r e s e r v o i r , b l o o d passed through an electromagnetic f l o w meter ( B i o t r o n i c s I n c . BL 610) and was pumped i n t o the l e f t lungs by a r o l l e r pump; constant f l o w and thus  constant  c a r d i a c output being maintained u s i n g a negative feedback c o n t r o l s i g n a l from the electromagnetic f l o w meter ( F i g . 1')-. Before opening the p e r i c a r d i u m , p r o p r a n o l o l (0.3 mg/kg, i n 20 ml of 0.9% s a l i n e ) was i n j e c t e d i n t r a v e n o u s l y t o reduce the t a c h y c a r d i a and arrhythmias which accompanied h a n d l i n g of the heart d u r i n g the s u r g i c a l procedure.  A priming  dose of h e p a r i n (500 u n i t s / k g i . v . , h e p a r i n sodium 100 u n i t s  9  Fig. 1  Diagram of method of r i g h t heart "bypass and p e r f u s i o n of the i s o l a t e d pulmonary arteries.  10  /mg, N u t r i t i o n a l Biochemical's Corp.) was i n j e c t e d p r i o r t o e s t a b l i s h i n g the r i g h t heart bypass. The r o o t of the main pulmonary a r t e r y was c a r e f u l l y separated from the a o r t a and a snare placed around the pulmonary a r t e r y j u s t above the pulmonary v a l v e .  Branches  of the r i g h t pulmonary a r t e r y s u p p l y i n g the f i r s t and t h i r d lobes of the r i g h t l u n g were a l s o d i s s e c t e d f r e e ; the r o o t of the second and f o u r t h lobes were t i e d t i g h t l y .  The  cannula i n the f i r s t r i g h t pulmonary a r t e r y branch provided the i n f l o w from the pump and was a l s o a double lumen s t a i n l e s s s t e e l cannula, an i n n e r tube of 0.5 mm bore was used f o r pressure r e c o r d i n g the l a r g e r outer tube of 3 mm bore for perfusion.  The t i p of the i n f l o w cannula was p l a c e d  c l o s e t o the pulmonary a r t e r y b i f u r c a t i o n t o i n s u r e  thorough  mixing of the p e r f u s a t e i n the a r t e r y , thus a c h i e v i n g an uniform temperature throughout the pouch.  The o u t f l o w  was through the t h i r d branch of the r i g h t pulmonary a r t e r y v i a a s i n g l e lumen 3 mm bore s t a i n l e s s s t e e l cannula.  Thus  the main pulmonary a r t e r y and i t s b i f u r c a t i o n became a c l o s e d pouch which was perfused w i t h b l o o d , or s a l i n e as s p e c i f i e d i n the d i f f e r e n t groups of experiments, by a r o l l e r pump which drew venous blood from the r e s e r v o i r or warm s a l i n e from a separate r e s e r v o i r .  Pressure i n the pulmon-  a r y a r t e r i a l pouch c o u l d be v a r i e d by c o n t r o l l i n g the speed of the r o l l e r pump and by a screw clamp placed on the o u t - f l o w of the c i r c u i t . The r i g h t h e a r t bypass and pulmonary a r t e r y pouch were prepared i n a l l the experiments d e s c r i b e d i n t h i s  thesis.  11 The r e s e r v o i r and t u b i n g were primed w i t h a mixture of 50$ Dextran (6$ Dextran 75 i n 0.9$ N a C l , Pharmacia or Travenol* Inc.)  and 50$ Ringer L a c t a t e s o l u t i o n (Travenol Inc.)  the  t o t a l p r i m i n g f l u i d was e i t h e r one, two o r three l i t e r s depending on the experiment.  During the experimental obser-  v a t i o n s a maintenance dose of h e p a r i n (50 u n i t s / k g  i.v.)  was admistered every t h i r t y minutes. C.  Hind-Limb And Kidney P e r f u s i o n  a)  Hind-limbs The h i n d - l i m b s were perfused i n s i x dogs t o i n v e s -  t i g a t e the e f f e c t of pulmonary a r t e r i a l d i s t e n s i o n on the hind-limb vascular resistance.  A r i g h t heart bypass was  prepared as d e s c r i b e d b e f o r e , then a f l a n k i n c i s i o n was made on the l e f t s i d e exposing a segment of the descending a o r t a between the r e n a l a r t e r i e s and the common i l i a c a r t e r i e s . Upon t y i n g the i n f e r i o r mesenteric and lumbar a r t e r i e s i n t h a t s e c t i o n a 5 mm diameter s t a i n l e s s s t e e l cannula was i n s e r t e d r o s t r a l l y below the r e n a l a r t e r i e s , the a r t e r i a l blood then passed through a constant f l o w r o l l e r pump and an electromagnetic f l o w meter ( B i o t r o n i c s I n c . BL 610) and entered the animal through a double lumen cannula (5 mm bore outer t u b e , 0.5 mm bore i n n e r tube f o r pressure  recording)  i n s e r t e d c a u d a l l y above the common i l i a c a r t e r i e s ( P i g . 2 ) . The pump was adjusted such t h a t the p e r f u s i o n pressure of the h i n d - l i m b was approximately the same as the systemic pressure a t the beginning of the experiment and the bld'od f l o w was then maintained constant throughout the experiment.  12  Fig. 2  Diagram of method of h i n d - l i m b p e r f u s i o n .  For both the limb p e r f u s i o n and kidney p e r f u s i o n experiments the r e s e r v o i r was primed w i t h 1 l i t e r of the Dextran and Ringer L a c t a t e m i x t u r e .  Continuous  anesthesia  was maintained by constant i n f u s i o n of 0.5% c h l o r a l o s e s o l u t i o n (0.5 g c h l o r a l o s e i n 100 ml of 0.9% sodium c h l o r i d e s o l u t i o n ) a t a r a t e of approximately 1.0 ml/min. The pulmonary a r t e r i a l pouch was perfused w i t h b l o o d at 37°C drawn from the r e s e r v o i r except f o r two of the limb p e r f u s i o n experiments i n which the pulmonary a r t e r i a l pouch was perfused w i t h c o o l s a l i n e of d i f f e r e n t temperat u r e s a f t e r completion of the normal experimental p r o t o c o l t o i n v e s t i g a t e i t s response t o c o o l i n g .  In another two of  the limb p e r f u s i o n experiments muscular j e r k s were observed, which are a f e a t u r e of c h l o r a l o s e a n e s t h e s i a , consequently s u c c i n y l c h o l i n e was given as a continuous i n f u s i o n at a r a t e of 0.5 mg/min t o g e t h e r w i t h the 0.5% c h l o r a l o s e . b)  Kidneys In s i x dogs the changes i n kidney r e s i s t a n c e i n  response t o pulmonary a r t e r i a l pressure were examined. The descending a o r t a was d i s s e c t e d f r e e i n two p l a c e s one about one i n c h above and the other two inches below the renal arteries.  T e s t i c u l a r or o v a r i a n and lumbar a r t e r i e s  i n t h a t s e c t i o n were t i e d and c u t .  A 5 nun diameter s t a i n -  l e s s s t e e l cannula was i n s e r t e d i n t o the l e f t  subclavian  a r t e r y d i r e c t i n g a r t e r i a l blood through a r o l l e r pump and an electromagnetic f l o w meter t o the descending a o r t a .  Pig, 3  Diagram of method of kidney p e r f u s i o n .  15  r o s t r a l l y below the r e n a l a r t e r i e s through a double lumen cannula (5 mm bore outer tube, 0.5 mm bore i n n e r t u b e ) . The a o r t a was t i e d j u s t above the r e n a l a r t e r i e s such t h a t the kidneys were perfused s o l e l y by the pump ( F i g . 3 ) . Because the d i s t a n c e between the two r e n a l a r t e r i e s v a r i e s , i n some dogs only one kidney was p e r f u s e d .  Renal p e r f u s i o n  pressure was measured through the 0.5 mm bore i n n e r cannula. Pump speed was adjusted so t h a t the r e n a l a r t e r i a l  pressure  was approximately the same as t h a t of the systemic at the beginning of the experiment.  E i t h e r constant f l o w (constant  pump speed) o r constant pressure (feedback c o n t r o l to the pump from the r e n a l a r t e r i a l pressure transducer) was p o s s i b l e . Both modes were used on separate o c c a s i o n s . D.  Cooling Ten dogs were prepared w i t h r i g h t h e a r t bypasses  as d e s c r i b e d before and the r i g h t femoral a r t e r y was cannu l a t e d f o r systemic a r t e r i a l pressure r e c o r d i n g .  The cons-  t a n t temperature b l o o d r e s e r v o i r composition and volume were the same as the l i m b and kidney p e r f u s i o n experiments. Continuous anesthesia was achieved by i n f u s i n g 0.5% c h l o r a l o s e s o l u t i o n i n 0.9% s a l i n e at about 1.0 ml/min.  However,  the pulmonary a r t e r y pouch was perfused w i t h 0.9% s a l i n e at 30°C i n s t e a d .  Cool s a l i n e was used i n t h i s case i n order  t o e l u c i d a t e the combined e f f e c t of c o o l i n g and d i s t e n d i n g the pulmonary a r t e r y .  16 In e i g h t of these t e n dogs the vagus nerves were cut i n the neck a f t e r completion of the experimental p r o t o c o l and the experiment repeated.  Before each experiment was  s t a r t e d , the a b i l i t y of the p r e p a r a t i o n to respond r e f l e x l y was checked by o c c l u d i n g both c a r o t i d a r t e r i e s .  By  c u t t i n g the vagus nerves any p a r t of the pulmonary a r t e r i a l r e f l e x which depends on them w i l l be e l i m i n a t e d . E.  Urine C o l l e c t i o n - K i d n e y s  Intact  Twenty-nine dogs were prepared f o r u r i n e c o l l e c t i o n from the i n t a c t k i d n e y s .  These dogs were d i v i d e d i n t o three  groups i n which the pulmonary a r t e r y pouches were subjected t o d i f f e r e n t pressure m a n i p u l a t i o n s .  The blood r e s e r v o i r  was primed w i t h 2 l i t e r s of 50% Ringer L a c t a t e and 50% Dextran as d e s c r i b e d before except f o r the i n c r e a s e d volume. In a d d i t i o n 40 ml of 1N NaHCOj was i n c o r p o r a t e d i n t o the r e s e r v o i r t o b r i n g the pH of the r e s e r v o i r to approximately 7.4.  Continuous anesthesia and volume replacement was main-  t a i n e d i n t h i s case by i n f u s i n g a mixture of 500 ml of 0.5% c h l o r a l o s e i n 0.9% s a l i n e and 80 ml of 1N NaHCOj d e l i v e r e d t o the dog at approximately 2 ml/min. Flank i n c i s i o n s were made on the l e f t and r i g h t sides.  The two u r e t e r s were d i s s e c t e d from the d o r s a l  abdominal w a l l and cannulated approximately f o u r inches below the k i d n e y s .  Cannulae used were about 30 cm l o n g  p o l y e t h y l e n e tubings w i t h 1.2 mm bore.  The  transversus,  17  abdominis, i n t e r n a l and e x t e r n a l oblique muscles and the s k i n were then sutured and u r i n e produced by the l e f t and r i g h t kidneys was  collected separately f o r analysis.  Urine samples were c o l l e c t e d every t e n minutes and a 5 ml b l o o d sample was taken every twenty minutes and c e n t r i f u g e d immediately f o r a plasma sample. The u r i n e volume was measured w i t h v o l u m e t r i c cylinders.  O s m o l a r i t i e s of the plasma and the u r i n e samp-  l e s were measured w i t h an osmometer (Osmette P r e c i s i o n Osmometer, P r e c i s i o n Systems) by the depression of f r e e z i n g p o i n t method.  To measure the sodium and potassium concen-  t r a t i o n s of the samples, they were f i r s t d i l u t e d (15 pi of sample to make up to 4 ml w i t h standard L i s o l u t i o n ) w i t h an automatic d i l u t e r ( F i s h e r D i l u t e r , Model 240).  The  standard L i s o l u t i o n contained 15 mEq of L i per l i t e r . Then a flame photometer (Instrumentation Laboratory  Inc.,  B o s t o n , Mass. Model 143) was used t o analyse the d i l u t e d samples. In t e n of the dogs, the pulmonary a r t e r i a l pouch pressure was kept constant a t 15 cm BL^O throughout the e n t i r e experiment.  Data obtained from these experiments  serves as c o n t r o l values and forms the b a s i s of comparison w i t h the o t h e r two sets i n t h i s s e r i e s .  In the second set  of nine dogs the pulmonary a r t e r i a l pouch pressure was kept at 5 cm H^O at the beginning of the experiment and r a i s e d t o 40 cm E 0 f o r a p e r i o d of 30 min then r e l e a s e d o  18 again t o 5 cm E ^ O .  For the l a s t t e n dogs the pulmonary-  a r t e r i a l pressure was 15 cm  EUjO  to s t a r t w i t h then i n c r e a s -  ed to 80 cm fL>0 f o r $0 min before i t was lowered back to 15 cm H 0 . 2  Blood from the constant temperature r e s e r v o i r  was used t o perfuse the pulmonary a r t e r y pouch.  From the  three s e t s of experiments we would be able t o see i f there was any graded response i n the u r i n e output and u r i n e composition i n response t o s t i m u l i of d i f f e r e n t magnitude from the pulmonary a r t e r y pouch. F.  Urine C o l l e c t i o n - I n t a c t And I s o l a t e d  Kidneys  Urine composition and volume can be v a r i e d by many d i f f e r e n t f a c t o r s .  Among them r e n a l a r t e r i a l  pressure,  sympathetic nervous a c t i v i t y to the kidneys and blood borne agents exert major i n f l u e n c e s .  An i n t a c t kidney w i l l be  s u b j e c t e d t o the c o n t r o l of a l l the mentioned f a c t o r s . However, f o r an i s o l a t e d kidney perfused at constant r e n a l a r t e r i a l pressure the a r t e r i a l pressure and sympathetic nervous a c t i v i t y f a c t o r s w i l l be e l i m i n a t e d , changes i n the u r i n e output and composition w i l l be d i c a t e d by blood borne  agents. In s i x dogs the r i g h t kidneys were kept i n t a c t , and  the u r e t e r s were cannulated as b e f o r e .  Flank i n c i s i o n was  made h i g h on the l e f t side about h a l f an i n c h below the l a s t r i b c u t t i n g t r a n s v e r s e l y across the e x t e r n a l and i n t e r n a l o b l i q u e muscles exposing the l e f t k i d n e y .  The u r e -  19  t e r , r e n a l a r t e r y and v e i n were d i s s e c t e d f r e e and a l l the nerves and connective t i s s u e s surrounding the kidney were t i e d and c u t .  A 5 m diameter s t a i n l e s s s t e e l cannula was  i n s e r t e d i n t o the l e f t s u b c l a v i a n a r t e r y t o draw a r t e r i a l b l o o d and then pumped i n t o the l e f t kidney through a 2 mm diameter "V" shaped cannula.  P e r f u s i o n pressure was mea-  sured from a s i d e arm of the cannula.  The r e n a l v e i n was  cannulated w i t h a 5 mi bore cannula and venous blood was d r a i n e d i n t o the r e s e r v o i r .  Urine output was c o l l e c t e d  through a 1.2 mm diameter p o l y e t h y l e n e t u b u l e cannulated i n t o the u r e t e r .  A f t e r c a n n u l a t i o n was completed the o n l y  connections of the kidney w i t h the animal were through the p e r f u s i o n cannulae.  The kidney was placed back i n t o the  c a v i t y c r e a t e d by the surgery and covered w i t h swabs soaked w i t h normal s a l i n e .  In ithis p o s i t i o n the kidney was warmed  by the perfused&blood and the surrounding t i s s u e .  Blood  f l o w t o the kidney was measured by an electromagnetic f l o w meter ( B i o t r o n i c I n c . BL 610) and the p e r f u s i o n pressure was kept constant by a feed-back s i g n a l from the pressure transducer which c o n t r o l s the r o l l e r pump. The blood r e s e r v o i r was primed w i t h three l i t e r s of Dextran and Ringer L a c t a t e mixture plus 60 ml of 1N NaHCO^ t o b r i n g the pH up to about 7»4.  For  continuous  a n e s t h e s i a and f l u i d replacement and to m a i n t a i n acid-base balance a mixture of 500 ml of 0.5% c h l o r a l o s e i n 0.9% s a l i n e , 180 ml of 0.44N NaHCO^ was i n f u s e d a t approximately 2 ml/min.  20 The pulmonary a r t e r y pouch was perfused w i t h blood a t body temperature.  I t s pressure was kept a t 10 cm JEL^O  a t the beginning of the experimental p e r i o d then r a i s e d t o 100 cm HgO f o r 30 min. and lowered back t o 10 cm H^O a f t e r wards.  Urine and plasma samples were c o l l e c t e d and a n a l y s -  ed as b e f o r e .  21 TABLE 1 Experiments Performed Dog #  Weight kg  1 2 3  38 26 25 26  .5 6  29 54  7  8 9 10 11 12 13 14 15 16 17 18 19 20 21 •22  Type of expt,  Techniques  (Hind-limb (perfusion  CLP  " , Pouch c o o l i n g  28 30 29 28 26 27  (Kidney (perfusion  30 29 35 35 32 30 22 26 23 22  (Pulmonary a r t e r y (pouch p e r f u s i o n ( w i t h 30°C s a l i n e  CRP, CRF, CRP CRP CRP, CRP,  GRP CRF  Pouch cooling Pouch cooling  Vagi i n t a c t , Vagi cut  CLP = Constant l i m b blood pressure GRP = Constant r e n a l b l o o d pressure CRP Constant r e n a l blood f l o w  , Vagi cut  22 TABLE 1 (continued) Dog #  Weight kg  Type of e x p t .  Techniques  23 2425 26 2? 28 29 30 31 32  2425 28 24 28 30 28 28 24 27  (Urine c o l l e c t i o n (control  Both kidneys i n t a c t  33 34 35 36 37 38 39 40 41  25 25 24 30 25 28 35 25 27  (Urine c o l l e c t i o n (pulmonary a r t e r y (pouch d i s t e n d e d ( t o 40 cm H 0  Both kidneys i n t a c t  42 43 44 45 46 47 48 49 50 51  25 22 25 30 28 27 23 26 25 33  (Urine c o l l e c t i o n (pulmonary a r t e r y (pouch d i s t e n d e d ( t o 80 cm H 0  Both kidneys i n t a c t  2  2  TABLE 1 (continued) Dog # 52 53 54 55 56 57  Weight kg 25 23 22 21 25 21  Type of e x p t .  Techniques  (Urine c o l l e c t i o n (pulmonary a r t e r y (pouch d i s t e n d e d ( t o 10G cm H 0  ( R i g h t kidney (intact, ( l e f t kidney (isolated  2  24-  EXPERIMENTAL PROTOCOL A f t e r completion of the s u r g i c a l procedures, the animal was allowed to s t a b l i z e f o r a p e r i o d of time (15 min. minimum f o r the l i m b , kidney p e r f u s i o n and pulmonary a r t e r y c o o l i n g experiments; $0 min. minimum f o r the u r i n e c o l l e c t * i o n experiments) and d u r i n g t h i s time a sample of the a r t e r i a l blood was taken and pH, PCO2 and P0  2  were measured  u s i n g a p p r o p r i a t e e l e c t r o d e s (Instrumentation L a b o r t o r i e s , Model 113-51).  I f necessary, adjustments were made t o the  r e s p i r a t o r y pump o r s m a l l i n f u s i o n s (10-30 mEq of sodium b i c a r b o n a t e s o l u t i o n , 1N) were given to m a i n t a i n an a r t e r i a l PC0 between 35 mm and 4-0 mm of mercury and pH w i t h i n the 2  range of 7«35 t o 7.4-2; no adjustments were made d u r i n g the subsequent c o n t r o l o r experimental p e r i o d s . To each pressure r e c o r d i n g cannula was attached a Statham s t r a i n gauge (Model  P23Gb),  the pressures and blood  f l o w r a t e s were recorded on an u l t r a v i o l e t l i g h t r e c o r d e r (Honeywell, V i s i c o r d e r 1508).  Mean pressure was obtained  by e l e c t r i c a l i n t e g r a t i o n and estimated by drawing a l i n e by eye through the average pressure f o r the measurement period.  In i n s t a n c e s where the mean pressure was v a r y i n g  c o n s i d e r a b l y i t was estimated by u s i n g a p l a n i m e t e r .  Zero  pressures were determined post mortem as the l e v e l s of the t i p s of the cannulae when f r e e i n a i r .  Systemic a r t e r i a l  p r e s s u r e , pressure i n the pulmonary a r t e r y pouch and limb p e r f u s i o n pressure were recorded on a f o u r channel tape  25 r e c o r d e r (Hewlett-Packard No. 1105). at slow tape speed (15/16 i n / s e c ) .  Recordings were made To a l l o w r a p i d scanning  of the t o t a l r e c o r d a t a s h o r t e r time base the tapes were played a t f a s t tape speed (15 i n / s e c ) .  A.  Limb And Kidney P e r f u s i o n C o n t r o l pressure i n the pulmonary a r t e r y pouch was  a d j u s t e d to about the same as the p e r f u s i o n pressure of the l e f t lungs a t the s t a r t of the experiment (average 18 cm H 0). 2  This pressure was maintained f o r 3 min and a r e c o r d  f o r measurement of v a r i a b l e s was taken d u r i n g the l a s t 1 min of the p e r i o d .  P e r f u s i o n pressure i n the pouch was i n c r e a s -  ed i n steps of 10 cm of water between the range of 0-80 cm H 0, then i n steps of 20 cm of water u n t i l a maximum of 2  120 cm H 0 was reached. 2  The pressure was r a i s e d f o r 3 min,  and again a r e c o r d f o r measurement of v a r i a b l e s was taken d u r i n g the l a s t 1 min of each p e r i o d .  Between each d i s t e n -  s i o n as w e l l as a t the beginning and the end of the e x p e r i ment the pulmonary a r t e r y pouch pressure was maintained a t the c o n t r o l l e v e l f o r three minutes; these i n t e r v a l s serve as c o n t r o l p e r i o d s .  The average pressure obtained from the  c o n t r o l periods before and a f t e r each experimental p e r i o d were compared w i t h those of the experimental p e r i o d .  Heart  r a t e changes were t r e a t e d s i m i l a r l y . The i s o l a t e d pouch of the main pulmonary a r t e r y and i t s branches were distended w i t h v a r i o u s pressures  in  26 12 dogs.  Recordings began approximately two hours a f t e r  thoracotomy had been performed.  In s i x dogs (dogs No. 1-6)  the pulmonary artery pouch was perfused with blood a t 37°C taken from the r e s e r v o i r and the hind-limbs were perfused with constant a r t e r i a l blood flow.  In another s i x dogs  (dogs No. 7-12) the pulmonary artery pouch and the kidneys were perfused with blood at 37°C.  The kidneys were perfused  e i t h e r with constant pressure or constant flow.  Pouch per-  f u s i o n was handled the same way as the limb perfusion experiments . In four of the above dogs (dogs No. 5» 6, 11 & 12) the pulmonary artery was cooled down to d i f f e r e n t temperatures a f t e r completion of the above p r o t o c o l .  Cooling was  achieved by i n f u s i n g normal s a l i n e of 1$°C and 30°C into the pulmonary artery pouch.  Each cooling period was 3  minutes long and before and a f t e r each cooling period 37°C s a l i n e was used to b r i n g the artery back to body temperature.  B.  Cooling In ten dogs the combined e f f e c t o f cooling and  d i s t e n s i o n of the pulmonary artery pouch was investigated. The pulmonary a r t e r y pouch was perfused with s a l i n e , the temperature of which could be v a r i e d .  Control periods were  taken with the main pulmonary a r t e r i a l pouch pressure kept between 0 and 2 cm H 0 and the s a l i n e was just b a r e l y flowo  27 ing, a l l o w i n g the temperature w i t h i n the pouch t o e q u i l i b r a t e t o body temperature.  Each c o n t r o l p e r i o d was f o u r minutes  l o n g w i t h the v a r i a b l e s measured during the f o u r t h minute. P e r f u s i o n pressure was r a i s e d by i n c r e a s i n g the s a l i n e f l o w to the pouch and a d j u s t i n g the screw clamp on the drainage tubing.  In each case when the p e r f u s i o n pressure was r a i s e d  a r e l a t i v e l y l a r g e s a l i n e f l o w compared w i t h the c o n t r o l was maintained, thus the temperature i n the pouch was expected t o become c l o s e to t h a t of the s a l i n e , u s u a l l y 30°0.  The  pressure was r a i s e d f o r three minutes and v a r i a b l e s were recorded d u r i n g the t h i r d minute.  Approximately the same  s a l i n e f l o w r a t e was used f o r each d i s t e n s i o n .  Perfusion  pressure was r a i s e d i n steps of 10 o r 20 cm HgO i n a s i m i l a r f a s h i o n as before u n t i l a maximum of 120 cm HgO was reached. In e i g h t of the dogs (dogs No.13, 14, 17-22) the vagus nerves were cut i n the neck a f t e r completion of the above procedures and the experiments repeated.  Before each  experiment was r e p e a t e d , the a b i l i t y of the p r e p a r a t i o n t o respond r e f l e x l y was checked by o c c l u d i n g both c a r o t i d arteries.  In every case there was an increase i n mean a r t -  e r i a l pressure and an increase i n heart r a t e . C.  Urine O o l l e c t i o n •>The u r e t e r s of the i n t a c t kidneys were cannulated  i n twenty-nine dogs f o r u r i n e c o l l e c t i o n .  Recordings began  at l e a s t t h i r t y minutes a f t e r the completion of the s u r g i c a l  28 procedures.  Each c o l l e c t i o n p e r i o d was ten minutes l o n g ,  the u r i n e produced d u r i n g t h a t e n t i r e p e r i o d was c o l l e c t e d f o r a n a l y s i s , a r e c o r d of the d i f f e r e n t pressures was taken d u r i n g the l a s t 1 minute of each p e r i o d . For dogs numbering 23-32 the pulmonary a r t e r y pouch was perfused w i t h venous blood at 37°C. was kept constant at 15 cm BLjO f o r 110 min.  The pressure In these exp-  eriments the pulmonary a r t e r i a l pouch pressure was kept const a n t , any changes i n the u r i n e composition and output are due t o s u r g i c a l i n t e r f e r e n c e s or j u s t n a t u r a l v a r i a t i o n of the preparations.  Since the next two sets of experiments were  prepared i n e x a c t l y the same f a s h i o n as dogs numbering 23-32, w i t h the exception of the pulmonary a r t e r i a l pouch  pressures  b e i n g v a r i e d , these animal thus serve as a set of c o n t r o l experiments which w i l l account f o r time course changes not a s s o c i a t e d w i t h the pulmonary a r t e r i a l pouch pressure manipulations. In nine dogs (dog No. 33-41) the pulmonary a r t e r i a l pouch pressure was maintained at 5 cm rLjO f o r 40 min. Then the pressure was r a i s e d t o 40 cm HgO and kept a t t h a t l e v e l f o r 30 min.  The pressure was lowered a f t e r w a r d back  t o 5 cm rL->0 and maintained f o r another 40 min. c o l l e c t e d as b e f o r e .  Urine was  Blood pressures were recorded and  u r i n e samples were analysed. For dogs numbered 42-51  the pulmonary a r t e r i a l  pouch pressure was kept a t 15 cm HpO f o r 40 min then i n c r e -  29 ased t o 80 cm B^O f o r 30 min and r e l e a s e d back t o 15 cm H 0 f o r another 4-0 min. 2  In order t o maintain the glomer-  u l a r u l t r a f i l t r a t e at a r e l a t i v e l y constant composition ( i . e . the blood c o m p o s i t i o n ) , no e x t r a f l u i d of any k i n d was added t o the animals i n these u r i n e c o l l e c t i o n e x p e r i ments o t h e r than p r i m i n g the r e s e r v o i r and the continuous i n f u s i o n of the a n e s t h e t i c agent. D.  Comparison Of I n t a c t And I s o l a t e d Kidneys The r i g h t kidneys of dogs numbered 52-57 were i n t a c t  and the l e f t kidneys were i s o l a t e d and perfused w i t h const a n t pressure throughout the experiment.  The p e r f u s i o n  pump was adjusted such t h a t the p e r f u s i o n pressure was about the same as the systemic a r t e r i a l pressure at the beginning of the experiment and kept constant by a negative feedback circuit.  Pulmonary a r t e r i a l pouch pressure i n these animals  maintained at 10 cm HgO f o r 4-0 min, 100 cm B^O f o r the next 30 min then lowered back t o 10 cm B^O f o r the l a s t 40 min. Urine" samples of the two kidneys were c o l l e c t e d and analysed separately.  The r e s u l t s were compared.  30 EVALUATION OF EXPERIMENTAL TECHNIQUES Constant Flow/Pressure P r e p a r a t i o n By Ohm's law the r e l a t i o n s h i p between the v o l t a g e , e l e c t r i c current and r e s i s t a n c e i n a simple r e s i s t i v e c i r c u i t can be expressed by V = IR. V = v o l t a g e drop across the r e s i s t o r . I = e l e c t r i c c u r r e n t through the r e s i s t o r . R = resistance. The v a r i a b l e s can be s u b s t i t u t e d and made t o represent the b l o o d p r e s s u r e , f l o w and r e s i s t a n c e across a c a r d i o v a s c u l a r bed as P = PR. P = pressure drop across a c a r d i o v a s c u l a r bed. F = blood f l o w through the same c a r d i o v a s c u l a r bed. R = r e s i s t a n c e of the bed. Suppose we want to measure the r e s i s t a n c e s of the c a r d i o v a s c u l a r bed, Ohm's equation can be rearranged t o  Since R i s dependent of both P and F, both v a r i a b l e s have t o be measured to o b t a i n R. I f we make one of the v a r i a b l e s constant such as keeping the blood f l o w F constant the change i n the r e s i s t a n c e w i l l be r e f l e c t e d d i r e c t l y by the other v a r i a b l e , i n t h i s case the p e r f u s i o n pressure  31 R - ^ R - -j;  also  R ©< P.  To measure the change i n the c a r d i o v a s c u l a r bed r e s i s t a n c e w i l l become a simple task of m o n i t o r i n g the change i n the p e r f u s i o n pressure.  S i m i l a r i l y i f the p e r f u s i o n pressure P  i s kept c o n s t a n t , the change i n r e s i s t a n c e becomes H o <  T».  A l l the experiments d e s c r i b e d i n t h i s t h e s i s were done w i t h a r i g h t h e a r t bypass such t h a t the venous b l o o d was drained d i r e c t l y i n t o the r e s e r v o i r which i s open to the atmosphere. Therefore we can c o n s i d e r the venous pressure as zero and pressure drop across any c a r d i o v a s c u l a r bed i s the same as the a r t e r i a l blood pressure i t i s subjected t o . For the l i m b p e r f u s i o n experiments only constant f l o w technique was used to perfuse the h i n d - l i m b s .  In the  kidney p e r f u s i o n experiments, because of the nature of the k i d n e y , both constant f l o w and constant pressure methods were used t o perfuse the kidneys i n separate experiments. A kidney i s i n v e s t e d i n a f i r m , strong f i b r o u s capsule which does not s t r e t c h much even under h i g h i n t e r n a l h y d r o s t a t i c pressure.  I t i s capable of a u t o r e g u l a t i n g b l o o d  f l o w , i t possesses a h i g h oxygen consumption per u n i t of t i s s u e weight and because of t h i s , a l s o r e q u i r e s a h i g h blood flow.  These p r o p e r t i e s make i t necessary t o u t i l i z e  both methods to i n v e s t i g a t e kidney r e s i s t a n c e  changes.  32 With constant r e n a l b l o o d f l o w an i n c r e a s e d r e n a l r e s i s t a n c e w i l l cause v a s o c o n s t r i c t i o n and e l e v a t e the i n t e r s t i t i a l pressure i n s i d e the kidney c a p s u l e .  When the  r i s e i n i n t e r s t i t i a l pressure i s e x c e s s i v e , i t w i l l compress the kidney tubules and a r t e r i e s , i n c r e a s i n g the r e n a l r e s i s tance f u r t h e r by a mechanical means, as a r e s u l t , h i g h l y augmenting the r e n a l p r e s s u r e .  With constant p r e s s u r e , on  the other hand, i n c r e a s e d kidney r e s i s t a n c e a l s o causes vasoconstriction.  Since the r e n a l pressure i s c o n s t a n t , the  c o n s t r i c t i o n i s r e f l e c t e d by a decreased r e n a l b l o o d f l o w . The c o n s t r i c t i o n can become so severe t h a t r e n a l blood f l o w can v i r t u a l l y cease.  Since the kidney r e q u i r e s a l a r g e  amount of blood supply f o r i t s oxygen consumption, e x c e s s i v e l y low r e n a l blood f l o w f o r a prolonged time can cause t i s s u e Jiypoxia and permanently damage the kidney.  Therefore cons-  t a n t pressure and constant f l o w methods were used t o perfuse the kidneys hoping t o e l i m i n a t e the u n d e s i r a b l e e f f e c t s of both and p e r m i t t i n g us t o observe the t r u e changes i n the kidney r e s i s t a n c e .  B.  Heart Rate C a l c u l a t i o n E l e c t r o c a r d i o g r a m was recorded from leads p l a c e d  i n the l e f t chest and the r i g h t l e g r e g i o n .  Heart r a t e was  c a l c u l a t e d by counting the e l e c t r o c a r d i o g r a m over a p e r i o d of 30 sec and e x t r a p o l a t e d to beats per minute.  At the end  of t h i s process of e x t r a p o l a t i o n a p o s s i b l e e r r o r of +2 beats per minute has been i n t r o d u c e d i n t o the heart r a t e .  33 Any changes of l e s s than + 2 beats per minute should thus not be considered as r e a l  C.  changes.  Pressure And Flow Recordings The pressures were recorded by u s i n g s t r a i n gauge  t r a n s d u c e r s , a f t e r proper a m p l i f i c a t i o n they are d i s p l a y e d on the u l t r a - v i o l e t l i g h t r e c o r d e r .  At the beginning of  each experiment the pressure r e c o r d i n g system?was c a l i b r a t e d a g a i n s t a mercury manometer o r a s a l i n e column over several f i x e d values.  D i s p l a y s c a l e of 10 cm B^O/cm was  used f o r the pulmonary a r t e r i a l pouch p r e s s u r e , 10 mm Hg/cm was used f o r the a r t e r i a l , l i m b and kidney p r e s s u r e s .  For  the constant pressure kidney p e r f u s i o n experiments the kidney pressure s c a l e used was 20 mm Hg/cm.  In each case  the r e s o l u t i o n of the record.was 0.5 mm, thus +0.5 cm ^ 0 , +0.5 mm Hg, and +1.0 mm Hg f o r the three d i f f e r e n t s c a l e s . C a r d i a c o u t p u t , limb and kidney p e r f u s i o n b l o o d flows were monitored w i t h p u l s e d l o g i c electromagnetic f l o w meters, and a f t e r proper a m p l i f i c a t i o n s d i s p l a y e d on the u l t r a - v i o l e t r e c o r d e r f o r measurement.  The performance of the f l o w meters  vrere t e s t e d i n steps between the f l o w r a t e of 50 and 3500 ml/min.  R e s u l t s show t h a t i n the t e s t e d range the f l o w  meter output i s l i n e a r .  D i s p l a y s c a l e of about 200 ml/min/cm  was used f o r the c a r d i a c output measurement.  Limb and  k i d n e y b l o o d f l o w was measured on a s c a l e of about 25 ml/min /cm.  No s i g n i f i c a n t d r i f t was observed i n e i t h e r the  pressure and f l o w r e c o r d i n g systems over the e n t i r e e x p e r i -  34-  mental p e r i o d . D,  Urine And Plasma A n a l y s i s Urine and plasma were analysed f o r sodium and  potassium c o n c e n t r a t i o n by u s i n g a flame photometer a f t e r dilution.  The flame photometer u t i l i s e s a l i t h i u m standard  (15 mEq L i / L ) .  The emission i n t e n s i t i e s of sodium and  potassium were compared w i t h t h a t of the l i t h i u m standard and a b u i l t - i n analog computer provided a d i g i t a l readout v i a a servo-counter. The machine was c a l i b r a t e d w i t h standard s o l u t i o n s . A s o l u t i o n c o n t a i n i n g 100 mEq/L of sodium and 100 mEq/L of potassium was used as a standard when u r i n e samples were a n a lysed.  A s o l u t i o n c o n t a i n i n g 14-0 mEq/L of sodium and 5.0 mE<|  /L of potassium was used when plasma samples were analysed. The flame photometer was r e c a l i b r a t e d a f t e r every 5 t o 10 samples.  G e n e r a l l y the readjustment necessary when r e c a l i b -  r a t i n g w i t h the standards was 1 o r 2 mEq/L f o r the u r i n e and 0.1 mEq/L f o r the plasma sodium standard.  D u p l i c a t e samples  were used to check the t o t a l e r r o r introduced by the d i l u t e r and the flame photometer, i n ten t e s t s the e r r o r was found t o be w i t h i n  +4$.  Plasma and u r i n e o s m o l a r i t y was measured using the method of f r e e z i n g p o i n t d e p r e s s i o n .  The osmometer u t i l i z e s  the s u p e r c o o l i n g technique and the sample was induced t o f r e e z e by s t i r r i n g .  A t h e r m i s t o r probe measured the temp-  35 erature of the sample throughout the e n t i r e p r o c e s s . b r a t i o n of the osmometer was checked w i t h standard  Calisolutions  of 100 mOs/kg and 500 mOs/kg at the beginning of each sample batch.  The osmometer was accepted as c a l i b r a t e d i f the  r e a d i n g of the standards were w i t h i n 5 mOs/kg of the manuf a c t u r e r ' s value.  T e s t i n g w i t h seven d u p l i c a t e samples  showed a p o s s i b l e e r r o r of 5% i n the o s m o l a r i t y r e a d i n g . Urine volumes were measured i n graduated c y l i n d e r s a t the time the u r i n e was c o l l e c t e d .  I f the u r i n e volume  f o r the 10 min c o l l e c t i o n p e r i o d was l e s s than 10 ml, the u r i n e was measured i n 10 ml graduated c y l i n d e r s , the a c c u r acy of which i s +0.05 n i l .  I f the u r i n e volume exceeded  10 ml i n 10 min the u r i n e was measured i n 25 ml graduated c y l i n d e r s , the accuracy of which i s +0.1 m l . . Sodium and potassium e x c r e t i o n s are c a l c u l a t e d by m u l t i p l y i n g the sodium and potassium concentrations w i t h the u r i n e volume. Osmolar clearance i s obtained by u s i n g the equation  °03  =  ?2  X V  OS  = osmolar clearance = urine osmolarity p OS  = plasma o s m o l a r i t y  V = u r i n e volume °H 0  = f r e e water clearance  2  and f r e e water clearance i s c a l c u l a t e d from C  H 0 ' 2  V  " °  O S  -  36 E.  Feedback C o n t r o l C i r c u i t s Constant pressure o r constant blood f l o w p e r f u s i o n  was made p o s s i b l e by e l e c t r i c feedback c o n t r o l c i r c u i t s . These c i r c u i t s monitor the performance of the system and make a p p r o p r i a t e adjustments, i f necessary, to m a i n t a i n constant p e r f u s i o n pressure o r f l o w .  The c i r c u i t c o n s i s t s of a sensor  (pressure transducer or f l o w meter) which senses the c o n t r o l l e d v a r i a b l e (blood pressure or b l o o d f l o w ) c o n s t a n t l y . S i g n a l from the sensor a f t e r proper a m p l i f i c a t i o n i s f e d i n t o a comparator which compares the sensor s i g n a l w i t h a p r e - s e t standard s i g n a l .  The comparator acts as a s u b t r a c -  t e r which s u b t r a c t s the sensor s i g n a l from the standard s i g n a l and the output of the comparator i s the d i f f e r e n c e of the two.  Again a f t e r proper a m p l i f i c a t i o n the comparator  output i s used t o c o n t r o l the r o l l e r pump ( F i g . 4 ) .  Any  d e v i a t i o n of the sensor s i g n a l from the standard s i g n a l w i l l cause the pump t o change i t s speed and/or f l o w d i r e c t i o n thus b r i n g i n g the pressure d r f l o w r a t e back to the p r e - s e t standard l e v e l .  D i f f e r e n t values of the c o n t r o l l e d v a r i a b l e  may be set by a l t e r a t i o n of the standard s i g n a l . The feedback c o n t r o l c i r c u i t s were h i g h l y e f f e c t ive.  In a l l the experiments r e p o r t e d there was no measurable  e r r o r c r e d i t e d t o the c o n t r o l system.  With a r e s o l u t i o n of  0.5 mm of the u l t r a - v i o l e t l i g h t r e c o r d e r there was no n o t i c e a b l e f l u c t u a t i o n of the c o n t r o l l e d v a r i a b l e t h r o u g h out the e n t i r e p e r f u s i o n p e r i o d which c o u l d be as l o n g as  37  P i g . 4-  Feedback c i r c u i t f o r the r o l l e r pump c o n t r o l . Same c i r c u i t was used i n constant pressure and constant f l o w p e r f u s i o n .  38 4# hours. F.  Mathematical Methods  a)  C o r r e c t i o n to absolute zero pressure Systemic a r t e r i a l pressure changes i n response t o  the pulmonary a r t e r i a l pressures f o r each i n d i v i d u a l experiments , were rearranged f i r s t , before averaging f o r the series.  During the experiment the absolute pressure at the  t i p of the pulmonary a r t e r y pouch cannula was not known, zero pressure was taken at a f i x e d r e f e r e n c e .  At the end of the  experiment the cannula was f r e e d t f i n the a i r and the pressure d i f f e r e n c e between the t i p of the cannula and the reference was measured and c o r r e c t i o n was made such t h a t the pressure a t the f r e e d cannula t i p was considered as the absolute zero.  Raw data were p l o t t e d on graph papers, s t r a i g h t l i n e s  were drawn between neighbouring p o i n t s then zero c o r r e c t i o n was made.  Stepv/ise increments of 10 cm HgO i n the pulmonary  a r t e r i a l pouch were marked using the absolute zero as r e f e r ence.  The changes i n systemic pressure a t pressures of 10,  20, 30, 40, 50, 60, 70, 80, 100, and 120 cm H 0 i n the p u l 2  monary a r t e r i a l pouch were e x t r a p o l a t e d from the graph and averaged between i n d i v i d u a l experiments of the same s e t .  b)  t-test When p a i r e d r e s u l t s were analysed the t - t e s t f o r  p a i r e d values was used.  In each case the value obtained  39  during the experimental  period was compared with the mean  value of the two c o n t r o l periods before and a f t e r i t . Differences were considered s i g n i f i c a n t i f 2P<0.10 o r P«0.05.  The choice of one or two t a i l e d t e s t was selected  f o r appropriate t e s t i n g conditions.  c)  Wilcoxon two sample rank t e s t (Mann-Whitney  U-test)  Results from the urine c o l l e c t i o n experiments were tested with nonparametric s t a t i s t i c a l method.  Each of the  urine c o l l e c t i o n experiments was, divided into three tions.  The f i r s t forty-minute  sec-  s e c t i o n i s c a l l e d period I ,  the second thirty-minute s e c t i o n i s c a l l e d period I I , and the l a s t forty-minute  +  s e c t i o n i s c a l l e d period I I I .  +  + +  Period I  + +  + Period I I + +  + Period I I I  + +  Since each v a r i a b l e was measured once every ten minutes, each period contains e i t h e r three or four samples of the same v a r i a b l e .  In the c o n t r o l experiments, the pulmonary  a r t e r y pouch pressure was constant throughout periods I , I I and I I I .  In two other sets of experiments the pulmonary  a r t e r y pouch pressure was e i t h e r at 5 or 15 cm ILjO during periods I and I I I and was r a i s e d to 40 or 80 cm H^O during period I I .  The sample values of each v a r i a b l e within each  period was then averaged and compared with that of another period.  As a r e s u l t , a set of ten numbers was  obtained  from the ten c o n t r o l experiments by subtracting the average sodium excretion rate i n period I from that of period  40 II.  S i m i l a r i l y , a set of nine numbers were obtained from  the nine experiments where the pulmonary a r t e r y pouch p r e s s ures were r a i s e d t o 40 cm EL^O i n p e r i o d I I .  These two sets  of 10 and 9 numbers are t e s t e d by the Wilcoxon two-sample rank t e s t ( G o l d s t e i n , 1968).  Any s i g n i f i c a n t d i f f e r e n c e  between the two sets w i l l be the r e s u l t of the i n c r e a s e i n the pulmonary a r t e r y pouch p r e s s u r e .  Natural variations  caused by the s u r g i c a l maneuver w i l l be e l i m i n a t e d .  4-1 RESULTS A.  C a r d i o v a s c u l a r E f f e c t s Of Graded Pulmonary A r t e r y Distension  a)  Systemic pressure and h e a r t r a t e changes There were no d i f f e r e n c e s i n the changes i n system-  i c pressure i n response t o changing the pressure i n the i s o l a t e d pulmonary a r t e r y pouch between the s i x dogs i n which the h i n d - l i m b s were perfused and the s i x dogs i n which the kidneys were perfused and t h e r e f o r e these r e s u l t s have been pooled.  P i g . 5 shows the average r e s u l t s of 14- t e s t s  (in  two dogs two sets of pouch d i s t e n s i o n s were performed) i n which venous blood at 37°C was used f o r the pulmonary artery perfusion. Mean c a r d i a c output of the experiments was 1820 ml/min, ranging from 755 to 2240 ml/min.  The average c o n t r o l  pouch pressure was 18 cm HgO (range 10 to 24- cm B^O), and t h a t of the systemic pressure was 124- mm Hg (range 104- mm Hg t o 14-9 Dim Hg).  Increase of the pulmonary a r t e r y pouch  pressure caused a r i s e i n the systemic pressure p r o p o r t i o n a l t o the r i s e i n the pulmonary a r t e r i a l p r e s s u r e .  The change  was s m a l l w i t h pouch pressure between 10-30 cm H 0 , but 2  became prominent beyond t h a t .  At pouch pressure of 120 cm  H 0 , the maximum t e s t e d , the average i n c r e a s e i n systemic 2  pressure was 12 mm Hg, 10% of c o n t r o l .  P a i r e d t - t e s t was  used to examine the changes which occurred by r a i s i n g the  42  <u  I6—1  co  Main Pulmonary Artery Pressure cmH 0 2  Fig. 5  Changes i n systemic pressure and heart r a t e caused by v a r y i n g the pulmonary a r t e r i a l pouch p e r f u s i o n pressure between 5 and 120 cm HgO. Values p l o t t e d are changes from c o n t r o l values observed w i t h the pulmonary a r t e r i a l pouch pressure maintained a t 18 cm ILjO. Values shown are the averages i n 12 experiments + SEM.  43 pouch pressure from c o n t r o l to 40 cm a p h y s i o l o g i c a l pressure.  rLjO  which i s  considered  This maneuver r e s u l t e d i n a 2%  r i s e of the systemic pressure corresponding t o about 3 mm Hg ( S t u d e n t ' s t - t e s t j 2P<0.005).  Therefore w i t h i n the p h y s i o l -  o g i c a l range although the i n c r e a s e i n systemic pressure was s m a l l , i t was h i g h l y s i g n i f i c a n t .  Prom P i g . 5 i t i s q u i t e  obvious t h a t any f u r t h e r increment of the pouch pressure beyond 40 cm HgO w i l l a l s o cause a s t a t i s t i c a l l y s i g n i f i c a n t r i s e i n the systemic pressure.  The systemic pressure changes  r e f l e c t the changes i n general p e r i p h e r a l r e s i s t a n c e because the c a r d i a c outputs were kept constant i n these experiments. Average c o n t r o l heart r a t e i n these experiments was 143 beats/min (range 92 to 183 beats/min).  The mean response  t o pulmonary a r t e r i a l pouch pressure i n c r e a s e appeared t o be a s l i g h t decrease i n heart r a t e when pulmonary a r t e r i a l pouch pressure was h i g h ( P i g . 5).  However, the changes were  always s m a l l and u s u a l l y w i t h i n +2 beats/min, which i s the range of e r r o r of counting over 30 sec p e r i o d s .  Paired  t - t e s t of heart r a t e d u r i n g the c o n t r o l and experimental p e r i o d s w i t h pulmonary a r t e r i a l pouch pressure o f 100 cm ^0  showed no s i g n i f i c a n t d i f f e r e n c e (2P>0.1).  b)  Change i n l i m b r e s i s t a n c e Hind-limb v a s c u l a r r e s i s t a n c e was measured i n s i x  dogs and was c a l c u l a t e d by d i v i d i n g the p e r f u s i o n pressure of the h i n d - l i m b by the blood f l o w .  Since the h i n d - l i m b  blood f l o w was constant and the r i g h t a t r i u m was connected t o the r e s e r v o i r , which was open t o the atmosphere m a i n t a i n i n g o u t f l o w pressure c o n s t a n t , the change i n limb r e s i s t a n c e was d i r e c t l y p r o p o r t i o n a l t o the change i n the limb p e r f u sion pressure. F i g . 6 shows t h a t when the pulmonary a r t e r y pouch pressure was r a i s e d above the c o n t r o l value (average 18 cm HgO) limb r e s i s t a n c e increased i n a p r o p o r t i o n a l f a s h i o n . As the pouch pressure was decreased there was a s l i g h t dropi n the average limb r e s i s t a n c e .  Mean c o n t r o l limb pressure  was 99 mm Hg and ranged from 82 t o 108 mm Hg.  Average l i m b  b l o o d f l o w was 182 ml/min ranging from 125 ml/min t o 285 ml /min.  At pouch pressure of 100 cm ^ 0 the average r i s e i n  l i m b r e s i s t a n c e (pressure) was 17% i n c o n t r a s t w i t h o n l y 8% i n the systemic p r e s s u r e .  Compared w i t h the i n c r e a s e i n  the systemic a r t e r i a l p r e s s u r e , the limb v a s c u l a r r e s i s t a n c e almost always shotted a g r e a t e r percentage i n c r e a s e at any pulmonary a r t e r y pouch p r e s s u r e . F i g . 7 i s p a r t of the r e c o r d of an experiment recorded on tape and played back at a reduced time base. Graded responses of the systemic a r t e r i a l pressure and limb pressure are c l e a r l y seen i n response t o d i f f e r e n t pulmonary a r t e r i a l pouch pressures i n the range of 50-80 cm H2O.  It  may a l s o be seen t h a t peak responses are observed about 1 minute a f t e r the change i n pulmonary a r t e r i a l pouch p r e s s ure and t h a t there has been some r e d u c t i o n i n response t o a  Fig. 6  Changes i n h i n d - l i m b and r e n a l r e s i s t a n c e i n response t o changes i n p e r f u s i o n pressure i n a pulmonary a r t e r i a l pouch. R e s u l t s f o r limb r e s i s t a n c e are average changes from values a t a pulmonary a r t e r i a l pouch pressure of 18 cm IL-jO i n 6 dogs + SEM. R e s u l t s f o r r e n a l r e s i s tance are c a l c u l a t e d s i m i l a r i l y i n 8 t e s t s i n 6 dogs.  46  I min.  cmH 0 2  O -1  50  Pig. 7  P a r t of the r e c o r d of one experiment showing changes i n systemic a r t e r i a l pressure (SAP, mm Hg), h i n d - l i m b p e r f u s i o n pressure (LP, mm Hg) and pulmonary a r t e r i a l pouch pressure (PAP, em HgO). Time base has been reduced by r e c o r d i n g on tape a t slow speed and r e p l a y i n g at a h i g h e r speed. Graded responses are shown to i n c r e a s i n g pulmonary a r t e r i a l pouch pressure over the range 45-75 cm ^ 0 .  47 more steady s t a t e by the t h i r d minute when measurements were made.  In f a c t the t r a n s i e n t changes were more r a p i d and  somewhat*greater than appears from t h i s r e c o r d as the comb i n a t i o n of the reduced time base and e l e c t r o n i c damping of the systemic pressure and limb p e r f u s i o n pressure t r a c e s i n c r e a s e s the apparent time constant of the system.  The  pulmonary a r t e r i a l p e r f u s i o n t r a c e was undamped and shows t h a t the o s c i l l a t i o n s imposed on the system by the r o l l e r pump were u s u a l l y l e s s than 5 cm EL^O i n amplitude.  c)  Changes i n kidney v a s c u l a r r e s i s t a n c e S i x dogs were prepared f o r kidney p e r f u s i o n .  In  two of the a n i m a l s , two sets of pouch d i s t e n s i o n s were p e r formed, thus a t o t a l of e i g h t sets of r e s u l t s were a v a i l a b l e . Three t e s t s were c a r r i e d out w i t h constant r e n a l blood f l o w p e r f u s i o n and f i v e t e s t s were done w i t h constant r e n a l a r t e r i a l blood p r e s s u r e .  The change i n r e n a l v a s c u l a r r e s i s t -  ance was measured as e i t h e r the change i n r e n a l b l o o d f l o w o r the change i n r e n a l p e r f u s i o n p r e s s u r e .  As the r e s u l t s  were s i m i l a r i n each case they have been p o o l e d . F i g . 6 shows the average r e s u l t s of the e i g h t tests.  The change i n r e n a l r e s i s t a n c e i n response t o changes  i n pulmonary a r t e r i a l pouch pressure were s m a l l and i n c o n sistent.  Maximum average change was -1.5$ compared w i t h  17$ i n the l i m b s .  In c o n t r a s t to the limb r e s i s t a n c e the  r e n a l v a s c u l a r r e s i s t a n c e i s not s i g n i f i c a n t l y a f f e c t e d by  48  changes of the pouch p r e s s u r e .  The average c o n t r o l a r t e r i a l  pressure was 105 mm Hg w i t h a minimum of 85 mm Hg and a m a x i mum of 125 mm Hg.  Since i n some cases only one kidney was  perfused and i n others both kidneys were p e r f u s e d , no comp a r i s o n of r e n a l blood f l o w i s made between i n d i v i d u a l dogs. In a l l experiments the r e n a l blood flows were found t o be of the order of 1-3 ml/min/gm kidney p e r f u s e d . d)  P e r f u s i o n w i t h s a l i n e at d i f f e r e n t temperatures I n almost a l l of the experiments r e p o r t e d above,  the p r e p a r a t i o n remained s t a b l e and responsive at the comp l e t i o n of the procedures.  S a l i n e , at d i f f e r e n t temperatures,  was perfused i n t o the pulmonary a r t e r i a l pouch t o i n v e s t i g a t e i t s response to c o o l i n g .  P i g . 8 i s a reduced time base  playback of one t y p i c a l experiment w i t h s e c t i o n s of c o o l i n g and rewarming.  Decrease i n systemic a r t e r i a l pressure and  limb p e r f u s i o n pressure were obvious i n every t e s t when the temperature of the s a l i n e was changed from 37°C t o 30°C o r t o 15°C.  This e f f e c t was present at e i t h e r low (15 cm ^ 0 )  or h i g h (80 cm ^ 0 ) pulmonary a r t e r y pouch p r e s s u r e .  In  both cases the decrease i n systemic and limb pressure was more than 10 mm Hg.  No q u a n t i t a t i v e a n a l y s i s of these  response has been made because of l i m i t a t i o n of equipment t o g i v e adquate t e m p e r a t u r e . c o n t r o l of the s a l i n e .  Instead  another s e r i e s of experiments was performed which would i l l u s t r a t e the combined e f f e c t of c o o l i n g and d i s t e n d i n g the pulmonary a r t e r i a l pouch.  49  I min.  Fig. 8  P a r t s of the r e c o r d of one experiment showing changes i n systemic a r t e r i a l pressure (SAP, mm Hg) and h i n d - l i m b p e r f u s i o n pressure (LP, mm Hg) i n response t o changing the temperature i n the pulmonary a r t e r i a l pouch. Records taken a t low and h i g h pulmonary a r t e r i a l pouch p r e s sure (PAP, cm H2O). The temperature i n the pouch immediately before the f i r s t panel has been 15°C.  50 B.  D i s t e n s i o n Of The Pulmonary A r t e r y With 30°C S a l i n e In t e n dogs experiments were performed to examine  the i n t e r a c t i o n of c o o l i n g and pulmonary a r t e r i a l pouch pressure.  The pulmonary a r t e r y pouch was perfused w i t h  s a l i n e a t 30°C.  During the c o n t r o l periods s a l i n e f l o w was  extremely slow (<5 ml/min) and pressure was low (0-2 cm HgO), d u r i n g the experimental periods when the pressure was r a i s e d the f l o w was r a p i d (approximately 100 ml/min), thus e x e r t i n g a c o o l i n g e f f e c t on the pulmonary a r t e r i a l w a l l .  The  p r e c i s e temperature a t the r e c e p t o r s i t e i s unknown but b e l i e v e d t o be l e s s than 37°C. P i g . 9 shows the change i n systemic pressure and heart r a t e observed d u r i n g combined c o o l i n g and i n c r e a s i n g pressure i n the pulmonary a r t e r y pouch.  There was a r e d u c -  t i o n i n systemic pressure when pouch pressures were low (1060 cm ^ 0 ) .  D i s t e n s i o n w i t h h i g h e r pressure (60-120 cm rL-,0)  caused an i n c r e a s e i n systemic pressure d e s p i t e the c o o l i n g . Mean c o n t r o l systemic pressure was 117 mm Hg, ranged from 93 t o 139 mm Hg.  Maximum average drop i n systemic pressure  was 7 mm Hg when the pouch pressure was at 10 cm HgO. Maximum mean i n c r e a s e i n systemic pressure was 10 mm Hg, and occurred at a pouch pressure of 120 cm H2O,which was the h i g h e s t pouch pressure t e s t e d .  There were no net changes i n  the systemic pressure a t the pouch pressure of 60 cm ^0$ presumably the c o o l i n g and the d i s t e n s i o n e f f e c t s c a n c e l l e d each other o u t .  Comparison w i t h F i g . 5 i n d i c a t e s t h a t c o o l -  Pig. 9  Changes i n mean systemic a r t e r i a l pressure and heart r a t e a s s o c i a t e d w i t h i n c r e a s i n g pouch . pressure from 0-2 cm B^O and s i m u l taneously c o o l i n g the pulmonary a r t e r i a l pouch from 37°C t o 30°C. Average r e s u l t s (+ SEM) i n 10 dogs.  52  i n g t o 30°C may have been somewhat more e f f e c t i v e a t r e d u c i n g systemic pressure a t low pulmonary a r t e r i a l pouch p r e s s ure than at h i g h pouch p r e s s u r e .  Mean c o n t r o l h e a r t r a t e  was 152 beats/min, and average changes i n response t o the pouch pressure were always s m a l l and w i t h i n +2 beats/min as shown on F i g . 9«  C.  E f f e c t Of Vagal S e c t i o n In e i g h t of the t e n animals t e s t e d above, the vagus  nerves were cut i n the neck, and the pulmonary a r t e r y pouch was a g a i n perfused w i t h 30°C s a l i n e over the whole pressure range.  Any r e f l e x response from the pulmonary a r t e r y which  r e q u i r e s the vagus nerves as p a r t of the pathway w i l l be e l i m i n a t e d by t h i s procedure. A f t e r vagotomy,the average c o n t r o l systemic p r e s s ure was 107 mm Hg w i t h minimum at 94 mm Hg and maximum at 120 mm Hg.  The average c o n t r o l h e a r t r a t e was..165 beats/min.  V a r i a t i o n of the pulmonary a r t e r i a l pouch pressure between 10 and 120 cm ^ 0 caused no s i g n i f i c a n t changes i n the s y s temic p r e s s u r e .  The maximum average change was -1 mm Hg i n  c o n t r a s t w i t h 10 mm Hg when the vagus nerves were i n t a c t and 12 mm Hg when warm b l o o d a t 37°C was used.  F i g . 10  shows t h a t the change i n systemic pressure v s . pouch pressure curve i s v i r t u a l l y p a r a l l e l to the a b s c i s s a .  Comparison  w i t h F i g . 9 w i l l show r e a d i l y t h a t the vagus nerves are e s s e n t i a l f o r both the c o o l i n g and d i s t e n s i o n r e f l e x from  P i g . 10  R e p e t i t i o n of the experiment shown i n P i g . 9 a f t e r c u t t i n g both c e r v i c a l vagus nerves. Average r e s u l t s (+SEM) from 8 of the 10 dogs used i n P i g . 9.  54-  the pulmonary a r t e r y .  Heart r a t e changes a f t e r vagotomy  again were always w i t h i n the range of counting e r r o r . D.  Urine C o l l e c t i o n Experiments To c o l l e c t u r i n e samples f o r a n a l y s i s a volume of  at l e a s t 1 ml i s needed, t h e r e f o r e t e n minutes was allowed f o r each c o l l e c t i o n p e r i o d .  As has been o u t l i n e d i n the methods  s e c t i o n , every experiment r e q u i r e d 110 min to complete, d u r i n g t h i s l o n g procedure, changes i n both hemodynamic and r e n a l f u n c t i o n s are p o s s i b l e .  In t e n animals a l l s u r g i c a l p r o -  cedures were completed,but pulmonary a r t e r i a l pouch p r e s s ure was maintained c o n s t a n t . These served as c o n t r o l s to give an i n d i c a t i o n of the degree of change and provide as a b a s i s f o r comparison.  a)  Cardiovascular e f f e c t s D i s t e n s i o n of the pulmonary a r t e r y pouch w i t h  blood a t 37°C has been shown t o cause an increase i n the systemic p r e s s u r e .  Results shown on the graphs i n the  p r e v i o u s s e c t i o n ( F i g . 5 ) were taken at the t h i r d minute of a three minute p e r i o d of d i s t e n s i o n .  In the u r i n e  c o l l e c t i o n experiments the pulmonary a r t e r i a l pouch was distended f o r t h i r t y minutes.  Changes observed i n these  experiments w i l l exclude any t r a n s i e n t response which might occurs and the r e s u l t s represent steady s t a t e r e f l e x changes i n i t i a t e d by d i s t e n s i o n of the pouch of the p u l -  55 monary a r t e r y .  The pouch pressures were maintained c l o s e  t o the d e s i r e d pressures and v e r y few minor adjustments were necessary d u r i n g the course of the experiment. R e s u l t s from the c o n t r o l experiments are shown i n F i g . 11,where the pouch pressure was kept constant a t 15 cm B^O f o r the 110 min experimental p e r i o d . pressure was 115 mm Hg.  Average systemic  Except f o r s m a l l f l u c t u a t i o n s ,  the systemic pressure was steady throughout the experiment. F i g . 12 represents the r e s u l t s of nine dogs i n which the systemic pressure was 112 mm Hg a t the beginning of the experiments where the pouch pressure was kept a t 5 cm H2O.  I n c r e a s i n g the pouch pressure t o 40 cm H2O caused a  s m a l l i n c r e a s e i n systemic pressure of approximately 3-4 mm Hg.  F i g . 13 represents the r e s u l t s on. 10 dogs where the  pulmonary a r t e r i a l pouch pressure was r a i s e d from 15 cm HgO t o 80 cm H2O, the systemic pressure i n c r e a s e d from 128 mm Hg to 135 nim Hg d u r i n g the time the pulmonary a r t e r i a l pouch pressure was r a i s e d .  The i n c r e a s e i n systemic p r e s -  sure was maintained d u r i n g the e n t i r e t e s t p e r i o d of 30 min and when the pouch pressure was r e l e a s e d back to 15 cm ^ 0 , the systemic pressure dropped back t o about 128 mm Hg. This response was c o n s i s t e n t and was seen i n a l l t e n animals tested. The systemic pressure responses of the three sets of experiments are shown on F i g . 14 f o r comparison.  The  r e s u l t s are c o n s i s t e n t w i t h those shown i n F i g . 5 i n which  Control  130 — CL  03  E E  11 0  d  2.5  100 —  E 01 \E O  o  -  120  X  2.0  E  1.5  A1  J  140  >  IX.  1  120 —  cz  E  —  >  100 — 80 —  60  cr  CO  i  180  -  160 — 14 0 -  >  Z )  120  cz  "E \ E  -  2.0 1.5 1.0 0.5  —  -  -  0.0 —  2 3 4  56  7 8 9  10 II  Time in 10 Min. Intervals  F i g . 11  Changes i n systemic a r t e r i a l p r e s s u r e , u r i n e output and composition a s s o c i a t e d w i t h t i m e . Pulmonary a r t e r i a l pouch pressure was kept a t 15 cm ELjO throughout the experiment. Average r e s u l t s (+ SEM) i n 10 dogs.  57 TABLE 2 C o n t r o l experiments ( u r i n e c o l l e c t i o n ) Time 10 min riods 1 2 5 4 5 6 7 8 9 10 11  Sys P mm Hg x + SEM  C ml/min x + SEM  117 115 114 112 111 110 110 112 112 114 115  2.1 2.1 1.9 2.2 2.2 2.2 2.1 2.0 2.2 2.2 2.0  5 4 4 3 5 3 3 3 3 4 4  G S  0.2 0.2 0.1 0.1 0.1 0.1 0.2 0.2 0.2 0.2 0.2  C U V UV ml/min juEq/min jiiEq/min ml/min x + SEM x + SEM x + SEM x + SEM R 0  -1.3 -1.2 -1.1 -1.2 -1.1 -1.1 -1.0 -0.8 -1.0 -0.8 -0.5  Na  0.1 0.2 0.2 0.1 0.1 0.1 0.2 0.2 0.4 0.2 0.3  91 80 76 83 92 96 93 88 86 94 92  K  19 16 17 16 15 16 15 17 19 22 22  138 12 140 11 137 8 151 8 149 10 154 12 150 12 146 13 149 13 153 12 152 11  0.8 0.9 0.9 1.0 1.1 1.1 1.1 1.2 1.3 1.3 1.4  0.2 0.2 0.2 0.1 0.1 0.2 0.2 0.3 0.3 0.3 0.3  58  140  cri  E  O  120 —  d  3.0 2.5  £  >  min  o -z.  ZD  >  >  cr < D =^  ZD  ZD  T  T  T  T  11 0  \  T  _L-LJ  T  T  T  T  T  2.0 J 200  -i  180  -  160  -  1 4 0— 120  -  100 180  -  160 — 140 —  Xj-r^T T T  120 —  c  >  -  £ £  o —  CO  130  /mi  X  CL  "E  E  2.0 — i 1 .5 1.0 — 0.5  -  0.0 —  |  2 3 4 5 6  7 8 9  10  II  Time in 10 Min. Intervals  F i g . 12  Changes i n systemic a r t e r i a l p r e s s u r e , u r i n e output and composition i n response t o pulmona r y a r t e r i a l pouch d i s t e n s i o n t o 40 cm I^O ( p e r i o d between the a r r o w s ) . During the c o n t r o l p e r i o d s , before and a f t e r the d i s t e n s i o n pouch pressure was kept a t 5 cm t^O. Average r e s u l t s (+ S.EM) i n 9 dogs.  59 TABLE 5 Pulmonary a r t e r y d i s t e n s i o n t o 40 cm B^O (urine c o l l e c t i o n ) Time 10 min riods 1 2 3 4 5 6 7 8 9 10 11  SysP mm Hg x + SEM 123 123 123 123 125 126 128 129 129 131 132  5 5 5 5 5 5 5 5 5 5 5  C ml/min x + SEM o a  2.5 2.5 2.6 2.6 2.6 2.6 2.7 2.7 2.9 2.9 2.9  0.3 0.2 0.2 0.2 0.2 0.2 0.2 0.3 0.2 0.2 0.2  C n V ml/min juEq/min juEq/min £ + SEM x + SEM x + SEM Na  -1.6 -1.5 -1.6 -1.5 -1.5 -1.4 -1.4 -1.4 -1.4 -1.3 -1.2  0.2 0.1 0.1 0.2 0.2 0.2 0.2 0.2 0.3 0.3 0.3  123 120 132 136 145 149 156 158 171 172 172  25 24 27 28 30 30 29 32 34 36 32  137 21 123 12 136 9 135 10 134 9 135 10 138 9 136 11 147 10 152 10 160 10  U ml/min x + SEM y o l  0.9 0.9 1.0 1.1 1.2 1.2 1.3 1.3 1.5 1.6 1.7  0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.2 0.3 0.3 0.3  60  X  Q_  £  CD  co O  —I  140  —  130  -  120  —  80  3.0  d  £ '£ O  150  2.5  1  2.0  J H J  T  T  LL  T  r  180 160 140  o  ZD  d  120  _  -  E  100  iv./  >  id-  8 0  -  180  -  Z3  D"  <D  >  120  -  2.0  _i  d  1.5  —  E \  1.0  160  ZD  ZD  140  1  0.5 0.0  i l  I.  -  2  3 4 5 6  Time  F i g . 13  7 8  9 10 II  in 10 Min. Intervals  Changes i n systemic a r t e r i a l p r e s s u r e , u r i n e output and composition i n response t o pulmona r y a r t e r i a l pouch d i s t e n s i o n t o 80 cm rLjO ( p e r i o d between the arrows). During the c o n t r o l p e r i o d s , before and a f t e r . t h e d i s t e n s i o n , pouch pressure was kept a t 15 cm HgO. Average r e s u l t s (+ SEM) i n 10 dogs.  61 TABLE 4 Pulmonary a r t e r y d i s t e n s i o n t o 80 cm FLjO Time 10 min periods 1 2 3 4 5 6 7 8 9 10 11  Sys P mm Hg x + SEM 132 129 129 128 136  .6 6 6 6 6  137 136 130 130 134 135  5 6 7 7 8 8  C os ml/min x + SEM e  2.3 2.3 2.3 2.2 2.6 2.5 2.6 2.6 2.6 2.5 2.8  0.3 0.3 0.4 0.4 0.4 0.4 0.3 0.4 0.4 0.4 0.4  H 0 ml/min x + SEM C  2  - 1 * 5 0.2 - 1 . 4 .0,2 -1.5,0.3 -1.3 0.2 -1.3 0.2 -1.1 0.2 -1.1 0.2 -1.1 0.2 -1.0 0.3 -0.9 0.3 -0.8 0.4  V  uv  ;uEq/min juEq/min x + SEM x + SEM :9126 91 24 -100 34 114 40 143 42 146 37 154 33 152 36 155 38 154 39 178 46  137 138 137 130 148 144 146 145 149 151 162  vol ml/min x + SEM U  K  17 20 22 21 23 22 22 22 23 21 25  0.8 0.9 0.9 ' 1.0 1.3 1.4 1.5 1.5 1.6 1.6 2.0  0.1 0.1 0,2 0.2 0.3 0.3 0.2 0.3 0.3 0.3 0.4  62  150 140 " 130 120 =C  | — CL"  80  T  140 130 H 120 ||0  cri  t  t  t  t  130 120 110 —I 100 -I  T  i—i—i—i—i—i—i—i  Control  T  m  r  Time in 10 Min. Intervals  F i g . 14  Changes i n systemic a r t e r i a l pressure i n the control and pulmonary a r t e r i a l pouch  disten-  s i o n experiments (40 and 80 cm ELpO).  Aver-  age r e s u l t s (+ S M ) 13.  taken from F i g . 11,  12 &  63  graded d i s t e n s i o n s of the pulmonary a r t e r i a l pouch e l i c i t e d i n c r e a s e s i n systemic pressure p r o p o r t i o n a l t o the degree of d i s t e n s i o n . The Wilcoxon two-sample rank t e s t was used t o analyse the d a t a .  For each experiment the f o u r systemic  pressure readings i n p e r i o d I were averaged and s u b t r a c t e d from the average value of the three readings i n p e r i o d (II-I).  II  The r e s u l t a n t values from the t e n c o n t r o l e x p e r i -  ments i n which the pouch pressure was kept constant f o r the e n t i r e 110 min were compared w i t h those where the pouch pressure was r a i s e d t o 80 cm B^O.  There was a s i g n i f i c a n t  i n c r e a s e i n the systemic pressure as the pouch was distended t o 80 cm H2O f o r 30 min when compared w i t h the c o n t r o l experiments (P<0.01).  S i m i l a r i l y f o r I I - I I I between the  same two groups of experiments P<0.025.  Systemic blood  pressure changes observed when the pulmonary a r t e r i a l pouch was distended from 5-40 cm H 0 were not s t a t i s t i c a l l y 2  significant.  b)  E f f e c t on u r i n e volume The volume of u r i n e e x c r e t e d i n c r e a s e d w i t h r e s p e c t  t o time i n a l l three s e t s of experiments.  The average  init-  i a l value was approximately 0.8 ml/min, and i n the case of the c o n t r o l experiments i t reached about 1.3 ml/min at the end of the 110 min. the whole p e r i o d .  The r a t e of i n c r e a s e was steady over In the experiments i n which the pouch was  64  F i g . 15  Changes i n u r i n e volume of the c o n t r o l and pulmonary a r t e r i a l pouch d i s t e n s i o n e x p e r i ments ( d i s t e n d i n g t o 40 and 80 cm rL^O) • Average r e s u l t s (+ SEM) taken from F i g . 11, 12 & 13*  65 distended t o 40 cm B^O there was a h i g h e r r a t e of i n c r e a s e , and a t the l a s t c o l l e c t i o n p e r i o d the average u r i n e output was 1.6 ml/min.  The r a t e of i n c r e a s e was again steady.  When compared w i t h the c o n t r o l experiments the d i f f e r e n c e i s not s i g n i f i c a n t .  D i s t e n s i o n of the pouch t o 80 cm B^O l e d  t o a step i n c r e a s e i n u r i n e e x c r e t i o n ( P i g . 15) when the pouch pressure was f i r s t r a i s e d , but there was no c o r r e s ponding drop when the pressure was r e l e a s e d .  The u r i n e  e x c r e t i o n continued t o i n c r e a s e u n t i l the average h i g h o f 2.0 ml/min was reached a t the end of the experiment. Apart from the step increase the response was s i m i l a r t o the other two sets of experiments.  S t a t i s t i c a l analysis  i n d i c a t e d t h a t the changes i n u r i n e volume i n the e x p e r i ments i n which pulmonary a r t e r i a l pouch pressure was r a i s e d t o 80 cm H 0 were not s i g n i f i c a n t l y d i f f e r e n t from those 2  in  the c o n t r o l experiments. Urine volume may be regarded as the sum o f f r e e water clearance and o s m o t i c a l l y o b l i g a t e d water (osmolar clearance).  These v a r i a b l e s were examined i n d i v i d u a l l y to  assess f u r t h e r any p o s s i b l e changes i n r e n a l f u n c t i o n i n response to pulmonary a r t e r y d i s t e n s i o n .  c)  E f f e c t on osmolar clearance Osmolar clearance was measured i n a l l of the u r i n e  c o l l e c t i o n experiments.  For the c o n t r o l experiments the  osmolar clearance was r e l a t i v e l y constant throughout the  66 e n t i r e experiment.  Mean value was about 2.1 ml/min and the  average change between each c o l l e c t i o n p e r i o d was always l e s s than 0.3 ml/min ( F i g . 16).  I n c r e a s i n g the pouch p r e s -  sure t o 40 cm ELjO d i d not evoke any n o t i c e a b l e changes i n the osmolar c l e a r a n c e .  S t a t i s t i c a l a n a l y s i s showed t h a t  there was no s i g n i f i c a n t d i f f e r e n c e from the c o n t r o l . D i s t e n s i o n of the pulmonary a r t e r y pouch to 80 cm ELjO r e s u l t e d i n a s m a l l i n c r e a s e i n the osmolar clearance from 2.2 ml/min t o about 2.6 ml/min; however a f t e r r e l e a s i n g the pouch pressure a t the end of the 30 min d i s t e n s i o n p e r i o d the osmolar clearance d i d not r e t u r n t o the p r e d i s tension l e v e l .  S t a t i s t i c a l a n a l y s i s showed t h a t the i n -  crease i n osmolar clearance by pulmonary a r t e r y pouch d i s t e n s i o n t o 80 cm ELjO i s not s i g n i f i c a n t l y d i f f e r e n t from the controls. Plasma o s m o l a r i t y was a l s o analysed i n a l l three s e t s of experiments.  There were no observable d i f f e r e n c e s  between each set, and the average value was about 290 mOs/kg. Only random f l u c t u a t i o n s of no more than 3$ were recorded. In general the plasma o s m o l a r i t y can be considered constant throughout any i n d i v i d u a l experiment.  Plasma sodium and  potassium were a l s o measured, again except f o r random f l u c t u a t i o n s of l e s s than % pEq/Jj  the average values are 145  and 5.0 juEq/L r e s p e c t i v e l y .  They a l s o can be c o n -  s i d e r e d t o be constant throughout i n d i v i d u a l experiments.  67  3.0 -i  c  2.5  -  2.0  -  1  3.0 u -  ~  25 -  t X ^ T  2.5 -,  1  80  T T T  T T  t  0 -  LI U r J  40  1 T T  2.0  Control  1.5 I  F i g . 16  I I I I I I I I I I Time in 10 Min. Intervals  I  Changes i n u r i n a r y osmolar clearance of the c o n t r o l and pulmonary a r t e r i a l pouch d i s t e n s i o n experiments ( d i s t e n d i n g t o 40 and 80 cm IL-jO). Average r e s u l t s (+ SEM) taken from F i g . 11, 12 & 13.;  68 d)  E f f e c t on sodium e x c r e t i o n The r e s u l t s of measurements of osmolar clearance  do not i n d i c a t e the content of i n d i v i d u a l s o l u t e s i n the urine.  Of a l l the s o l u t e s , sodium i s of p a r t i c u l a r i n t e r e s t  because of the importance of sodium as the major e x t r a c e l l u l a r c a t i o n and i t s r e l a t i o n s h i p to e x t r a c e l l u l a r f l u i d volume.  Changes i n sodium e x c r e t i o n are w i d e l y accepted as  p o s s i b l y i n f l u e n c i n g e x t r a c e l l u l a r f l u i d volume. The t e n c o n t r o l experiments showed t h a t sodium e x c r e t i o n was steady around 92 ;iEq/min throughout the e n t i r e 110 min.  No v a r i a t i o n corresponding t o time was seen.  The  nine experiments i n which the pulmonary a r t e r i a l pouch was d i s t e n d e d to 40 cm ELpO produced a r i s e i n sodium e x c r e t i o n ( P i g . 17) from 127 ;iEq/min to 150 jiEq/min and continued t o r i s e to 168 ^iEq/min a f t e r the pressure was r e l e a s e d .  When  compared w i t h the c o n t r o l experiments, however, the change was not s t a t i s t i c a l l y s i g n i f i c a n t .  On the other hand,  r e s u l t s from experiments where the pouch was distended t o 80 cm ELpO showed almost a 50$ i n c r e a s e i n the average r a t e o f sodium e x c r e t i o n from about 100 juEq/min t o 148 pBq/mln, This i n c r e a s e i n p e r i o d I I  from p e r i o d I i s very s i g n i f i c a n t  (2P<0.02) when compared w i t h the c o n t r o l experiments. period III  In  of the d i s t e n s i o n experiments, the average sodium  e x c r e t i o n r a t e continued to i n c r e a s e s l i g h t l y t o 160 ^iEq/min., when the i n c r e a s e i n sodium e x c r e t i o n i n p e r i o d I I I  from  p e r i o d I was compared between the d i s t e n s i o n and c o n t r o l  69  180 160 14 0 120 100 80  80  200 180 160 Z3 cr 140 120 100  40  >  140 120 100 80 60  Control  I  P i g . 17  I I I I I I I I I l Time in 10 Min. Intervals  Changes i n u r i n a r y sodium e x c r e t i o n of the c o n t r o l and pulmonary a r t e r i a l pouch d i s t e n s i o n experiments ( d i s t e n d i n g to 40 and 80 cm HgO). Average r e s u l t s (+ SEM) taken from P i g . 11, 12 & 13.  70 experiments 2P>0.05.  Thus r a i s i n g the pulmonary a r t e r i a l  pouch pressure from 5 cm B^O t o 80 cm HgO was a s s o c i a t e d w i t h a s i g n i f i c a n t i n c r e a s e i n sodium e x c r e t i o n .  Although  the average sodium e x c r e t i o n remained e l e v a t e d a f t e r removal of the d i s t e n s i o n , t h e s t a t i s t i c a l s i g n i f i c a n c e of t h i s change i s d o u b t f u l .  e)  E f f e c t on potassium e x c r e t i o n Potassium i s the o t h e r major c a t i o n excreted i n  the u r i n e besides sodium.  Its regulation i s closely linked  t o t h a t of sodium v i a the aldosterone system.  Along the  d i s t a l tubule of the kidney aldosterone promotes the r e a b s o r p t i o n of sodium and the e x c r e t i o n of potassium.  In  i t s absence, sodium e x c r e t i o n i n the u r i n e w i l l i n c r e a s e w i t h a corresponding decrease i n the potassium e x c r e t i o n . F i g . 18 shows the potassium e x c r e t i o n d u r i n g the c o n t r o l experiments and the experiments w i t h pulmonary a r t e r y d i s t e n s i o n t o 40 and 80 cm H 0 . 2  In a l l three cases the mean  potassium e x c r e t i o n was approximately 140 >iEq/min a t the beginning o f the experiments.  As expected, i t remained  r e l a t i v e l y constant throughout the e n t i r e 110 min experimenta l p e r i o d , f o r the c o n t r o l experiments, w i t h maximum v a r i a t i o n l e s s than 20 ^iEq/min.  I n c r e a s i n g the pressure  i n the  pulmonary a r t e r y pouch d i d not cause any s t a t i s t i c a l l y  71  I20  Time in IO Min. Intervals  i i j  P i g . 18  Changes i n u r i n a r y potassium e x c r e t i o n of the c o n t r o l and pulmonary a r t e r i a l pouch d i s t e n s i o n experiments ( d i s t e n d i n g to 4-0 and 80 cm H 0). Average r e s u l t s (+ SEM) taken from P i g . 11, 12 & 13. 2  72 s i g n i f i c a n t changes of the me°an potassium e x c r e t i o n .  From  F i g . 18 i t can be seen t h a t no s i n g l e stepwise changes of more than 20 ;iEq/min was recorded and except f o r one s i n g l e c o l l e c t i o n p e r i o d the mean potassium e x c r e t i o n was always l e s s than 16 /iEq/min.  Compared w i t h the sodium e x c r e t i o n  ( F i g . 17) no c o r r e l a t e d r i s e o r f a l l of the potassium e x c r e t i o n was observed.  f)  E f f e c t on f r e e water clearance Free water clearance i s a good i n d i c a t o r of  changes i n a n t i - d i u r e t i c hormone a c t i v i t y .  Normally, a n t i -  d i u r e t i c hormone promotes the r e a b s o r p t i o n of water i n the d i s t a l t u b u l e and c o l l e c t i n g duct t o produce h y p e r t o n i c u r i n e , thus negative f r e e water c l e a r a n c e . A gradual increase i n mean f r e e water clearance was observed throughout both the c o n t r o l and the d i s t e n s i o n experiments ( F i g . 1 9 ) .  The average i n i t i a l value of a l l  experiments was about -1.5 ml/min and i n each s e r i e s there was an increase a t approximately the same r a t e u n t i l the average h i g h of -0.5 ml/mih was reached.  There were no  i n c r e a s e s or decreases corresponding to manipulations of the pressure i n the pulmonary a r t e r y pouch.  As can be,*seen  from F i g . 19 the average f r e e water clearance of the three s e r i e s of experiments was always n e g a t i v e , and there was no s i g n i f i c a n t d i f f e r e n c e between them.  73  0 80  -1 -2  0 c E \  -I  O  -2  CM  X  o  0 Control  -2 -> I  F i g . 19  I I I I I I I I Time in 10 Min. Intervals  Changes i n u r i n a r y f r e e water clearance of the c o n t r o l and pulmonary a r t e r i a l pouch d i s t e n s i o n experiments ( d i s t e n d i n g t o 4-0 and 80 cm rLjO). Average r e s u l t s (+ SEM) from same experiments shown i n F i g . 11, 12 & 13.  74 TABLE 5 S t a t i s t i c a l r e s u l t s ( u r i n e c o l l e c t i o n experiments)  Pulmonary a r t e r y d i s t e n s i o n pressure  Pulmonary a r t e r y d i s t e n s i o n pressure  80 cm H 0  40 cm HgO  2  Periods tested Sys. P.  II-I  P<0.01  2  ++  II-III  P<0.025  II-I  III-I  P<0.05  ++  ++  ++  ++  'OS  'H 0  III-I  ++  ++  2P<0.02 ++  u.v o l  ++  * 2P>0.05 ++ Not t e s t e d . B e l i e v e d t o be not s i g n i f i c a n t l y d i f f e r e n t from the c o n t r o l by observing the raw d a t a .  75 E.  Urine C o l l e c t i o n With One Kidney I s o l a t e d And Perfused Two p o i n t s emerged from the previous s e r i e s of exp-  eriments.  F i r s t ., i n order to demonstrate s i g n i f i c a n t  changes i n u r i n a r y e x c r e t i o n i n the r e l a t i v e l y short time p e r i o d s ( f o r r e n a l response), i t was necessary to use h i g h d i s t e n d i n g pressure i n the pulmonary a r t e r y pouch.  Second-  l y , the prolonged increase i n sodium e x c r e t i o n a f t e r r e l e a s e of d i s t e n s i o n of the pulmonary a r t e r y pouch from 80 cm HgO suggested t h a t the r e n a l response may not w h o l l y be accounted f o r i n terms of hemodynamic changes a f f e c t i n g the k i d n e y , and suggested the p o s s i b i l i t y of a blood borne agent a f f e c t i n g the kidney.  To t e s t the l a t t e r p o s s i b i l i t y , s i x  experiments were performed i n which one kidney was t o t a l l y i s o l a t e d and perfused at constant pressure while the other kidney was i n t a c t and autoperfused.  Plasma o s m o l a r i t y ,  sodium and potassium c o n c e n t r a t i o n s were a l s o measured i n these s i x experiments.  A g a i n , except f o r a few random  i n s i g n i f i c a n t f l u c t u a t i o n s , they can be considered constant throughout i n d i v i d u a l experiments.  The average plasma  o s m o l a r i t y f o r a l l s i x experiments was 285 mOs/kg and the sodium and potassium c o n c e n t r a t i o n s were 145 and 5.0 juEq/L.  a)  I n t a c t kidney I n c r e a s i n g the pulmonary a r t e r i a l pouch pressure  from 10 cm HgO t o 100 cm H^O, then l o w e r i n g i t back to 10 cm H 0 , provoked a r e f l e x i n c r e a s e i n systemic a r t e r i a l p  pressure.  76  The i n c r e a s e i n systemic pressure from about 110 mm Hg t o 125 mm Hg c o i n c i d e d w i t h the r i s e i n pulmonary a r t e r i a l pouch pressure and on l o w e r i n g i t , the systemic pressure d r o p ped from 116 mm Hg to 103 mm Hg.  Since the c a r d i a c output  was kept c o n s t a n t , the changes i n systemic pressure  also  r e f l e c t e d a change i n systemic v a s c u l a r r e s i s t a n c e .  The  i n c r e a s e i n systemic pressure i s c o n s i s t e n t w i t h r e s u l t s from e a r l i e r d e s c r i b e d experiments.  P a i r e d t - t e s t between  the systemic pressure d u r i n g the d i s t e n s i o n p e r i o d and the average pressure of the e i g h t c o l l e c t i o n periods before and a f t e r d i s t e n s i o n shows t h a t the i n c r e a s e i n systemic a r t e r i a l pressure was h i g h l y s i g n i f i c a n t v/ith P<0.005. Urine volume i n t h i s case showed a c l e a r response t o the pulmonary a r t e r i a l pouch d i s t e n s i o n .  With an i n i t i a l  value of 0.4-4- ml/min i t i n c r e a s e d to 0.66 ml/min a f t e r d i s t e n s i o n and dropped from 0.74- to 0.4-8 ml/min upon the r e l e a s e of the p r e s s u r e .  P a i r e d t - t e s t y i e l d e d P value of l e s s than  0.0025, thus the i n c r e a s e i n u r i n e volume i s s i g n i f i c a n t . Osmolar clearance from the i n t a c t kidney e x h i b i t ed an i n c r e a s e i n response t o pulmonary a r t e r i a l  pressure.  Before d i s t e n s i o n the average osmolar clearance of the s i n g l e kidney was about 0.8 ml/min; d i s t e n s i o n to 100 cm HgO r a i s e d the osmolar clearance t o 0.96 ml/min and r e l e a s i n g the pressure dropped i t t o 0.62 ml/min.  The change i n  osmolar clearance was synchronous w i t h the i n c r e a s e i n systemic a r t e r i a l pressure and was s t a t i s t i c a l l y very  I  2 3 4 5 6 7 8 9  Time  F i g . 20  10 I I  in 10 Min. Intervals  Changes i n systemic a r t e r i a l pressure and u r i n a r y f u n c t i o n i n the i n t a c t kidney a s s o c i a t e d w i t h pulmonary a r t e r i a l pouch d i s t e n s i o n t o 100 cm H2O (periods between a r r o w s ) . During the c o n t r o l periods before and a f t e r the d i s t e n s i o n pouch pressure was kept a t 10 cm H2O. Average r e s u l t s (+ SEM) i n 6 dogs".  78 TABLE 6 Kidney p e r f u s i o n experiments ( i n t a c t kidneys) Time  10 min periods 1 2 3 4 5  6 7 8 9 10 11  SysP mm Hg x + SEM  C ml/min x + SEM  113 6 111 6 110 7 no 7 126 8 122 8 116 8 103 7 104 7 105 7 107 7  0.9 0.8 0.8 0.7 1.0 1.0 0.9  o s  0.6 0.6 0.6 0.7  0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.1  C ml/min x + SEM Q  -0.5 0.1 -0.4 0.1 -0.3 0.1 -0.3 0.1 -0.4 0.1 -0.2 0.1 -0.2 0.1 -0.1 0.1 -0.1 0.1 -0.1 0.1 -0.1 0.1  V  V  v o l  jiEq/min ^lEq/min x + SEM x + SEM  26 14 22 10 20 10 17 7 28 8 35 9 34 10 17 13 13 13  7 5 4 4  U ml/min x + SEM  58 12 60 11 61 11 61 8 78 6 78 ^4 70 7 51 10 52 12 53 13 54 11  0.4 0.4 0.4 0.4 0.7 0.8 0.7 0.5 0.5 0.5  0.1 0.1 0.1 0.1 0.1 0.2 0.2 0.1 0.2 0.2 0.6 0.2  79 s i g n i f i c a n t ( p a i r e d t - t e s t ; P<0.0005). With the pouch pressure at 10 cm rL^O, sodium e x c r e t i o n from the i n t a c t kidney decreased s t e a d i l y from 25.7 to 16.5 /iEq/min.  As the pressure was r a i s e d , i t i n c r e a s  ed t o the average of 32.0 jiEq/min over the 30 minutes d i s t e n s i o n p e r i o d and decreased to 13.9 jaEq/min a f t e r the pouch pressure was r e l e a s e d back to 10 cm rl^O.  Paired t - t e s t  shows a s i g n i f i c a n t r i s e i n the sodium e x c r e t i o n (P<0.0025),. The i n c r e a s e i n sodium e x c r e t i o n i n response t o pulmonary pouch d i s t e n s i o n was s i m i l a r t o increases observed i n the p r e v i o u s groups of experiments; u n l i k e the previous r e s u l t s the output dropped about 16.5 j&Eq/min a f t e r r e l e a s i n g the pulmonary a r t e r i a l pressure i n s t e a d of c o n t i n u i n g t o r i s e . Potassium e x c r e t i o n from the i n t a c t kidney r e s ponded q u i t e d i f f e r e n t l y from the experiments shown i n P i g . 18.  An i n c r e a s e of 17.3 ;uEq/min, from 60.9 t o 78.2  /iEq/min, was recorded when the pulmonary a r t e r i a l was r a i s e d from 10 t o 100 cm HgO ( P i g . 20).  pressure  When the p r e s s -  ure was r e l e a s e d , potassium e x c r e t i o n r a t e decreased from 69.8 to 50.8 ^LEq/min, a decrease of 19 .nEq/min.  The i n c r e -  ase i n potassium e x c r e t i o n was s t a t i s t i c a l l y s i g n i f i c a n t ( p a i r e d t - t e s t ; P<0.01). Free water clearance from the i n t a c t kidney was s i m i l a r t o the three sets of u r i n e c o l l e c t i o n experiments described e a r l i e r .  There was a steady i n c r e a s e from the  beginning of the experiment t o the end without any n o t i c e -  80 able breaks i n the r a t e of i n c r e a s e which c o u l d be r e l a t e d t o changes i n the pulmonary a r t e r i a l pouch p r e s s u r e . Maximum average f r e e water clearance was -0.4-5 ml/min and minimum average value was -0.07 ml/min, the d i f f e r e n c e was l e s s than 0.4- ml/min. b)  I s o l a t e d kidney The composition and the volume o f u r i n e samples  were d i s t i n c t l y d i f f e r e n t from the i n t a c t k i d n e y .  Most  of these d i f f e r e n c e s can be a t t r i b u t e d to the f a c t t h a t a l l n e u r a l i n f l u e n c e s were disconnected and the i n c r e a s e i n the systemic pressure could not have d i r e c t l y a f f e c t e d the i s o l a t e d constant pressure perfused k i d n e y .  Theoret-  i c a l l y any change i n the u r i n e composition and volume of the i s o l a t e d kidney c o u l d only be brought about by c i r c u l a t i n g b l o o d borne agents. With the i s o l a t e d k i d n e y , the r e n a l p e r f u s i o n pressure was kept at an average of 123 nim Hg.  The average  r e n a l blood f l o w decreased s t e a d i l y from 274- ml/min down t o 208 ml/min.  The l a r g e s t stepwise change was from 269  ml/min to 253 ml/min which occurred when the pulmonary a r t ery pressure was r a i s e d from 10 t o 100 cm HgO, however, when the pressure was lowered the b l o o d f l o w continued t o decrease w i t h a r e l a t i v e l y steady r a t e without any apparent break i n the t r e n d .  There was a gradual i n c r e a s e i n the  u r i n e volume s t a r t i n g from 0.84- ml/min to 1.79 ml/min a t  81 _o o o  c "E  CD  <D C  T3  E  o  o c "E  O  >  c "E  cr a> ZD  o >  1.4 - i 1.2 1.0 0.8 + 0.4 0.0 -0.4  o  c E  10-100  2 8 0 -i 260 240 220 200 -  l i l i  L_L - L J _ L  -i -  90 - i 80 70 60 80 60 40 1.6 1.2 0.8 0.4 0.0  3  . L T  t r  X  I 2 3 4 5 6 7 8 9 10 II Time in 10 Min. ^Intervals  P i g . 21  Changes i n r e n a l b l o o d f l o w and u r i n a r y f u n c t i o n i n the i s o l a t e d constant pressure p e r fused (average p e r f u s i o n pressure = 123 mm Hg) kidney a s s o c i a t e d w i t h pulmonary a r t e r i a l pouch d i s t e n s i o n t o 100 cm ^ 0 . Average r e s u l t s (+ SEM) i n 6 dogs.  82 TABLE 7 Kidney p e r f u s i o n experiments ( i s o l a t e d kidneys) Time 10 min periods  BB? 0 mt/W&n ml/min x '+ SEM x + SEM  0 ml/min x + SEM  1 2  274 14 276 16  -0.3  3 4  273 19  5 6 7 8 9 10 11  O S  269 253 24-8 243 235 228 216  21 15 12 12 16 16 19  209 17  1.1 1.1 1.1 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.1  0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.1 0.1 0.1 0.2  -0.2 -Oil  0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7  0.1 0.1 0.1 0.1 0.1 0.1 0.1 0.1  0.1 0.1 0.1  U V ;uEq/min x + SEM N a  68 23 68 19 69 18 76 19 77 18 82 14 80 11 79 10 73 9 69 '9 69 9  RBP = Renal b l o o d f l o w Average r e n a l p e r f u s i o n pressure = 123 mm Hg  0 ml/min x + SEM y o l  V  juEq/min x + SEM 64 8 65 6 65 6 72 7 71 5 73 4 71 4 73 5 73 6 73 8  75 9  0.8 1.0 1.1 1.2 1.3 1.5 1.5 1.6 1.7 1.7 1.8  0.2 0.2 0.2 0.2 0.2 0.1 0.1 0.1 0.2 0.2 0.2  83 the end of the experiment.  The i n c r e a s e was c o r r e l a t e d t o  the pulmonary a r t e r i a l pouch p r e s s u r e . There were s m a l l increases i n sodium e x c r e t i o n r a t e d u r i n g the experiment corresponding approximately to the p e r i o d of pulmonary a r t e r y pouch d i s t e n s i o n .  The  average e x c r e t i o n r a t e before d i s t e n s i o n was 70.1 jaEq/min, d u r i n g the d i s t e n s i o n p e r i o d i t i n c r e a s e d to 79.7 .uEq/min and f e l l back to 72.4 juiEq/min a f t e r the r e l e a s e of p r e s s u r e . Comparison of sodium e x c r e t i o n r a t e between the d i s t e n s i o n and c o n t r o l periods showed no s i g n i f i c a n t d i f f e r e n c e (0.10>P>0.05).  These experiments do not confirm an i n c r e a s e  i n sodium e x c r e t i o n w i t h pulmonary a r t e r y d i s t e n s i o n i n the i s o l a t e d perfused k i d n e y . The potassium e x c r e t i o n r a t e i n c r e a s e d s l i g h t l y over the experimental p e r i o d from 63.6 joEq/min t o 75.3 ^iEq/min.  There were no changes i n the e x c r e t i o n r a t e which  c o u l d be r e l a t e d t o the pulmonary a r t e r y pouch d i s t e n s i o n . Osmolar clearance d u r i n g the 110 minute e x p e r i mental p e r i o d was almost c o n s t a n t , the minimum clearance was 1.10 ml/min and the maximum clearance was 1.23 ml/min, a d i f f e r e n c e of o n l y 0.12 ml/min.  S t a t i s t i c a l t e s t s showed  no c o r r e l a t i o n w i t h the pulmonary a r t e r i a l pouch p r e s s u r e . This r e s u l t i s i n c o n t r a s t w i t h t h a t from the i n t a c t kidney i n which the r i s e i n pulmonary a r t e r i a l pressure l e d to a s i g n i f i c a n t i n c r e a s e i n osmolar c l e a r a n c e .  84 Free water clearance of the i s o l a t e d kidney took on the same shape as the other u r i n e experiments, t h a t i s the clearance rose s t e a d i l y throughout the experiment w i t h no s i g n i f i c a n t changes r e l a t e d t o the pulmonary a r t e r i a l pressure.  However, the i s o l a t e d kidney was d i f f e r e n t i n one  a s p e c t , the f r e e water clearance became p o s i t i v e , l a t e r i n the experiment.  At the beginning of the experiment the  average f r e e water clearance was -0.27 ml/min, a f t e r t h i r t y minutes the clearance was 0.01 ml/min and a t the end i t was 0.68 ml/min compared w i t h the i n t a c t kidney where the average f r e e water clearance was always n e g a t i v e .  85 TABLE 8 S t a t i s t i c a l r e s u l t s ( i n t a c t and i s o l a t e d kidney experiments) I n t a c t Kidney  Data  T T  11,  tested Blood pressure CL  I+III  T T  II,  *  *  0.0025<P<0.005 P<0.0005  e  I s o l a t e d kidney  I+III d  Blood flow  js  -  * *  O S  C  H 0  0.05<P<0.1  2  U  Na  0.0005<P<G.0025  V  UV  0.005<P<0.01  K  U  -  0.0005<P<0.0025  *  P>0.1  * 0.05<P<0.10 * *  86 DISCUSSION A.  Review Whereas the p r o p e r t i e s of the systemic a r t e r i a l  baroreceptors have been s t u d i e d i n c o n s i d e r a b l e d e t a i l (reviewed by Heymans and N e i l , 1958} Korner, 1971} P a i n t a l , 1973; Kirchheim, 1976) there have been r e l a t i v e l y few s t u d i e s of the f u n c t i o n of the pulmonary a r t e r i a l b a r o receptors.  Indeed,recent reviewers (see above) have a t t a c h -  ed l i t t l e importance t o r e f l e x e s from t h i s a r e a . a)  Embryological evidence Eberhard Koch (19,31) was the f i r s t t o recognize  the s i g n i f i c a n c e of the anatomical l o c a t i o n of the mammalian b a r o r e c e p t o r areas.  He p o i n t e d out that these areas were  developed from the embryonic v i s c e r a l arch v e s s e l s and suggested t h a t these arch v e s s e l s were a l l provided w i t h corresponding v i s c e r a l nerves i n the embryo. s i n u s formed from v i s c e r a l arch I I I glossopharyngeal  nerve.  The c a r o t i d  i s s u p p l i e d by the  The a o r t i c arch baroreceptor area  d e r i v e d from arch IV i s i n n e r v a t e d by a branch of the supe r i o r l a r y n g e a l n e r v e , the nerve of v i s c e r a l arch IV. He a l s o drew a t t e n t i o n t o the vagal sensory i n n e r v a t i o n of the ductus a r t e r i o s u s , a VI arch s t r u c t u r e which develops i n t o the main pulmonary a r t e r y and i t s b i f u r c a t i o n s . Prom the embryological evidence the pulmonary a r t e r y b a r o r e c e p t o r s are p o t e n t i a l l y as important as the systemic a r t e r i a l receptors.  87 b)  H i s t o l o g i c a l studies Receptors i n the pulmonary a r t e r y and i t s main  branches have been d e s c r i b e d by Dogiel (1898, 1903) and Karsner (1911) which do not have c o n s i s t e n t d i s t r i b u t i o n s . Nonidez (1937, 1939) r e p o r t e d a pressor r e c e p t o r area of the pulmonary a r t e r y b i f u r c a t i o n w i t h f l a t t e n e d nerve f i b e r s , ending i n conspicuous r i n g s i n the pulmonary a r t e r y and which appeared t o o r i g i n a t e from the upper t h o r a c i c ganglia.  S i m i l a r h i s t o l o g i c a l f i n d i n g s have a l s o been  p u b l i s h e d by L a r s e l l and Dow (1933), Nonidez (1941), Boyd (1941), B i a n c o n i and Green (1959) w i t h c a t s , dogs, and the human b e i n g s .  Nerve f i b e r s were o c c a s i o n a l l y seen i n  the t u n i c a externa of the l a r g e pulmonary a r t e r i e s but never w i t h i n the muscular l a y e r s .  The endings are most f r e q u e n t l y  d e s c r i b e d as myelinated nerve f i b e r s i n the a d v e n t i t i a , t e r m i n a t i n g at the j u n c t i o n of the media and a d v e n t i t i a , or p e n e t r a t i n g the outer l a y e r s of the media and ending as an i r r e g u l a r c o l l e c t i o n of c o i l e d f i b e r s , sometimes w i t h s w e l l i n g s and enlargements on the t e r m i n a l t w i g s .  Coleridge,  K i d d and Sharp (1961) r e p o r t e d the e x i s t e n c e of a b a r o r e c e p t o r area i n the l e f t and r i g h t pulmonary a r t e r i e s of dogs which i s much more e x t e n s i v e than p r e v i o u s l y v i s u a l i z e d . The r e c e p t o r s l o c a t e d i n , o r i n contact w i t h the media take the form of f i n e branching c o i l e d nerve f i b e r s compactly arranged w i t h i n an area of connective t i s s u e .  They are  s u p p l i e d by myelinated f i b e r s from the l e f t and r i g h t vagus nerves.  P h y s i o l o g i c a l experiments by B i a n c o n i and Green  88 (1959), C o l e r i d g e , Kidd and Sharp (1961) have shown t h a t they respond t o pressure a p p l i e d t o the pulmonary a r t e r y . S t u d i e s i n man, dog and cat by G r i g o r ' e v a (1962) r e v e a l e d sensory nerve elements i n a l l three l a y e r s of the pulmonary artery.  A few branchings of a myelinated nerve t e r m i n a t i n g  i n a l a r g e area of c r i s s - c r o s s found i n the a d v e n t i t i a . the media.  unmyelinated f i b e r s were  S i m i l a r r e c e p t o r s were found i n  In a d d i t i o n many f i b e r s w i t h bushy endings are  i n d i r e c t contact w i t h muscular elements i n a l l l a y e r s of the pulmonary a r t e r y . Nonidez (1937) d e s c r i b e d an e p i t h e l i o i d mass i n the a d v e n t i t i a on the d o r s a l aspect of the pulmonary trunk immediately caudal to i t s p o i n t of b i f u r c a t i o n .  I t was  s u p p l i e d w i t h blood from a s m a l l branch of the a o r t a and a branch from the l e f t coronary a r t e r y .  K r a h l (1962)  r e p o r t e d a glomus, a homologue of the c a r o t i d and a o r t i c glomera s i t u a t e d i n the same p o s i t i o n .  Because of the  nature of i t s blood supply Nonidez (1937) dismissed the i d e a t h a t i t might f u n c t i o n as a chemoreceptor f o r venous blood.  This view i s supported by V f e r i t y , Hughes and Bevan  (1964), who made a study of the glomus t i s s u e i n the r e g i o n of the a o r t a and pulmonary a r t e r y i n cats and found no evidence to show t h a t the pulmonary a r t e r y s u p p l i e d the tissue.  They a l s o noted t h a t the q u a n t i t y of the glomus  t i s s u e might vary from a few c e l l s i n a s i n g l e l o b u l e t o l a r g e m u l t i l o b u l a r masses.  Hughes (1965a, 1965b) suggested  t h a t the blood supply of the glomus t i s s u e i s d e r i v e d from  89 the venae vasorum of the pulmonary a r t e r y and p a r t s of the a o r t a ; t h i s i n e f f e c t would he a p o r t a l type of c i r c u l a t i o n s u p p l y i n g venous blood t o the glomus t i s s u e .  The s i g n i f i -  cance of such a system i s not known.  c)  I n n e r v a t i o n of the pulmonary a r t e r y The nervous connections of the pulmonary a r t e r y  baroreceptors were i n v e s t i g a t e d by C o l e r i d g e , Kidd and Sharp (1961).  Ten f i b e r s were d i s s e c t e d from the r i g h t vagus, of  which f i v e were l o c a t e d i n the r e c u r r e n t c a r d i a c nerve.  This  nerve i s formed at about the l e v e l of the caudal c e r v i c a l g a n g l i o n , r e c e i v i n g f i l a m e n t s from the g a n g l i o n , r i g h t r e c u r r e n t l a r y n g e a l nerve and v a g a l t r u n k .  I t runs c a u d a l l y and  m e d i a l l y between the s u p e r i o r vena cava and t r a c h e a , and sends branches t o the r i g h t pulmonary a r t e r y .  The remaining  r i g h t vagal f i b e r s pass behind the s u p e r i o r vena cava to the r i g h t pulmonary a r t e r y i n the vagal c a r d i a c nerves which a r i s e from the vagal trunk between the ansa s u b c l a v i a and the l e v e l of the azygos v e i n . A s i m i l a r study was done by Bevan and V e r i t y (1961) i n cats.  Using the nomenclature of Mizeres (1955) they d e s -  c r i b e d the r e c u r r e n t c a r d i a c nerve and sometimes the c r a n i o v a g a l c a r d i a c nerves as c a r r y i n g the main i n n e r v a t i o n t o the pulmonary a r t e r y b a r o r e c e p t o r s .  The r e c u r r e n t c a r d i a c  nerve i s a moderately l a r g e nerve a r i s i n g from the r i g h t r e c u r r e n t l a r y n g e a l nerve as i t loops around the r i g h t  sub-  90 clavian artery.  I t u s u a l l y r e c e i v e s a c o n t r i b u t i o n of v a r y -  i n g s i z e from the v a g a l trunk and another from the s t e l l a t e ganglion.  The nerve passes d o r s a l l y t o the a n t e r i o r vena  c a v a , l a t e r a l l y to the c r a n i o c e p h a l i c a r t e r y and a r c h of the a o r t a , t o the pulmonary b i f u r c a t i o n where i t d i v i d e s i n t o a n t e r o l a t e r a l and p o s t e r o l a t e r a l branches. e r o l a t e r a l branch i s the s m a l l e s t .  The a n t -  These branches f a n out  over the a n t e r i o r and p o s t e r i o r aspects of the main p u l monary a r t e r y and communicate w i t h p l e x i around the r i g h t and l e f t pulmonary a r t e r i e s and the p r e t r a c h e a l p l e x e s . Some pulmonary a f f e r e n t f i b e r s are the p e r i p h e r a l axons of c e l l bodies i n the s p i n a l g a n g l i a .  They reach the  lungs without i n t e r r u p t i o n through the s t e l l a t e and middle cervical ganglia.  Edgeworth (1892) t r a c e d l a r g e c a r d i o -  pulmonary myelinated f i b e r s through these sympathetic gangl i a as f a r as the d o r s a l r o o t s and suggested they might connect w i t h the d o r s a l r o o t g a n g l i a . G r i g o r ' e v a (1962) cut the v a g i or e i t h e r the nodose ganglion or the s p i n a l g a n g l i a Cg-T^, as a r e s u l t the baroreceptors i n the a d v e n t i t i a and the media and the bushy nervous endings i n contact w i t h the muscular elements of the pulmonary a r t e r y degenerated.  This would i n d i c a t e  t h a t the sensory i n n e r v a t i o n of the area i s from both the vagus nerves and the s p i n a l nerves.  91 Eor the glomus t i s s u e there i s a r i c h p e r g l o meral nerve plexus to which vagal and sympathetic f i b e r s can be t r a c e d .  Boyd (1961) d e s c r i b e d t h a t the nervous  supply i s d e r i v e d from the conjoined bundles of vagal and sympathetic f i b e r s which pass towards the heart between the a o r t a and the pulmonary t r u n k .  The f i b e r s are of w i d e l y .  v a r y i n g c a l i b e r s , suggesting an extensive spectrum of f i b e r d i a m e t e r s , but whether these f i b e r s are myelinated or not i s unclear.  In a d d i t i o n to nerve endings r e l a t e d to the  glomus c e l l s t h e r e i s a r i c h nerve supply t o the a r t e r i o l e s i n the orgaii.  d)  Electrophysiological  studies  E l e c t r o p h y s i o l o g i c a l s t u d i e s by r e c o r d i n g from t h e vagus nerves have c l e a r l y demonstrated a c t i o n p o t e n t i a l s o r i g i n a t i n g from the pulmonary a r t e r y (Coleridge and K i d d , 1960).  Coleridge and K i d d (1961) occluded the main p u l -  monary a r t e r y and observed c e s s a t i o n of a c t i o n p o t e n t i a l i n s l i p s of vagus nerves.  When the l u n g r o o t s were occluded  the r a t e of f i r i n g of a c t i o n p o t e n t i a l s i n c r e a s e d .  Inflat-  i o n of a b a l l o o n i n the pulmonary a r t e r y produced s i m i l a r effect.  A f t e r k i l l i n g the a n i m a l , they were able t o t r a c e  the nerve f i b e r s back to s i t e s i n the pulmonary a r t e r y \irhich generated an a c t i o n p o t e n t i a l when touched.  Corre-  l a t i n g the pulmonary a r t e r i a l pressure and the a c t i o n p o t e n t i a l s i n the a f f e r e n t vagal f i b e r s Coleridge and K i d d (1961) observed a corresponding r e l a t i o n s h i p .  As the pressure  92 i n c r e a s e d from an average of about 18/7 t o 50/24 mm Hg ( s y s t o l i c / d i a s t o l i c ) the impulse discharge i n c r e a s e d from a mean of approximately 1 t o 26 p u l s e s / c a r d i a c c y c l e and the maximum frequency went from about 25 t o 200 impulses/sec. In t e n baroreceptors t e s t e d , the t h r e s h o l d pressures w i t h i n the range 16-25/7-13 mm Hg.  were  They a l s o showed t h a t  p u l s a t i l e pressure i n the pulmonary a r t e r y i s much more e f f e c t i v e i n producing a c t i o n p o t e n t i a l s than a steady pressure.  In one o f t h e i r i s o l a t e d pulmonary a r t e r y p r e p -  a r a t i o n s a steady pressure f a i l e d t o generate any a c t i o n p o t e n t i a l while a p u l s a t i l e pressure w i t h the s y s t o l i c  press-  ure l e s s than the steady pressure d i d . S i m i l a r r e s u l t s were obtained i n the i n t a c t p r e p a r a t i o n s . The l a r g e myelinated vagal f i b e r s from the pulmona r y a r t e r y a c t i v e l y discharge a t pressures normally present i n the pulmonary a r t e r y , s i g n a l i n g b e a t - t o - b e a t changes i n pressure (see above paragraph).  Coleridge, Coleridge,  Dangel, K i d d , Luck and S l e i g h t (1973) measured the conducti o n v e l o c i t y of these f i b e r s , i n f i v e cases they range from 18.1 t o 30.0 m/sec.  In a d d i t i o n there are f i n e myelinated  and unmyelinated C f i b e r s a r i s i n g from the pulmonary a r t e r y not connected w i t h baroreceptors ( C o l e r i d g e , Coleridge and Luke, 1965; C o l e r i d g e , C o l e r i d g e , Dangel, K i d d , Luck and S l e i g h t , 1973). spontaneous  These endings had a sparse,  discharge o r they were q u i e s c e n t .  irregular They d i d  not respond to pressures w i t h i n the p h y s i o l o g i c a l range but were s t i m u l a t e d by h i g h pressures  (60-110 mm Hg) and  93 the conduction v e l o c i t y averaged 1.3 m/sec.  These  endings  appear t o be d i s t r i b u t e d over the main pulmonary a r t e r y and the l e f t and r i g h t branches whereas the endings of the l a r g e myelinated f i b e r s are l o c a t e d almost e x c l u s i v e l y i n the r i g h t and l e f t main pulmonary a r t e r i e s ( C o l e r i d g e and K i d d , 1960; Bevan and K i n n i s o n , 1965a, 1965b; V e r i t y and Bevan, 1962).  Coleridge et a l (1973) a l s o n o t i c e d some  f i b e r s whose endings were s t i m u l a t e d by both systemic hypoxia and a high pressure i n t h e i r pulmonary sac (70-120 mm Hg). They suggested these were chemoreceptors ( p o s s i b l y the glomus c e l l s ) l o c a t e d on or i n the pulmonary a r t e r y , the b l o o d supply t o which might be occluded by extreme d i s t e n s i o n of the pulmonary a r t e r y . More r e c e n t l y N i s h i , Sakanashi and Takenaka (1974), Uchida (1975) recorded a c t i o n p o t e n t i a l s from a f f e r e n t f i b e r s i n the l e f t c a r d i a c sympathetic nerve i n n e r v a t i n g mechano-sensitive r e c e p t o r s i n the w a l l of the pulmonary artery.  These f i b e r s showed i r r e g u l a r a c t i v i t y ; however,  a s l i g h t e l e v a t i o n i n pulmonary a r t e r i a l pressure w i t h i n the range of 2.5-5/0-4 mm Hg ( s y s t o l i c / d i a s t o l i c )  elicited  impulses synchronous w i t h the s y s t o l i c pressure p u l s e , while a f u r t h e r e l e v a t i o n of the pressure d i d not cause a marked increase i n pulses/cardiac c y c l e .  A sustained  pressure  o n l y produced a t r a n s i e n t b u r s t of a c t i v i t y f o l l o w e d by a p r o g r e s s i v e decrease i n the d i s c h a r g e .  There i s a p o s s i b i l i t y  t h a t these f i b e r s represent aberrant v a g a l f i b e r s , s i n c e t h e r e may be vagal contamination of the i n f e r i o r c a r d i a c  94 nerve.  However, t h i s i s extremely u n l i k e l y because a f f e r e n t  f i b e r s responding to mechanical stimulation of the pulmonary a r t e r y have also been recorded from the t h i r d ramus of the l e f t t h o r a c i c sympathetic nerve.  e)  Drug stimulation The  studies  c r o s s - s e c t i o n a l area of the pulmonary artery  i s greater than the sum of the area of the r i g h t and l e f t branches, t h i s phenomenon i s the reverse of other major a r t e r i a l b i f u r c a t i o n s (Fry, Patel and DeFreitas, Despite the overwhelming evidence of a f f e r e n t  1962).  innervation  of the pulmonary a r t e r i e s , the r e f l e x e f f e c t s generated from these receptors  are s t i l l i n doubt.  Porszasz-Gibiszer  Porszasz, Gyorgy and  (1955) observed bradycardia,  hypotension  and apnoea i n dogs following i n j e c t i o n of c a p s a i c i n . Bevan (1961, 1962) experimented on cats and thought that the receptors  s e n s i t i v e t o capsaicin were located i n the  pulmonary a r t e r y .  Analysis of possible s i t e s of action by  Porszasz, Such and Porszasz-Gibiszer  (1957) found that i n  dogs c a p s a i c i n i n j e c t i o n s a t the main pulmonary b i f u r c a t i o n produced the l a r g e s t responses; on the other hand i n j e c t i o n beyond the b i f u r c a t i o n had l i t t l e or no e f f e c t . with r e s u l t s a f t e r vagotomy, they postulated  Together,  that the vagal  r e f l e x was due to a c t i v a t i o n of baroreceptors near the p u l monary b i f u r c a t i o n by c a p s a i c i n . Coleridge  However, Coleridge,  and Kidd (1964) showed capsaicin can pass f r e e l y  through the pulmonary artery into the intrapulmonary vas-  95 c u l a r bed d e s p i t e t h a t i t was i n j e c t e d i n t o the r i g h t s i d e o f the c i r c u l a t i o n o n l y .  They were able t o o b t a i n e f f e c t s  w i t h i n j e c t i o n s beyond the hilum i n t o the vasculai? bed o f the l u n g i t s e l f , and sometimes the e f f e c t occurred w i t h i n 1-2 s e c , w e l l w i t h i n the pulmonary c i r c u l a t i o n t i m e .  There-  f o r e they proposed t h a t some other intrapulmonary r e c e p t o r s besides the pulmonary a r t e r y baroreceptors are responsive to capsaicin.  This view i s i n d i r e c t l y supported by the f a c t  t h a t c o o l i n g the vagus nerves to 8-10°C blocks conduction i n the f i b e r s of the extrapulmonary baroreceptors  (Coleridge,  K i d d and Sharp, 1961), but the e f f e c t of c a p s a i c i n was not always a b o l i s h e d by the same maneuver, i n s t e a d i t has to be cooled to 2-5° C ( C o l e r i d g e , Coleridge and K i d d , 1964). The temperature d i f f e r e n t i a t i o n suggests t h a t a f f e r e n t nervous f i b e r s of d i f f e r e n t diameters are i n v o l v e d .  The  pulmonary a r t e r y baroreceptors w i t h l a r g e r f i b e r s can be b l o c k e d w i t h a h i g h e r temperature while the other i n t r a pulmonary r e c e p t o r s have s m a l l e r diameter f i b e r s r e q u i r i n g a lower b l o c k i n g temperature.  The nature and f u n c t i o n of  these intrapulmonary r e c e p t o r s are not c l e a r . S i m i l a r c a r d i a c and r e s p i r a t o r y e f f e c t s were r e p o r t e d by Bevan and V e r i t y (1961) by u s i n g l o b e l i n e . More d e t a i l e d work by Bevan (1962), Bevan and K i n n i s o n (1965a, 1965b) r e v e a l e d t h a t s m a l l amounts (1-2 jig/kg) of l o b e l i n e i n j e c t e d i n t o r i g h t s i d e of the heart caused only v e n t i l a t o r y changes w i t h i n 1-2 sec w h i l e l a r g e r amounts i n i t i a t e i n a d d i t i o n , b r a d y c a r d i a and hypotension.  Atropine  96  reduced but not abolishtithe hypo tens i o n .  Electrophysiolo-  g i c a l s t u d i e s by C o l e r i d g e , C o l e r i d g e and Kidd (1964-), Bevan and K i n n i s o n (1965b) showed t h a t both c a p s a i c i n and l o b e l i n e i n c r e a s e d the a f f e r e n t discharge of pulmonary a r t e r y r e c e p t o r s even i n the absence of changes i n the pulmonary a r t e r y pressure w i t h i n 1-2 sec of i n j e c t i o n i n t o the r i g h t atrium.  V e r i t y , Hughes and Bevan (1965) e x p l a i n e d t h i s r a p i d  e f f e c t by assuming t h a t l o b e l i n e d i f f u s e s t o sensory i n the media to cause the r e f l e x e f f e c t .  endings  Bevan s p e c u l a t e d  the v e n t i l a t o r y r e f l e x response as a mechanism to lower the pulmonary a r t e r i a l p r e s s u r e .  He s t a t e d t h a t the immed-  i a t e r e f l e x response to a r i s e i n pulmonary a r t e r y pressure was v e n t i l a t o r y i n h i b i t i o n and a d i m i n u t i o n i n venous This process would tend to l o w e r y t h e output of  return.  the r i g h t s i d e of the heart and i n t u r n the pulmonary a r t e r y pressure.  The v e n t i l a t o r y r e f l e x obsersed by Bevan and  K i n n i s o n (1965a) was the r e s u l t s of l o b e l i n e i n j e c t i o n s and there i s not enough d i r e c t evidence t o support t h i s t h e o r y of pulmonary a r t e r y pressure r e g u l a t i o n v i a v e n t i l ation.  Moreover there are s e r i o u s questions r e g a r d i n g how  the l o b e l i n e reaches the r e c e p t o r s (Bevan, 1965) and whether l o b e l i n e s t i m u l a t e s chemoreceptors or b a r o r e c e p t o r s .  f)  Pulmonary a r t e r y d i s t e n s i o n s t u d i e s More d i r e c t s t i m u l a t i o n of the pulmonary a r t e r y  w i t h h y d r a u l i c pressure should give a b e t t e r i n d i c a t i o n of  97 the t r u e p h y s i o l o g i c a l f u n c t i o n s of the pulmonary a r t e r y o  baroreceptors.  C h u r c h i l l and Cope (1929) using c a t s , l i g -  a t e d the v e s s e l s of one l u n g and having cannulated the c o r responding pulmonary a r t e r y r a i s e d the s t a t i c pressure the v e s s e l s .  in  Bradycardia and hypotension r e s u l t e d , but  r e s p i r a t i o n was a f f e c t e d i n c o n s i s t e n t l y .  Experimenting w i t h  dogs, Schwiegk (1935) obtained the same r e s u l t s i n s i m i l a r experiments, furthermore he proved t h a t the e f f e c t s were r e f l e x and were dependent on the i n t e g r i t y of the i p i g i . A f a l l i n systemic pressure was observed when the pulmonary a r t e r y pressure was r a i s e d 10 mm Hg, the accompanied bradyc a r d i a v a r i e d from 10-24 beats per minute.  Later experi-  ments by Schweitzer (1936) and P a r i n (194-7) were much l e s s consistent.  In S c h w e i t z e r ' s r e p o r t , hypotension and brady-  c a r d i a were observed o n l y i n two of the twelve cats t e s t e d . The s t a t i c pulmonary pressures used by both Schweitzer and P a r i n were v e r y h i g h compared w i t h the normal mean pulmonary a r t e r i a l pressure.  The technique used by these i n v e s t i g a t -  ors may be c r i t i z e d because the r i s e i n the pulmonary a r t e r y pressure a l s o a f f e c t e d a r t e r i a l , c a p i l l a r y and venous p r e s sures of the pulmonary c i r c u i t .  Thus any response  elicited  from i n c r e a s i n g the pulmonary a r t e r y pressure can not be considered t o be caused by the pulmonary a r t e r y b a r o r e c e p tors alone. Aviado, L i , Kalow, Schmidt, T u r n b u l l , P e s k i n and Hess (1951) performed cross c i r c u l a t i o n experiments, i n which b l o o d f l o w i n g i n the r i g h t heart was i s o l a t e d .  Increasing  98 the pulmonary a r t e r i a l pressure induced a vagal r e f l e x bradyc a r d i a but no hypotension, however t h i s c l a i m was not supp o r t e d by t h e i r experimental r e c o r d s .  Indeed, i n one of  t h e i r f i g u r e s which showed a r i s e of r i g h t heart plus p u l monary p e r f u s i o n pressure there was no change i n h e a r t r a t e . The technique of Aviado et a l (1951) allowed a more d i s c r i m i n a t i v e study of the pulmonary a r t e r y , however the r i g h t h e a r t was s t i l l a f f e c t e d . Lewin, Cross, Reiben and S a l i s b u r y (1961) devised a complete h e a r t bypgcss w i t h an oxygenator, and the animal was perfused w i t h constant b l o o d f l o w .  The pulmonary a r t e r y  was distended w i t h blood or a b a l l o o n c o n t a i n i n g 18-28 ml of a i r .  I n f l a t i o n of the b a l l o o n l e d t o an i n c r e a s e i n  systemic a r t e r i a l pressure which was a b o l i s h e d by c u t t i n g o r c o o l i n g (temperature u n s p e c i f i e d ) the lagus nerves. The s t i m u l i provided by the b a l l o o n c o u l d not be q u a n t i t i z e d and u s i n g b l o o d the, pulmonary a r t e r i a l pressure had to be r a i s e d t o 80-200 mm Hg to produce the response.  Since the  systemic blood f l o w was c o n s t a n t , the authors concluded t h a t the response was due t o vasomotor changes.  Osorio and Russek  (1962) introduced a b a l l o o n o r a c u f f e d c y l i n d e r which d i d not impede blood f l o w , i n t o the main branches of the p u l monary a r t e r y .  Two types of responses were r e p o r t e d .  With  a "weak" d i s t e n s i o n they observed e i t h e r no change or a f a l l i n systemic, p r e s s u r e , whereas " s t r o n g e r " d i s t e n s i o n caused a r i s e ; no heart r a t e changes were observed.  I n f l a t i o n of  a b a l l o o n i n the pulmonary a r t e r y gives a n o n - s p e c i f i c  99 s t i m u l u s , f o r only a s m a l l p o r t i o n of the b a l l o o n i s a c t u a l l y i n contact w i t h the pulmonary a r t e r i a l w a l l and the p r e s s ure e x e r t e d by the b a l l o o n i s not measurable. C o l e r i d g e and K i d d (1963) i n s e r t e d a tube i n t o the l e f t main pulmonary a r t e r y of dogs and perfused the r i g h t main pulmonary a r t e r y and t h a t p o r t i o n of the l e f t pulmonary a r t e r y o u t s i d e the sleeve w i t h c o n t r o l l e d p r e s s u r e s . When the pulmonary a r t e r y sac pressure was e l e v a t e d to between 20-60 mm Hg there was e i t h e r no e f f e c t (10 dogs) or a f a l l i n systemic pressure (8 dogs) and i n the m a j o r i t y of cases (58 of 72 t e s t s ) there was no change i n h e a r t r a t e . When the sac pressure was r a i s e d to over 80 mm Hg the systemi c pressure i n c r e a s e d i n 28 of 30 t e s t s .  An i n c r e a s e i n  r e s p i r a t o r y movements was a l s o noted d u r i n g h i g h pressure d i s t e n s i o n of the s a c .  g)  Summary 1.  Embryological s t u d i e s i n d i c a t e the p o s s i b l e  presence of a p o p u l a t i o n of sensory endings i n the pulmonary a r t e r y which i s developed from the VI v i s c e r a l a r c h . 2.  H i s t o l o g i c a l s t u d i e s confirm the e x i s t e n c e  of r e c e p t o r s i n the pulmonary a r t e r i a l w a l l .  They are e i t h e r  c o i l e d f i b e r s w i t h enlargements on the t e r m i n a l twigs or f i b e r s w i t h bushy endings.  In a d d i t i o n glomus t i s s u e s which  resemble chemoreceptors were found i n the a d v e n t i t i a .  100 3.  The pulmonary a r t e r y i s innervated by both  vagal and sympathetic a f f e r e n t f i b e r s .  The r e c e p t o r s w i l l  degenerate i f e i t h e r one of these f i b e r s i s c u t . 4.  E l e c t r o p h y s i o l o g i c a l s t u d i e s have l o c a l i z e d  r e c e p t o r s to the r i g h t and l e f t main pulmonary a r t e r i e s . Those connected w i t h t h i c k myelinated f i b e r s are a c t i v e w i t h i n the p h y s i o l o g i c a l pressure range, those connected w i t h s m a l l myelinated or unmyelinated f i b e r s respond only t o abnormal h i g h pressure outside the p h y s i o l o g i c a l  range.  Sympathetic a c t i v i t y b e l i e v e d t o o r i g i n a t e from the pulmona r y a r t e r y has a l s o been r e p o r t e d . 5.  Capsaicine and l o b e l i n e s t i m u l a t e r e c e p t o r s  i n the pulmonary a r t e r y and r e s u l t i n hypotension and v e n t ilation inhibition.  However, the l o c a t i o n and the type  of r e c e p t o r s (chemoreceptors/baroreceptors)  stimulated i s  not c e r t a i n . 6.  Rise i n the s t a t i c pressure i n the pulmonary  a r t e r y and other v e s s e l s i n the pulmonary c i r c u i t l e d to b r a d y c a r d i a and hypotension w i t h no e f f e c t of r e s p i r a t i o n . The r e s u l t s are not c o n s i s t e n t ; i n one r e p o r t only two out of twelve animals 7.  responded.  I s o l a t e d r i g h t heart and pulmonary a r t e r y  d i s t e n s i o n induced a vagal r e f l e x bradycardia and no hypot e n s i o n , but the evidence i s not c o n v i n c i n g .  101 8.  "Weak" i n f l a t i o n of a b a l l o o n i n the pulmon-  a r y a r t e r y brought a drop i n the systemic p r e s s u r e , a " s t r o n g e r " i n f l a t i o n caused a r i s e .  No heart r a t e  responses  were r e p o r t e d . 9.  P e r f u s i o n of the main pulmonary a r t e r y , the  r i g h t branch of the b i f u r c a t i o n and p a r t of the l e f t b i f u r c a t i o n l e d t o a f a l l i n systemic pressure when the p e r f u s i o n pressure was between 20-60 mm Hg.  With pressure above  80 mm Hg a r i s e i n systemic pressure was observed. no heart r a t e changes were observed.  Again  102 B.  C a r d i o v a s c u l a r E f f e c t Of Pulmonary A r t e r y D i s t e n s i o n I t i s apparent t h a t w i t h the exception of the exp-  eriments of C o l e r i d g e and Kidd (1963) and Lewin, C r o s s , Rieben and S a l i s b u r y (1961) previous s t u d i e s o f r e f l e x e s a r i s i n g from pulmonary a r t e r i a l d i s t e n s i o n have not l o c a l i s e d the stimulus to the pulmonary a r t e r y and i t s r i g h t and l e f t main branches where the r e c e p t o r s are known t o l i e . A l t e r n a t i v e l y the stimulus a p p l i e d t o the extra-pulmonary p a r t s of the pulmonary a r t e r y has not been adequately c o n trolled.  The present experiments were designed to a l l o w  d i s t e n s i o n of the pulmonary a r t e r y and i t s r i g h t and l e f t branches at c o n t r o l l e d pressure w h i l s t c a r d i a c output was maintained constant by means of a constant f l o w r i g h t heart bypass.  This allowed changes i n systemic v a s c u l a r r e s i s t a n c e  t o be d i r e c t l y r e l a t e d to changes i n systemic a r t e r i a l ure.  press-  A l s o as p r e l i m i n a r y experiments had i n d i c a t e d t h a t the  system might be a f f e c t e d by s m a l l changes i n temperature ( l a t e r confirmed as d e s c r i b e d i n r e s u l t s ) the temperature of the pulmonary a r t e r i a l p e r f u s a t e was maintained a t t h a t of the systemic b l o o d .  I t i s not p o s s i b l e r e v i e w i n g p r e -  v i o u s work to determine whether o r not temperature changes i n pulmonary a r t e r i a l p e r f u s i o n may have been a f a c t o r c o n t r i b u t i n g t o the v a r i a b i l i t y of some of the observed effects. There i s l i t t l e doubt from the r e s u l t s d e s c r i b e d t h a t i n c r e a s i n g the pressure i n the pulmonary a r t e r i e s  103 causes an i n c r e a s e i n systemic v a s c u l a r r e s i s t a n c e . Although the changes are r e l a t i v e l y s m a l l over the p h y s i o l o g i c a l range of pulmonary a r t e r i a l pressure they do appear t o form a continuum w i t h the l a r g e r responses observed at h i g h e r pulmonary a r t e r i a l p r e s s u r e s .  The use of a steady  pulmonary a r t e r i a l pressure r a t h e r than a p u l s a t i l e one (which would have been more d i f f i c u l t to adequately c o n t r o l ) i s l i k e l y to underestimate the e f f e c t s of s m a l l changes i n pulmonary a r t e r i a l p r e s s u r e .  For the pulmonary a r t e r y b a r o -  r e c e p t o r s have been shown t o be more responsive t o p u l s a t i l e pressure ( C o l e r i d g e and K i d d , 1961).  I t should a l s o be  noted t h a t the animals had a c t i v e a r t e r i a l baroreceptors; r e f l e x e s (as i n d i c a t e d by c a r o t i d o c c l u s i o n ) which would be l i k e l y t o reduce the magnitude of the responses.  The r e s u l t s  d i f f e r markedly from those of Coleridge and Kidd (1963) i n t h a t we have shown very s i g n i f i c a n t increases i n systemic pressure w i t h 4-0 cm ILpO (30 mm Hg) pressure i n the pulmonary a r t e r y , a pressure w i t h i n the range i n which they observed hypotension.  Our hypothesis t h a t an i n c r e a s e i n a f f e r e n t  impulse discharge from the r e c e p t o r s i n the w a l l s of the pulmonary a r t e r i e s causes an i n c r e a s e i n systemic v a s c u l a r r e s i s t a n c e r e c e i v e s support from the o b s e r v a t i o n t h a t r e d u c i n g the temperature of the p e r f u s i n g f l u i d from 37°C to 30°C was a s s o c i a t e d w i t h a s i g n i f i c a n t f a l l i n systemic a r t e r i a l pressure.  This r e l a t i v e l y s m a l l temperature change i s u n -  l i k e l y t o b l o c k nerve f i b e r s and must be the r e s u l t of a r e d u c t i o n i n a c t i v i t y i n r e c e p t o r s i n or c l o s e to the p u l -  104 monary a r t e r i a l w a l l s .  Both baroreceptors and chemoreceptors  have p r e v i o u s l y been shown t o be a f f e c t e d by temperature (McQueen and E y z a g u i r r e , 1974; A n g e l l James, 1971).  How-  e v e r , i t i s p o s s i b l e t h a t the temperature s e n s i t i v e r e c e p t o r s are not the pulmonary a r t e r i a l b a r o r e c e p t o r s .  I f the e f f e c t s  of temperature are mediated through these baroreceptors the e f f e c t s of c o o l i n g would provide evidence of a s i g n i f i c a n t t o n i c v a s o c o n s t r i c t e r tone a r i s i n g as a r e s u l t of the a c t i v i t y of these r e c e p t o r s .  The suggestion of C o l e r i d g e and  K i d d (1963) and C o l e r i d g e et a l (1973) t h a t a t h i g h pulmona r y a r t e r i a l pressures there may be o b s t r u c t i o n of blood f l o w t o chemoreceptors l y i n g c l o s e t o the w a l l of the p u l monary a r t e r i e s i s a v a l i d one.  However, i t seems u n l i k e l y  t h a t such a mechanism would account f o r the responses observed over the lower range of pressures used (40 cm H 0 ) . 2  The change i n systemic v a s c u l a r r e s i s t a n c e observed i n response t o d i s t e n s i o n of the pulmonary a r t e r y has been demonstrated to be accompanied by a somewhat g r e a t e r percentage increase i n v a s c u l a r r e s i s t a n c e i n the perfused h i n d - l i m b s but no change i n the v a s c u l a r r e s i s t a n c e i n the kidneys.  That the s e n s i t i v i t y of v a r i o u s v a s c u l a r beds t o  a r t e r i a l b a r o r e c e p t o r s t i m u l a t i o n ma^, d i f f e r has been c l e a r l y shown (Cox and Bagshaw, 1975; K i r c h h e i m , 1976).  Renal r e s i s -  tance v e s s e l changes have been d e s c r i b e d as f o l l o w i n g i d e n t i c a l d i r e c t i o n s as muscle v e s s e l s but showing l e s s s i t i v i t y (Kendrick, Oberg and Wennergren, 1972a).  senThese  d i f f e r e n c e s have been c o r r e l a t e d w i t h v a r y i n g v a s o c o n s t r i c -  105 t o r f i b e r discharge i n the cat (Kendrick, Oberg and Wennerg r e n , 1972b).  Under other circumstances i t has been shown  t h a t d i s t e n s i o n of the pulmonary v e i n - l e f t a t r i a l j u n c t i o n i s a s s o c i a t e d w i t h a decrease i n r e n a l v a s c u l a r r e s i s t a n c e (Mason and Ledsome, 1974) and a decrease i n e f f e r e n t symp a t h e t i c nerve a c t i v i t y t o the kidney (Karim, K i d d , Malpus and Penna, 1972) but w i t h no change i n h i n d - l i m b v a s c u l a r r e s i s t a n c e o r e f f e r e n t s c i a t i c nerve a c t i v i t y .  The p a t t e r n  of response to pulmonary a r t e r i a l d i s t e n s i o n d i f f e r s from both of the above i n t h a t no s i g n i f i c a n t changes have been observed i n r e n a l v a s c u l a r r e s i s t a n c e i n the presence of marked increases i n h i n d - l i m b v a s c u l a r r e s i s t a n c e .  However,  s i n c e the pulmonary a r t e r i e s and the l e f t a t r i u m both form  r  a p a r t of the low pressure v a s c u l a r system (Gauer and Henry, 1963) the pressures i n these areas are a l t e r e d i n a s i m i l a r f a s h i o n by changes i n blood volume or the d i s t r i b u t i o n of the b l o o d volume.  An increase i n blood volume causing a  r i s e i n pulmonary a r t e r i a l and l e f t a t r i a l pressure c o u l d cause a r i s e i n systemic a r t e r i a l pressure w i t h no change or a f a l l i n renal vascular resistance.  Under these c i r -  cumstances an i n c r e a s e i n sodium e x c r e t i o n from the kidneys would be p r e d i c t e d .  Marked d i f f e r e n c e s i n r e n a l v a s c u l a r  r e s i s t a n c e have been demonstrated between dogs i n which the a r t e r i a l pressure has been lowered by i n d u c t i o n of c a r d i o genic shock compared t o those w i t h hemorrhagic shock ( G o r f i n k e l , S z i d o n , H i r s c h and Pishman, 1972).  In c a r d i o -  106  genie shock the l e f t a t r i a l and pulmonary a r t e r i a l are r a i s e d .  I t i s possible that r e f l e x vascular  pressures  responses  a r i s i n g from pulmonary a r t e r i a l and l e f t a t r i a l r e c e p t o r s c o n t r i b u t e t o the d i f f e r e n c e s i n r e n a l blood f l o w observed d u r i n g c a r d i o g e n i c shock compared t o hemorrhagic  shock.  I t i s apparent t h a t n e i t h e r i n c r e a s i n g the pressure i n the pulmonary a r t e r i e s nor c o o l i n g the pulmonary a r t e r i e s were a s s o c i a t e d w i t h any s i g n i f i c a n t changes i n heart r a t e . The experiments may be c r i t i c i z e d on the b a s i s t h a t p r o p r a n o l o l (0.3 mg/kg) was given d u r i n g the p r e p a r a t i o n .  However,  i t was approximately 3 h r s . a f t e r the p r o p r a n o l o l was given t h a t the experimental records were taken and by t h i s time complete b e t a - a d r e n e r g i c b l o c k of the heart would not be expected.  A l l dogs showed an i n c r e a s e i n heart r a t e d u r i n g  c a r o t i d o c c l u s i o n i n d i c a t i n g t h a t a t l e a s t a vagal e f f e r e n t pathway was i n t a c t and some dogs demonstrated s i n u s a r r h y thmia.  Thus the f a i l u r e t o demonstrate changes i n heart  r a t e was not due t o the i n a b i l i t y of the heart t o respond. The e f f e c t s of i n c r e a s i n g the pressure i n the p u l monary a r t e r i e s and the e f f e c t s o f c o o l i n g the pulmonary a r t e r i e s were w h o l l y dependent upon the i n t e g r i t y of the vagus nerves.  No changes i n v a s c u l a r r e s i s t a n c e or heart  r a t e were seen a f t e r c u t t i n g both vagus nerves.  It is there-  f o r e l i k e l y t h a t the a f f e r e n t pathway f o r the r e f l e x r e s p o n ses i s i n the vagus nerves.  107 Recent work u s i n g i n d i r e c t techniques has suggested t h a t impulses a r i s i n g from cardiopulmonary r e c e p t o r s e x e r t a t o n i c r e s t r a i n t on a d r e n e r g i c discharge ( G u a z z i , L i b r e t t i and Z a n c h e t t i , 1962; Mancia, Donald and Shepherd,  1973;  K o i k e , Mark, H e i s t a d and Schmid, 1975; Mancia and Donald, 1975)*  The p r e c i s e l o c a t i o n of such cardiopulmonary r e c e p -  t o r s has not been i d e n t i f i e d .  Our R e s u l t s demonstrate t h a t  r e c e p t o r s i n o r c l o s e t o the w a l l s of the pulmonary a r t e r i e s generate a s i g n i f i c a n t v a s o c o n s t r i c t o r tone which may be i n c r e a s e d by pulmonary a r t e r i a l d i s t e n s i o n or decreased by cooling.  I n l e s s d i r e c t experiments i t may be t h a t t h i s  v a s o c o n s t r i c t o r e f f e c t i s overwhelmed by impulses from other cardiopulmonary r e c e p t o r s .  However, the r e s u l t s of e x p e r i -  ments r e f e r r e d to above which compare c a r d i o v a s c u l a r r e f l e x responses before and a f t e r c u t t i n g the vagus nerves must be interpreted with caution.  I t i s l i k e l y t h a t vagal s e c t i o n  causes a much more complex s e r i e s of i n t e r a c t i o n s than can reasonably be d e s c r i b e d as a removal of e i t h e r a net t o n i c i n h i b i t o r y or e x c i t a t o r y a c t i v i t y . The v a s o c o n s t r i c t o r tone generated by d i s t e n s i o n of the pulmonary a r t e r y pouch has been shown t o a f f e c t the h i n d - l i m b s but not the kidney v e s s e l s and t o cause a r i s e i n systemic pressure i n the face of a c t i v e a r t e r i a l b a r o receptor r e f l e x e s .  The hypothesis t h a t changes i n b l o o d  volume or i n the d i s t r i b u t i o n of blood volume may a f f e c t the discharge from pulmonary a r t e r y baroreceptors and l e a d t o m o d i f i c a t i o n of s o l u t e e x c r e t i o n by the kidney  108 i s an a t t r a c t i v e one and has been t e s t e d e x p e r i m e n t a l l y .  109 C.  Urine E x c r e t i o n From The I n t a c t Kidneys In Response To Pulmonary A r t e r y D i s t e n s i o n The kidneys respond w i t h changes i n u r i n a r y e x c r e t -  i o n only s l o w l y t o r e f l e x changes, t h e r e f o r e a l o n g e r l a t e n c y i s u s u a l l y r e q u i r e d between the a p p l i c a t i o n of the stimulus and any observable changes i n the u r i n e composition.  In  the s e r i e s of experiments d e s c r i b e d , the pulmonary a r t e r y s t i m u l a t i o n periods were t h i r t y minutes l o n g hoping t h a t i t would be l o n g enough t o d e t e c t any a l t e r a t i o n of u r i n e e x c r e t i o n r a t e or composition.  Because of the v a r i a b i l i t y  of u r i n e f u n c t i o n i n i n d i v i d u a l animals comparisons of r e f l e x responses between experimental and c o n t r o l animals i s not always p r a c t i c a l .  A base f o r comparison was obtained by  c o l l e c t i n g u r i n e samples i n each animal before and a f t e r the pulmonary a r t e r i a l pouch pressure was changes.  Each of  these c o n t r o l periods was f o r t y minutes l o n g .  Since the  e f f e c t s of the r i g h t heart bypass and the s u r g i c a l maneuvers on r e n a l f u n c t i o n was not known i t was decided t o prepare a group of animals without a p p l y i n g the pulmonary a r t e r y stimulus.  Urine samples from t h i s group of experiments  w o u l d : r e f l e c t e f f e c t s of the s u r g i c a l p r e p a r a t i o n .  In  o r d e r to make an absolute comparison w i t h the pulmonary a r t e r y s t i m u l a t i o n experiments these experiments are required. Urine a n a l y s i s of t h i s type would r e v e a l more accurate i n f o r m a t i o n i f the experimental p e r i o d c o u l d be  110  prolonged.  Under the present c o n d i t i o n s the l e n g t h of the  experiment was d i c t a t e d by the volume of the blood r e s e r v o i r , because hemorrhage from the s u r g i c a l wounds i n a h e p a r i n i z e d animal c r e a t e d a problem.  For a t y p i c a l experiment the two  l i t e r s of Dextran and Ringer L a c t a t e mixture i n the r e s e r v o i r was completely l o s t two hours a f t e r s t a b l i z a t i o n (about three and h a l f hours a f t e r s t a r t i n g the r i g h t heart bypass).  I n c r e a s i n g the volume of the a r t i f i c i a l p e r f u s a t e  would a l l o w the experiment to be prolonged, however t h i s w i l l f u r t h e r decrease the h e m a t o c r i t , a f f e c t the c o n c e n t r a t i o n s of b l o o d borne agents and p o s s i b l y change r e n a l f u n ction. The u r i n e c o l l e c t i o n experiments w i t h both kidneys i n t a c t proved t h a t adequate volumes of u r i n e were produced by the p r e p a r a t i o n s .  A n a l y s i s of plasma samples showed  t h a t the plasma o s m o l a r i t y , sodium and potassium c o n c e n t r a t i o n s were v i r t u a l l y constant throughout any s i n g l e e x p e r i ment and alv/ays w i t h i n the normal p h y s i o l o g i c a l ranges. Gradual i n c r e a s e i n f r e e water clearance i n a l l three s e t s of experiments may i n d i c a t e a decrease i n ADH o r p o s s i b l y washout of the r e n a l medullary c o n c e n t r a t i o n g r a d i e n t because of low h e m a t o c r i t .  Other than the s l i g h t change i n  f r e e water c l e a r a n c e , systemic a r t e r i a l p r e s s u r e , osmolar c l e a r a n c e , sodium and potassium e x c r e t i o n were a l l steady throughout the c o n t r o l experiments.  Results from these  c o n t r o l experiments c l e a r l y demonstrated the q u a l i t y of the p r e p a r a t i o n which d i d not s e r i o u s l y i m p a i r the c a r d i o v a s c u l a r  111 and r e n a l f u n c t i o n s of the animals. D i s t e n s i o n of the pulmonary a r t e r y pouch t o 40 cm HgO induced a s m a l l r i s e i n the sodium e x c r e t i o n r a t e and an almost u n n o t i c a b l e i n c r e a s e i n the mean systemic a r t e r i a l p r e s s u r e , "both changes were s t a t i s t i c a l l y i n s i g n i f i c a n t . Based on the time course of these two v a r i a b l e s i t i s doubtf u l t h a t the changes were r e s u l t s of the pulmonary pouch distensions.  Osmolar clearance and potassium e x c r e t i o n r a t e s  were steady.  Even though no s i g n i f i c a n t changes i n r e n a l  f u n c t i o n s were observed i n these experiments i t i s p o s s i b l e t h a t 40 cm rLpO of steady pressure i s an inadequate stimulust o i n i t i a t e a r e n a l r e f l e x from the pulmonary a r t e r y ; a h i g h e r pressure was used i n another set of experiment t o investigate this p o s s i b i l i t y . D i s t e n s i o n of the pulmonary a r t e r y pouch to 80 cm EUO c r e a t e d a s i g n i f i c a n t i n c r e a s e i n sodium e x c r e t i o n r a t e . The i n c r e a s e i n sodium e x c r e t i o n r a t e continued in^s.ome'sexperiments even a f t e r the r e l e a s e of the pouch p r e s s u r e .  As  was expected the d i s t e n s i o n a l s o s i g n i f i c a n t l y r a i s e d the systemic blood pressure which returned;;to normal a f t e r the pouch pressure was r e l e a s e d .  Again no s i g n i f i c a n t changes  were observed i n the osmolar and potassium e x c r e t i o n r a t e s . Examining the r e s u l t s from the c o n t r o l and the two s e t s of pulmonary pouch d i s t e n s i o n experiments showed t h a t the i n c r e a s e i n sodium e x c r e t i o n r a t e was a s s o c i a t e d w i t h r i s e i n systemic b l o o d pressure (see P i g . 1 $ ) .  The r i s e  112 was n o t i c e a b l e w i t h i n minutes a f t e r the pulmonary a r t e r y pouch was distended to 80 cm BLpO.  The r a p i d nature of  the i n c r e a s e suggested a hemodynamic e f f e c t probably secondary to c a r d i o v a s c u l a r or n e u r a l changes.  The time course  of the sodium e x c r e t i o n response i s s i m i l a r t o O'Connor's c a r o t i d a r t e r y o c c l u s i o n experiments (1955, 1958).  He  occluded both the c a r o t i d a r t e r i e s of conscious dogs and as a r e s u l t the a r t e r i a l pressure increased by about 40 mm Hg accompanied by a r i s e i n sodium e x c r e t i o n .  O'Connor  b e l i e v e d t h a t the sodium response was the d i r e c t e f f e c t o f the i n c r e a s e d a r t e r i a l pressure on the kidneys and d i f f e r ed from the e f f e c t s of neurohypophysial hormones, a d r e n a l i n e or a d r e n o c o r t i c a l s t e r o i d s which are u s u a l l y slower.  The  present experiments are d i f f e r e n t from the c a r o t i d a r t e r y o c c l u s i o n experiments i n one important a s p e c t .  The sodium  e x c r e t i o n r a t e continued t o i n c r e a s e even a f t e r the r e l e a s e of the pulmonary a r t e r i a l pouch pressure i n s t e a d of r e t u r n i n g t o the c o n t r o l l e v e l .  The prolonged nature of the sodium  response may i n d i c a t e r e l e a s e of a c i r c u l a t i n g agent a f f e c t i n g sodium e x c r e t i o n and being r e l e a s e d by pulmonary a r t e r y pouch d i s t e n s i o n . Since the r o l e of a c i r c u l a t i n g agent cannot be s e p a r a t e l y assessed i n the i n t a c t kidney experiments, another s e r i e s of s i x experiments were performed w i t h one kidney of the animal i n t a c t and the other kidney t o t a l l y i s o l a t e d and perfused w i t h c o n t r o l l e d p r e s s u r e .  The iso'Q  l a t e d kidney was subjected t o the i n f l u e n c e of hormonal  113 f a c t o r s o n l y , f o r a l l other v a r i a b l e s were t i g h t l y c o n t r o l l ed.  These i n t a c t and i s o l a t e d kidney experiments are d i f f e r -  ent from the p r e v i o u s l y d i s c u s s e d i n t a c t kidneys experiments i n more than one way.  The surgery r e q u i r e d to prepare an  i s o l a t e d kidney was more extensive than t h a t f o r the animals w i t h both kidneys i n t a c t .  The e x t r a surgery c r e a t e d more  wounded area and hemorrhage, thus a l a r g e r volume (3 l i t e r s ) o f a r t i f i c i a l perfusate was needed t o prime the r e s e r v o i r compared w i t h 2 l i t e r s i n the i n t a c t kidneys s e r i e s .  The  i n c r e a s e d volume of p e r f u s a t e would f u r t h e r change the blood c o m p o s i t i o n , modifying i t s hemodynamic c h a r a c t e r i s t i c s and may have a g r e a t e r e f f e c t on the u r i n e and s o l u t e e x c r e t i o n . Therefore no d i r e c t q u a n t i t a t i v e comparison of the two s e r i e s o f u r i n e c o l l e c t i o n experiments can be made.  However,  between the i n t a c t and the i s o l a t e d kidneys of the same animals the d i f f e r e n t i n f l u e n c e s of the hemodynamic, n e u r a l and hormal f a c t o r s can be e l u c i d a t e d . There i s a marked d i f f e r e n c e between the r e s u l t s from the i n t a c t and i s o l a t e d k i d n e y s .  In the i n t a c t kidney  t h e r e were s i g n i f i c a n t stepwise i n c r e a s e s i n the sodium, potassium e x c r e t i o n r a t e s , osmolar clearance and u r i n e volume.  The increases corresponded t o the pulmonary a r t e r y  pouch d i s t e n s i o n and the r i s e i n systemic a r t e r i a l that followed.  pressure  Upon r e l e a s e of the pouch pressure the  a r t e r i a l b l o o d pressure and the above mentioned u r i n a r y v a r i a b l e s r e t u r n e d to the p r e - d i s t e n s i o n l e v e l again i n a stepwise manner s i m i l a r t o O'Connor's c a r o t i d a r t e r y  114o c c l u s i o n r e s u l t s (1958).  Free water clearance i s the o n l y  v a r i a b l e which d i d not seem t o be a f f e c t e d by the pouch distension.  The c l o s e resemblance w i t h O'Connor's r e s u l t s  confirms the s i g n i f i c a n t hemodynamic e f f e c t on r e n a l s o l u t e e x c r e t i o n i n response t o pulmonary a r t e r y d i s t e n s i o n . The i s o l a t e d kidney o f f e r e d an e x c e l l e n t o p p o r t u n i t y to study s e p a r a t e l y the hemodynamic and hormonal e f f e c t s on the kidney.  Under the i n f l u e n c e of blood borne agents alone  t h e r e were no s i g n i f i c a n t changes i n any of the u r i n a r y v a r i a b l e s i n response to pulmonary a r t e r y pouch d i s t e n s i o n , o n l y the sodium e x c r e t i o n r a t e showed a s m a l l increase c o r r e s ponding approximately to the d i s t e n s i o n .  Since the i n c r e a s e  i s not s t a t i s t i c a l l y s i g n i f i c a n t we can not conclude t h a t the pouch d i s t e n s i o n r e l e a s e s a blood borne agent which i n f l u e n c e s the sodium e x c r e t i o n r a t e . Renal f u n c t i o n i s a f f e c t e d by many d i f f e r e n t f a c t o r s , g e n e r a l l y they can be d i v i d e d i n t o three groups: hemodynamic, n e u r a l and hormonal f a c t o r s .  The r e s u l t s of  the u r i n e c o l l e c t i o n experiments w i l l be analysed i n terms of these f a c t o r s . As e a r l y as 1925, S t a r l i n g and Verney recognized the r e l a t i o n s h i p between r e n a l p e r f u s i o n pressure and the e x c r e t i o n of water and c h l o r i d e .  Using a h e a r t - l u n g - k i d n e y  p r e p a r a t i o n they concluded t h a t there i s a d i r e c t r e l a t i o n s h i p between p e r f u s i o n p r e s s u r e , glomerular f i l t r a t i o n r a t e , water and c h l o r i d e e x c r e t i o n .  S e l k u r t , H a l l and Spencer  (1949), P i t t s and Duggan (1950) s t u d i e d the e f f e c t of reduced r e n a l p e r f u s i o n pressure on sodium e x c r e t i o n by the i n s i t u dog kidney and observed increases i n t u b u l a r f r a c t i o n a l sodium r e a b s o r p t i o n as f i l t r a t i o n r a t e was d e creased.  Thus the e f f e c t of decreased p e r f u s i o n pressure  i n r e d u c i n g sodium e x c r e t i o n was not a t t r i b u t e d s o l e l y t o a r e d u c t i o n i n the f i l t e r e d l o a d of sodium.  Increasing the  r e n a l p e r f u s i o n pressure on the other hand depresses t u b u l a r sodium r e a b s o r p t i o n , S e l k u r t (195"0, S e l k u r t , Womack and D a i l e y (1965) r e p o r t e d an i n c r e a s e d sodium e x c r e t i o n without an e q u i v a l e n t r i s e i n f i l t r a t i o n r a t e as p e r f u s i o n pressure was heightened i n the dog k i d n e y . In the same h e a r t - l u n g - k i d n e y p r e p a r a t i o n , S t a r l i n g and Verney (1925) a l s o observed increased sodium c h l o r i d e e x c r e t i o n when i s o t o n i c s a l i n e was added t o the blood p e r f u s i n g the p r e p a r a t i o n .  They r e f e r r e d to t h i s e f f e c t as  d i l u t i o n a l d i u r e s i s and a t t r i b u t e d i t t o an increased glomerular f i l t r a t i o n r a t e .  More r e c e n t l y , C r a i g , M i l l s ,  O s b a l d i s t o n and Wise (1966), N i z e t (1968), N i z e t , Godon and Mahieu (1968) have observed increased sodium e x c r e t i o n by i s o l a t e d perfused kidneys when the p e r f u s i n g blood i s d i l u t e d by a d d i t i o n of i s o t o n i c s a l i n e .  N i z e t , Godon and  Mahieu (1968) b e l i e v e d t h a t t h i s e f f e c t i s caused by a decrease i n plasma p r o t e i n c o n c e n t r a t i o n through an i n t r a r e n a l mechanism,  However, w i t h the evidence a v a i l a b l e we  can not conclude t h a t the i n c r e a s e i n sodium e x c r e t i o n i s due t o the d i l u t i o n of any s i n g l e c o n s t i t u e n t i n the b l o o d .  116 Another f a c t o r t h a t i s a f f e c t e d by b l o o d d i l u t i o n i s the hematocrit.  Martino and E a r l e y  (1967) suggested t h a t a  r e d u c t i o n i n the hematocrit would decrease the v i s c o s i t y of the blood which i n t u r n would reduce the i n t e r n a l r e s i s t a n c e to f l o w through the r e n a l c i r c u l a t i o n . Both C r a i g , M i l l s , O s b a l d i s t o n and Wise  (1966), N i z e t , Godon and Mahieu (1968)  r e p o r t e d increased sodium e x c r e t i o n and s o l u t e - f r e e water clearance i n a s s o c i a t i o n w i t h a f a l l i n hematocrit when i s o t o n i c s a l i n e was added t o the b l o o d p e r f u s i n g the i s o l a t ed dog k i d n e y .  But i n t h e i r s t u d i e s the c o n c e n t r a t i o n of  p r o t e i n i n plasma was decreased a l s o , t h e r e f o r e the i n c r e a s ed sodium e x c r e t i o n cannot be a t t r i b u t e d e n t i r e l y to e i t h e r p r o t e i n or r e d blood c e l l c o n c e n t r a t i o n . s t u d i e s by Nashat and P o r t a l Tappin and Wilcox  Better controlled  (1967), -Nashat, S c h o l e f i e l f ,  (1969) decreased the hematocrit i n dogs  without a decrease i n plasma p r o t e i n c o n c e n t r a t i o n o r i n c r e a s e i n blood volume.  They observed an i n c r e a s e d  u r i n e f l o w , sodium e x c r e t i o n and r e n a l plasma f l o w .  However,  they d i d not f i n d a decrease i n sodium e x c r e t i o n as hematoc r i t was i n c r e a s e d . In order t o perform a r i g h t heart bypass i n the present experiments the e x t r a c o r p o r e a l c i r c u i t was primed with physiological f l u i d .  As has been mentioned e a r l i e r ,  e i t h e r two o r three l i t e r s of Dextran and Ringer L a c t a t e mixture were needed f o r the constant temperature r e s e r v o i r i n the u r i n e c o l l e c t i o n experiments.  Since the average  weight of the dogs used was o n l y about 22 kg the added  117 a r t i f i c i a l p e r f u s a t e should have a s i g n i f i c a n t d i l u t i o n a l e f f e c t on the plasma p r o t e i n c o n c e n t r a t i o n and lowered the hematocrit t o below 30%.  E i t h e r one or both of these mechan-  isms i s expected to increase the sodium e x c r e t i o n r a t e and the f r e e water c l e a r a n c e .  Since pulmonary a r t e r y pouch  d i s t e n s i o n i s b e l i e v e d to i n c r e a s e the sodium e x c r e t i o n r a t e i t i s important to be able t o d i s t i n g u i s h between the d i l u t i o n - h e m a t o c r i t e f f e c t and the pouch d i s t e n s i o n e f f e c t . The c o n t r o l experiments where the pulmonary a r t e r y pouch was not distended served t h i s purpose w e l l .  After s t a b l i -  z a t i o n the animals seemed t o have reached an e q u i l i b r i u m s t a t e f o r sodium e x c r e t i o n r a t e as the value became more o r l e s s constant throughout the e n t i r e 110 min u r i n e c o l l e c t i o n period.  Therefore the sodium e x c r e t i o n response from the  d i s t e n s i o n experiments must be i n i t i a t e d from the pulmonary artery.  The f r e e water clearance p a t t e r n i n the c o n t r o l  experiments i s most i n t e r e s t i n g , i t increased s t e a d i l y w i t h respect to time.  Although no d i r e c t proof i s a v a i l a b l e ,  t h i s p a t t e r n c o u l d very w e l l be caused by the low hematoc r i t i n the blood and the change i n the r e n a l r e s i s t a n c e that followed.  In the pulmonary a r t e r y pouch d i s t e n s i o n  experiments, f r e e water clearance p a t t e r n were the same as the c o n t r o l s i n each case, t h e r e f o r e we can conclude t h a t the pulmonary a r t e r i a l d i s t e n s i o n had no e f f e c t on f r e e water c l e a r a n c e . The kidneys are r i c h l y s u p p l i e d w i t h nerve endings. The r e n a l nerves are d e s c r i b e d as a r i s i n g , i n l a r g e measure,  118 from the c o e l i a c plexus (De Muylder, 1952; Shvalev, 1966).  Mitchell,,1956;  There are a l s o f i b e r s r e a c h i n g the r e n a l  plexus from the t h o r a c i c and upper splanchnic nerves, the i n t e r m e s e n t e r i c nerves, and the s u p e r f i c i a l hypogastic plexus.  Parasympathetic f i b e r s supply the u r e t e r , r e n a l  p e l v i s and c o l l e c t i n g t u b u l e s .  McKenna ,and Angelakos  (1968a)  observed i n the dog t h a t adrenergic nerves entered the kidney w i t h the r e n a l a r t e r y and branched w i t h a r t e r i a l supply as i t d i v i d e d up to the i n t e r l o b u l a r a r t e r i e s and a f f e r e n t a r t e r i o l e s t o the glomerulus.  In a d d i t i o n t o the nerve  f i b e r s l y i n g adjacent to the smooth muscle c e l l s of the i n t e r l o b a r and arcuate a r t e r i e s , f i b e r s were a l s o found i n the connective t i s s u e surrounding these v e s s e l s .  Cholinergic  f i b e r s i n the kidney appear t o have e s s e n t i a l l y the same d i s t r i b u t i o n as the adrenergic nerves (McKenna and Angelakos, 1968b), but no c h o l i n e r g i c f i b e r s are found i n a s s o c i a t i o n w i t h the g l o m e r u l i , e f f e r e n t a r t e r i o l e s , v e i n s o r t u b u l e s . Because of the widespread i n n e r v a t i o n of the k i d n e y , s t r i p p i n g of the t i s s u e about the r e n a l a r t e r y destroys only a p o r t i o n of the nerves; f o r complete d e n e r v a t i o n , f i b e r s must be s e c t i o n e d around the r e n a l v e i n , the u r e t e r , and c a p s u l e ; or the kidney must be completely i s o l a t e d . Despite the d e t a i l e d knowledge about r e n a l nervous  inner-  v a t i o n l i t t l e i s known about i t s f u n c t i o n i n u r i n e output control.  Since Claude B e r n a r d ' s o b s e r v a t i o n t h a t i p s i -  l a t e r a l u r i n e f l o w increased when the splanchnic  nerves  were s e c t i o n e d on one s i d e , l i t t l e r e a l advance has been  11.9 made.  One major o b s t a c l e being t h a t r e s u l t s from anesthe-  t i z e d and conscious animals are very d i f f e r e n t .  Berne (1952)  compared denervated and i n t a c t kidneys i n both a n e s t h e t i z e d and conscious dogs.  In the a n e s t h e t i z e d animals the glom-  e r u l a r f i l t r a t i o n r a t e and sodium e x c r e t i o n tended t o be h i g h e r i n the denervated k i d n e y , whereas i n the  conscious  animal the glomerular f i l t r a t i o n r a t e and u r i n a r y sodium e x c r e t i o n of the innervated and the i n t a c t kidneys were the same.  Berne concluded t h a t the h i g h e r u r i n a r y sodium  e x c r e t i o n from the denervated kidney i n the a n e s t h e t i z e d animal was due t o the v a s o c o n s t r i c t i n g e f f e c t of the anest h e t i c s on the i n t a c t kidney causing a r e d u c t i o n i n glome r u l a r f i l t r a t i o n r a t e and thus a r e d u c t i o n i n e x c r e t i o n ; and t h a t the v a s o c o n s t r i c t i o n was caused by impulses c a r r i e d a l o n g the r e n a l nerves.  More r e c e n t l y , evidence has accum-  u l a t e d f o r r e d i s t r i b u t i o n of r e n a l b l o o d f l o w , and glomeru l a r f i l t r a t i o n and the importance of these f a c t o r s f o r r e g u l a t i o n of s a l t and water balance has been r e c o g n i z e d . N e u r a l c o n t r o l i s thought to have a r o l e i n the r e g u l a t i o n of i n t r a r e n a l blood f l o w . Pomeranz, B i r t c h and Barger (1968) performed experiments i n which they e i t h e r s t i m u l a t e d the r e n a l nerves r e f l e x l y by reducing the pressure i n c a r o t i d sinuses o r by s t i m u l a t i n g the s p l a n c h n i c nerve while measuring the d i s t r i b u t i o n of blood f l o w w i t h i n the kidney w i t h ^ K - d i s a p p e a r ance curve.  They found t h a t m i l d r e n a l nerve s t i m u l a t i o n  was a s s o c i a t e d w i t h a r e d i s t r i b u t i o n of i n t r a r e n a l blood  120 f l o w even though there might be no a l t e r a t i o n i n t o t a l blood flow.  The p e r f u s i o n of the outer c o r t e x f e l l , w h i l e t h a t  of the outer medulla r o s e .  T u t t l e and Shadier (1965) used a  thermal washout technique and showed t h a t there i s a r e d i s t r i b u t i o n of i n t r a r e n a l blood f l o w i n animals w i t h a low u r i n a r y e x c r e t i o n of sodium due t o s a l t d e p r i v a t i o n .  When  u r i n a r y e x c r e t i o n of sodium i s h i g h they have found an i n c r e a s e i n c o r t i c a l blood f l o w w i t h a decreased blood flow t o the outer medulla.  Sparks, Kopald, C a r r i e r e , Chimosky  and Barger (1965) r e p o r t e d low o u t e r r e n a l c o r t e x and r e l a t i v e l y h i g h e r outer medulla blood f l o w i n dogs w i t h c h r o n i c congestive heart f a i l u r e which i s a s s o c i a t e d w i t h s a l t and water r e t e n t i o n .  Furthermore Barger (1966) i n d i c a t e d t h a t  i n t r a r e n a l d i s t r i b u t i o n of blood f l o w i s a l t e r e d i n congest i v e heart f a i l u r e by abnormal adrenergic a c t i v i t y .  This  e f f e c t can be a b o l i s h e d by n e u r o t r a n s m i t t e r b l o c k e r s . Based on t h i s evidence Barger (1966) proposed t h a t r e d i s t r i b u t i o n of i n t r a r e n a l blood f l o w can a l t e r u r i n a r y sodium e x c r e t i o n and t h a t blood f l o w may be c o n t r o l l e d by r e n a l nervous a c t i v i t y .  F a i l u r e t o demonstrate changes i n t o t a l  r e n a l v a s c u l a r r e s i s t a n c e i n response to pulmonary a r t e r i a l pouch d i s t e n s i o n does not t h e r e f o r e n e c e s s a r i l y mean t h a t there was no changes i n r e n a l nerve a c t i v i t y or t h a t there were no changes i n the d i s t r i b u t i o n of blood f l o w i n the kidney. Besides mechanical and n e u r a l f a c t o r s kidney f u n c t i o n i s s t r o n g l y i n f l u e n c e d by hormonal f a c t o r s .  ADH i s  121 one of the most important hormones known to r e g u l a t e u r i n e volume.  I t i s w e l l known t h a t when the plasma c o n c e n t r a t i o n  of ADH i s h i g h a l a r g e amount of s o l u t e - f r e e water i s r e a b sorbed i n the d i s t a l tubules and the c o l l e c t i n g ducts of the k i d n e y , the u r i n e excreted w i l l be h y p e r t o n i c and the volume s m a l l .  Low plasma c o n c e n t r a t i o n of ADH l e d t o l a r g e  volume of hypotonic u r i n e (Handler and O r l o f f , 1973).  One  mechanism t h a t i s thought to r e g u l a t e the r e l e a s e of ADH i s l e f t a t r i a l pressure.  This i s of p a r t i c u l a r i n t e r e s t  t o us because l e f t a t r i a l pressure r e f l e c t s the blood volume i n an a n i m a l , s i m i l a r l y an i n c r e a s e d blood volume should a l s o i n c r e a s e the pulmonary a r t e r i a l pressure.  Henry,  Gauer and Reeves (1956) suggested t h a t the l e f t  atrial  r e c e p t o r s f u n c t i o n as volume r e c e p t o r s which i n f l u e n c e u r i n e flow.  Since then many groups have r e p o r t e d d i u r e s i s as a  r e s u l t of i n f l a t i n g a b a l l o o n i n the l e f t a t r i u m (Ledsome, Linden and O'Connor, 1961; L y d t i n and Hamilton, 1964; Ledsome and L i n d e n , 1968; Lawrence, Ledsome and Mason, 1973)•  Numerous systemic and pulmonary hemodynamic  changes  are induced by the b a l l o o n i n f l a t i o n i n c l u d i n g increases  in  h e a r t r a t e ( C a r s w e l l , Hainsworth and Ledsome, 1970; Lawrence, Ledsome and Mason, 1973), pulmonary a r t e r y pressure  (Henry,  Gauer and Reeves, 1956) and decreases i n c a r d i a c output ( K a h l , F l i n t and S z i d o n , 1974).  However, the d i u r e s i s is  1  w i d e l y b e l i e v e d t o be caused by a decrease i n the concent r a t i o n o f c i r c u l a t i n g ADH.  Using bioassay  techniques  Shu'ayb, Moran and Zimmerman (1965), Johnson, Moore and  122 Segar (1969), Bermman, M a r v i n , Jochim and Roberts (1971) submitted evidence t h a t endogenous ADH t i t e r s decrease d u r i n g l e f t a t r i a l distension.  The r e s u l t s presented by these  groups are f a r from c o n c l u s i v e because of the low p r e c i s i o n of the h y d r a t e d , a n e s t h e t i z e d r a t assay and have been cont e s t e d by s e v e r a l i n v e s t i g a t o r s .  Other groups reasoned  t h a t i f suppression of endogenous ADH mediates t h i s  response,  then an exogenous i n f u s i o n of ADH d u r i n g the p e r i o d of a t r i a l d i s t e n s i o n should a b o l i s h the d i u r e s i s .  Ledsome  and Mason (1972) demonstrate t h a t i n f u s i n g 0.4—1.0 m-u/kg-min of ADH can b l o c k the increase i n f r e e water clearance induced by l e f t a t r i a l d i s t e n s i o n .  S i m i l a r r e s u l t s were a l s o r e p o r t -  ed by K i n n e r y and D i S c a l a (1972).  In the same r e p o r t  Ledsome and Mason (1972) a l s o d e s c r i b e d an i n c r e a s e i n osmolar clearance i n response t o l e f t a t r i a l d i s t e n s i o n , i n f u s i o n of ADH had no e f f e c t on t h i s response and no e x p l a n a t i o n has been o f f e r e d f o r t h i s e f f e c t .  Contradicting results  were presented by Kappagoda, L i n d e n , Snow and Whitaker (1974). Using t h e i r own bioassay technique which they c l a i m to be more s e n s i t i v e , they d i d not f i n d a d i m i n u t i o n i n plasma ADH t i t e r s during a t r i a l distension.  Based on these r e s u l t s  they concluded t h a t ADH does not mediate the d i u r e t i c r e s ponse of l e f t a t r i a l d i s t e n s i o n .  A more recent study by  the same group (Kappagoda, L i n d e n , Snow and Whitaker, 1975) p r o v i d e d f u r t h e r support f o r t h e i r v i e w , acute p i t u i t a r y c a u t e r i z a t i o n was not found t o a b o l i s h the d i u r e t i c response to l e f t a t r i a l d i s t e n s i o n .  Some e a r l i e r i n v e s t i g a t o r s  also  123 doubted the r o l e of ADH i n the l e f t a t r i a l response.  Goetz,  Hermeck, S l i c k and Starke (1970), Goetz, Bond, Hermeck and Trank (1970) b e l i e v e d t h a t i f a r i s e i n l e f t  atrial  pressure causes a d i u r e s i s by suppressing ADH r e l e a s e , then the a n t i d i u r e t i c e f f e c t a s s o c i a t e d w i t h a f a l l i n l e f t a t r i a l pressure should s t i m u l a t e ADH r e l e a s e .  Using a b i o -  assay technique they f a i l e d to demonstrate an i n c r e a s e i n plasma ADH c o n c e n t r a t i o n .  Because of the r e l a t i v e l y low  p r e c i s i o n of ADH bioassay i t i s d i f f i c u l t t o evaluate some of these experimental r e s u l t s , the recent development of radioimmunoassay procedures promises to improve the p r e c i s i o n , s p e c i f i c i t y , and s e n s i t i v i t y of the measurement of ADH i n plasma (Goetz, Bond and Bloxham, 1975).  De T o r r e n t e ,  Robertson, McDonald and S c h r i e r (1975) employed a r a d i o immunoassay technique and showed t h a t i n a group of anest h e t i z e d dogs l e f t a t r i a l d i s t e n s i o n was connected w i t h a d i u r e s i s which was a s s o c i a t e d w i t h a decrease i n plasma ADH concentration.  A second group of a c u t e l y hypophysectomized  dogs showed no s i g n i f i c a n t changes.  Cardiac o u t p u t , r e n a l  a r t e r i a l p r e s s u r e , glomerular f i l t r a t i o n r a t e and s o l u t e e x c r e t i o n were comparable i n the two groups; the d i u r e s i s was b e l i e v e d t o be due to the change i n plasma ADH concentration. The o p e r a t i o n of the r e n i n - a n g i o t e n s i n - a l d o s t e r o n e system i n the r e g u l a t i o n of sodium balance and e x t r a c e l l u l a r f l u i d volume are c l o s e l y r e l a t e d w i t h blood pressure so t h a t r e g u l a t i o n of these f u n c t i o n s can be viewed t e n t a t i v e l y as  124  a s i n g l e coordinated process.  This i s because negative o r  p o s i t i v e changes i n sodium balance are o r d i n a r i l y accompanied by an i s o m o t i c c o n t r a c t i o n or expansion of blood volume and of the e x t r a c e l l u l a r f l u i d .  Sodium c o n c e n t r a t i o n does not  u s u a l l y change a p p r e c i a b l y w i t h changes i n sodium balance because of the tendency to preserve i s o s m o l a r i t y by the removal or a d d i t i o n of a p p r o p r i a t e amounts of water t o the e x t r a c e l l u l a r f l u i d (Laragh and Sealey, 1973)•  125 S t u d i e s of the h a l f - l i f e of r e n i n have been c a r r i e d out by many groups ( S c h a e c h t e l i n , G e g o l i and Gross, L e e , 1969).  1964;  Using c r o s s - c i r c u l a t i o n technique, w i t h nephrec-  tomized r e c i p i e n t r a t s , observing the decay of a c t i v i t y a f t e r a r e n i n - r e l e a s i n g stimulus suggests t h a t r e n i n has a h a l f l i f e i n the c i r c u l a t i o n of about 15-20 min.  However, i n  a study on three nephrectomized human beings  Hannon,  Deruyck, Joossens and Amery (1969) found a much l o n g e r r e n i n h a l f - l i f e ranging from 42 to 120 min.  Assaykeen,  Otsuka and Ganong (1968) r e p o r t e d the h a l f - l i f e of r e n i n t o be 79 and 45 min i n two dogs.  Renin has no known p h y s i o -  l o g i c a l a c t i o n of i t s own other than a n g i o t e n s i n l i b e r a t i o n . Given i n t r a v e n o u s l y , i t c h a r a c t e r i s t i c a l l y produces a r i s e i n blood pressure a f t e r a delay of 15-20 sec.  The r i s e i n  pressure i s g r a d u a l , and the height and the d u r a t i o n of the response i s p r o p o r t i o n a l to the amount i n j e c t e d , compared w i t h a n g i o t e n s i n which produces an immediate response.  The  p r e s s o r a c t i o n of r e n i n i s now e x p l a i n e d by the k i n e t i c s of endogenous a n g i o t e n s i n l i b e r a t i o n from c i r c u l a t i n g r e n i n s u b s t r a t e (Lee, 1969).  126  In 1954, Skeggs, Mash, Kahn and Shumway discovered two forms of a n g i o t e n s i n .  A n g i o t e n s i n I i s a decapeptide  produced by the a c t i o n of r e n i n on the r e n i n s u s t r a t e , angiotensin II  i s an octapeptide formed a f t e r the removal  of the t e r m i n a l h i s t i d y l l e u c i n e from a n g i o t e n s i n I.»  In  the absence of plasma, a n t i o t e n s i n I e x h i b i t s no s i g n i f i c a n t v a s o c o n s t r i c t o r p r o p e r t i e s whereas a n g i o t e n s i n I I potent p r e s s o r substance.  is a  A n g i o t e n s i n I I has a very short  b i o l o g i c a l h a l f - l i f e ; a f t e r intravenous i n j e c t i o n the p r e s s o r response i n an assay animal l a s t s f o r only 1-3 min.  Methot,  Meyer, B i r o n , L o r a i n , Lagrue and M i l l i e z (1964-), Hodge, Kg, and Vane (1967), B i r o n , Meyer and P a n i s s e t (1968) have r e p e a t e d l y shown t h a t 70% or more of a s u p r a p h y s i o l o g i c a l i n f u s i o n of a n g i o t e n s i n I I through the l i v e r .  i s removed i n one c i r c u l a t i o n  This r a p i d removal of a n g i o t e n s i n  accounts f o r i t s short h a l f - l i f e .  Angiotensin II  i s the  most powerful n a t u r a l l y oecuring v a s o c o n s t r i c t o r substance known.  When i n f u s e d i n t r a v e n o u s l y i t i s approximately 50  times more potent than norepinephrine on a molar b a s i s ( C a r p e n t e r , Davis and Ayers, 1961).  I t produces a r i s e of  s y s t o l i c , d i a s t o l i c , and mean a r t e r i a l p r e s s u r e ; s l o w i n g of the heart r a t e and r e d u c t i o n i n c a r d i a c output; s l i g h t i n c r e a s e i n i n t r a t h o r a c i c blood volume, r i s e i n pulmonary a r t e r y and pulmonary wedge p r e s s u r e ; a decrease i n glomerul a r f i l t r a t i o n , r e n a l plasma f l o w , u r i n e f l o w and u r i n a r y sodium e x c r e t i o n .  Another s t r i k i n g p h y s i o l o g i c a l a c t i o n  127 of a n g i o t e n s i n I I  i s i t s e f f e c t on the adrenal c o r t e x t o  evoke a prompt and s u s t a i n e d increase i n aldosterone s e c r e tion. When aldosterone i s i n j e c t e d i n t o the r e n a l a r t e r y o f dogs, a l a t e n t p e r i o d of some 20 to 60 min f o l l o w s before any e f f e c t s are. seen.  A f t e r t h i s l a t e n t p e r i o d , sodium  e x c r e t i o n i n the u r i n e i s reduced, whereas the e x c r e t i o n of potassium and hydrogen ions i s i n c r e a s e d (Barger, B e r l i n and Tulenko, 1958; Ganong and Mulrow, 1958).  The decreased  sodium e x c r e t i o n i s not accompanied by changes i n glomeru l a r f i l t r a t i o n r a t e o r i n the serum sodium c o n c e n t r a t i o n . This i n d i c a t e s an e f f e c t on the r e n a l t u b u l a r e p i t h e l i u m . Increased e x c r e t i o n of potassium and hydrogen ions on the o t h e r hand i s a s s o c i a t e d w i t h a concomitant decrease i n t h e i r c o n c e n t r a t i o n i n plasma and i n d i c a t e s a s t i m u l a t i o n of r e n a l t u b u l a r s e c r e t i o n of these i o n s .  Often a q u a n t i t a t i v e  r e l a t i o n s h i p i s i m p l i e d between the sodium ions reabsorbed and the potassium ions s e c r e t e d i n the u r i n e i n response t o a l d o s t e r o n e , i n analogy w i t h the coupled sodium f o r potassium t r a n s p o r t i n r e d c e l l membranes.  Evidence f o r such a  q u a n t i t a t i v e r e l a t i o n s h i p i n the k i d n e y , however, i s l a c k i n g . G i e b i s c h , Klose and Malnic (1967) examined the nature of sodium r e a b s o r p t i o n and potassium s e c r e t i o n i n the k i d n e y . They suggested t h a t a c t i v e sodium r e a b s o r p t i o n from t u b u l a r lumen produces an e l e c t r i c a l p o t e n t i a l g r a d i e n t across the t u b u l a r e p i t h e l i u m w i t h the lumen negative to p e r i t u b u l a r surface.  The e l e c t r i c a l g r a d i e n t f o r c e s potassium from body  128 f l u i d s i n t o t u b u l a r u r i n e and c o n s t i t u t e s the process of potassium s e c r e t i o n .  Aldosterone s t i m u l a t e s d i s t a l t u b u l a r  r e a b s o r p t i o n of sodium, i t w i l l i n c r e a s e t r a n s e p i t h e l i a l e l e c t r i c a l p o t e n t i a l s i n t h i s p o r t i o n of the nephron and t h e r e f o r e enhance r e n a l s e c r e t i o n of potassium.  Thus the  r e n a l e f f e c t of aldosterone i s enhancing s e c r e t i o n of potassium i s i n d i r e c t and secondary t o sodium t r a n s p o r t which e x p l a i n s the l a c k of q u a n t i t a t i v e r e c i p r o c a l r e l a t i o n s h i p between sodium and potassium e x c r e t i o n .  Tait, Tait, Little  and Laumas (1961) i n j e c t e d r a d i o a c t i v e aldosterone i n t o normal s u b j e c t s and measured i t s disappearance.  They r e p o r t -  ed t h a t the h a l f - l i f e of aldosterone i s about 30 min i n a normal s u b j e c t .  Ayers, D a v i s , Lieberman, Carpenter and  Berman (1962), D a v i s , 01ichney, Brown and B i n n i o n (1965) subsquently showed that i n experimental c a v a l o c c l u s i o n , e s p e c i a l l y h e p a t i c venous c o n g e s t i o n , the aldosterone h a l f l i f e can be prolonged.  Since the l i v e r i s the main s i t e  of b i o l o g i c a l i n a c t i v a t i o n of aldosterone (Bougas, F l o o d , L i t t l e , T a i t , T a i t and Underwood, 1964), i t i s n a t u r a l t h a t aldosterone h a l f - l i f e i s a l s o prolonged i n p a t i e n t s w i t h h e p a t i c c i r r h o s i s (Coppage, I s l a n e , Cooner and L i d d l e , 1962). There remain c e r t a i n e f f e c t s not explained by G i e b i s c h , Klose and M a l n i c ' s t h e o r y .  Ganong and Mulrow  (1958) i n j e c t e d aldosterone i n t o the a o r t a and r e n a l a r t e r y of the dog, they n o t i c e d an e a r l y i n c r e a s e i n potassium e x c r e t i o n which preceded the more s u s t a i n e d decrease i n sodium e x c r e t i o n .  More s i g n i f i c a n t l y , Williamson (1963)  129 s t u d i e d the e f f e c t of actinomycin D i n b l o c k i n g the sodium^ r e t a i n i n g a c t i o n of aldosterone on the r a t k i d n e y , he noted t h a t the e a r l y enhanced s e c r e t i o n of potassium i n response t o aldosterone was not prevented.  Fimognari, F a n e s t i l and  Edelman (1967) repeated W i l l i a m s o n ' s experiment, they o b s e r v ed e s s e n t i a l l y the same responses.  The mechanism of t h i s  a c t i o n of aldosterone on potassium s e c r e t i o n i s not known. One f e a t u r e of the r e n a l t u b u l a r response t o the a c t i o n of aldosterone t h a t has r e c e i v e d much a t t e n t i o n i s the sodium escape phenomenon.  I t was noted t h a t prolonged  a d m i n i s t r a t i o n of aldosterone or other m i n e r a l o c o r t i c o i d s l e d t o an i n c r e a s e d e x t r a c e l l u l a r volume and a p p r o p r i a t e g a i n i n body weight.  A f t e r s e v e r a l days, however, the sub-  j e c t began to excrete sodium i n h i s u r i n e i n amounts e q u a l i n g o r exceeding h i s d a i l y i n t a k e d e s p i t e continued a d m i n i s t r a t i o n of aldosterone or m i n e r a l c o r t i c o i d (Relman and Schwartz, 1952; August, Nelson and Thorn, 1958; Strauss and E a r l e y , 1959).  The major edematous  states—congestive  h e a r t f a i l u r e , n e p h r o t i c syndrome, and c i r r h o s i s — a r e  assoc-  c i a t e d w i t h f a i l u r e of the escape phenomenon t o occur (August and Nelson, 1959).  In most of these sodium escape  s t u d i e s the glomerular f i l t r a t i o n r a t e s e i t h e r showed no s i g n i f i c a n t change or a minimal change i n the opposite d i r e c t i o n t o t h a t i n sodium e x c r e t i o n .  Therefore some  i n v e s t i g a t o r s considered the changes i n sodium e x c r e t i o n were due t o changes i n t u b u l a r r e a b s o r p t i o n .  Other r e s e a r c h -  ers a l s o considered the p o s s i b i l i t y of a n a t r i u r e t i c  130 hormone r e g u l a t i n g the sodium balance (Smith, 1957).  Since  the standard d e v i a t i o n of i n d i v i d u a l determinations of i n u l i n clearance i s 5-10%, i t can not be r u l e d out t h a t the change i n sodium e x c r e t i o n i s caused by s m a l l changes i n glomerular f i l t r a t i o n rate.  This problem i*as r e s o l v e d when de Wardener,  M i l l s , Clapham and Hayter (1961) showed t h a t i n dogs r e c e i v i n g l a r g e amounts of s a l t - r e t a i n i n g s t e r o i d s and v a s o p r e s s i n an i n f u s i o n of s a l i n e caused a r i s e i n u r i n a r y sodium e x c r e t i o n even when glomerular f i l t r a t i o n r a t e was d e l i b e r a t e l y lowered by i n f l a t i n g a b a l l o o n p l a c e d i n the thoracic aorta. Bahlmann, McDonald, Ventom and de Wardemer (1967) expanded the blood volume w i t h e i t h e r Hartmann s o l u t i o n and 2.5% albumin or c r o s s - c i r c u l a t i o n donation.  An increase i n  u r i n a r y sodium e x c r e t i o n w i t h a r i s e i n PAH clearance was observed i n both the i n n e r v a t e d and denervated kidneys d e s p i t e the f a c t t h a t p e r f u s i o n pressure was lowered a few m i l l i m e t e r s of mercury by t i g h t e n i n g an a o r t a snare above the o r i g i n o f both r e n a l a r t e r i e s .  The sodium response was  not due t o a d i l u t i o n a l e f f e c t , i t i s l i k e l y a c i r c u l a t i n g substance was i n v o l v e d .  Tobian, Coffee and McCrea (1967)  connected two r e s e r v o i r s between an i s o l a t e d r a t ^ k i d n e y and a rat.  The i s o l a t e d kidney was s u p p l i e d w i t h blood from  the a r t e r i a l r e s e r v o i r a t constant pressure w h i l e the r e n a l venous blood drained i n t o the venous r e s e r v o i r and r e t u r n e d t o the r a t .  When a mixture of t w o - t h i r d s blood and o n e - t h i r d  Ringer s o l u t i o n was p l a c e d i n t o the venous r e s e r v o i r without  131 expanding the r a t ' s blood volume, there was no i n c r e a s e i n sodium e x c r e t i o n by the i s o l a t e d kidney.  But when the same  amount of blood was i n f u s e d i n t r a v e n o u s l y i n t o the r a t there was u s u a l l y a l a r g e r i s e i n sodium e x c r e t i o n .  Even though  t h e r e i s s t r o n g evidence of a n a t r i u r e t i c agent connected w i t h blood volume expansion there i s no s t a n d a r d i z e d technique t o assay i t s a c t i v i t y . Cort (1966) i n i t i a t e d a technique whereby the r a t e of u r i n e f l o w r a t e of the a n e s t h e t i z e d water-loaded r a t was measured.  L i c h a r d u s , P l i s k a , Uhrin and B a r t h (1968), C o r t ,  Dousa, P l i s k a , L i c h a r d u s , S a f a r o v a , Vranesic and Rudinger (1968) i n j e c t e d plasma concentrates t h a t had been taken b e f o r e and a f t e r body f l u i d expansion i n t o hydrated r a t s . The i n j e c t i o n of c o n t r o l plasma concentrate d i d not produce any s i g n i f i c a n t change i n u r i n e f l o w , but the i n j e c t i o n of concentrated experimental plasma obtained a f t e r volume expans i o n produced a s i g n i f i c a n t r i s e .  However, the concentrated  e x t r a c t prepared according t o Cort has an o s m o l a r i t y of about 3,000 mOs/kg, i t has been c r i t i c i z e d f o r i t s osmotic activity.  In f a c t groups repeated the experiment and  obtained w i d e l y v a r i a b l e r e s u l t s .  Another technique of  measuring the s h o r t - c i r c u i t c u r r e n t across a f r o g s k i n was a l s o explored by C o r t .  P l a i n serum or' plasma concen-  t r a t e were p l a c e d on the s e r o s a l s i d e of the s k i n and Prog Ringer s o l u t i o n was placed on the o t h e r .  The s h o r t - c i r c u i t  c u r r e n t across the f r o g s k i n d i r e c t l y r e l a t e s to sodium t r a n s p o r t across the s k i n .  In s e v e r a l r e p o r t s Cort and  132 Lichardus (1963a, 1963b), Cort (1966), C o r t , Dousa, P l i s k a , L i c h a r d u s , S a f a r o v a , Vranesic and Rudinger (1968) claimed t h a t the s h o r t - c i r c u i t c u r r e n t rose w i t h the a d d i t i o n of the c o n t r o l serum and f e l l w i t h the experimental serum.  Close  examination of the three r e p o r t s r e v e a l e d w i d e l y d i f f e r e n t time courses i n response t o the experimental serum samples. There i s no ready e x p l a n a t i o n to t h i s discrepancy and t h e r e f o r e the r e s u l t s are q u e s t i o n a b l e . R e c e n t l y , Sealey, Kirshman and Laragh (1969), V i s k o p e r , Czaczkes, Schwartz and Ullman (1969) measured the sodium e x c r e t i o n of hydrated r a t s t o t e s t the n a t r i u r e t i c a c t i v i t y of e x t r a c t s prepared by e i t h e r g e l f i l t r a t i o n or microfiltration.  Sealey et~al (1969) used e x t r a c t s p r e p a r -  ed from plasma and u r i n e from man or animals maintained on a h i g h - s a l t i n t a k e a f t e r s a l i n e i n f u s i o n and from p a t i e n t s w i t h primary aldosteronism or e s s e n t i a l h y p e r t e n s i o n . V i s k o p e r et a l (1969) obtained e x t r a c t s of u r i n e from p a t i e n t s s u f f e r i n g from hypertension a f t e r they have been g i v e n an intravenous i n f u s i o n of h y p e r t o n i c s a l i n e .  Both  groups r e p o r t e d s i g n i f i c a n t r i s e i n u r i n a r y sodium e x c r e t i o n r a t e from the assay r a t s .  Pearce and Veress (1975) obtained  plasma samples from blood volume expanded r a t s .  Gel f i l -  t r a t i o n separated the samples i n t o f o u r f r a c t i o n s and each f r a c t i o n was i n j e c t e d i n t o hydropenic r a t s f o r n a t r i u r e t i c activity.  Only the l a r g e p r o t e i n f r a c t i o n (molecular weight  exceeding 30,000) of experimental plasma produced a s i g n i f i c a n t l y g r e a t e r n a t r i u r e s i s than the corresponding f r a c t i o n  133 from e i t h e r c o n t r o l plasma o r a f r a c t i o n a t e d 5.6$ albumin solution.  This n a t r i u r e t i c a c t i v i t y , Pearce a t t r i b u t e d to  a hormonal f a c t o r , e i t h e r a p r o t e i n or a p r o t e i n bound moiety, generated by v a s c u l a r expansion. I t has been shown t h a t pulmonary a r t e r y pouch d i s t e n s i o n i s / a s s o c i a t e d w i t h an i n c r e a s e d systemic a r t e r i a l pressure ( P i g . 5, 13, 20). For the i n t a c t kidneys the r e n a l p e r f u s i o n pressure i n c r e a s e d the same amount as the systemic pressure t h e r e f o r e i t i s expected t h a t the r e n a l f u n c t i o n w i l l be a l t e r e d .  As has been d i s c u s s e d e a r l i e r , i n c r e a s e d  r e n a l p e r f u s i o n would cause an i n c r e a s e d sodium e x c r e t i o n r a t e by two mechanisms: i n c r e a s e d glomerular f i l t r a t i o n r a t e as a d i r e c t r e s u l t of the i n c r e a s e d r e n a l p e r f u s i o n p r e s s u r e , thus p r e s e n t i n g more sodium t o the r e n a l t u b u l e s ; depression of sodium r e a b s o r p t i o n by the r e n a l t u b u l e s , which i s not connected w i t h the glomerular f i l t r a t i o n r a t e . P i g . 13, 20 indeed showed an i n c r e a s e d sodium e x c r e t i o n r a t e i n a s s o c i a t i o n w i t h a r a i s e d systemic p r e s s u r e .  In  the two f i g u r e s the pulmonary a r t e r i a l pouch pressure were e l e v a t e d t o 80 and 100 cm H 0 r e s p e c t i v e l y , and i n both 2  cases there were s i g n i f i c a n t r i s e s i n the systemic a r t e r i a l pressure corresponding t o the pouch d i s t e n s i o n , the r e n a l sodium e x c r e t i o n r a t e s a l s o showed s i g n i f i c a n t i n c r e a s e s . In c o n t r a s t when the pouch pressure was i n c r e a s e d t o 4-0 cm H 0 ( P i g . 12) i t d i d not cause 2  a s i g n i f i c a n t change i n  the systemic a r t e r i a l p r e s s u r e , consequently the change i n the sodium e x c r e t i o n was not s i g n i f i c a n t .  134 Although the r e l a t i o n s h i p between r e n a l p e r f u s i o n pressure and sodium e x c r e t i o n r a t e i s most obvious, there are other f a c t o r s we must c o n s i d e r .  In the u r i n e c o l l e c t i o n  experiments the constant temperature blood r e s e r v o i r was primed w i t h 2 o r 3 l i t e r s of a r t i f i c i a l p e r f u s a t e .  The  o s m o l a r i t y of the perfusate was about 295 mOs/kg t h e r e f o r e an osmotic d i u r e s i s was not expected, but the e x t r a p e r f u s a t e had a d i l u t i o n e f f e c t on the plasma p r o t e i n s and lowered the h e m a t o c r i t .  Lowering of plasma p r o t e i n c o n -  c e n t r a t i o n i s known t o i n c r e a s e the sodium e x c r e t i o n r a t e . R e s u l t s from the c o n t r o l experiments helps to determine the d i l u t i o n e f f e c t s on the r e n a l f u n c t i o n .  After a  s u f f i c i e n t s t a b l i z a t i o n p e r i o d the sodium e x c r e t i o n r a t e of the c o n t r o l experiments s e t t l e d t o a r e l a t i v e l y s t a b l e l e v e l ( F i g . 11, 17) and no changes were observed the three c o l l e c t i o n p e r i o d s .  throughout  In experiments where the  pulmonary a r t e r y pouch was distended the sodium e x c r e t i o n r a t e i n the p r e - d i s t e n s i o n c o n t r o l p e r i o d ( p e r i o d I ) were always steady.  From t h i s r e s u l t , we conclude t h a t the sodium  e x c r e t i o n r a t e changes w i t h pulmonary a r t e r y pouch d i s t e n s i o n t o 80 and 100 cm rJ^O was not caused by the b l o o d d i l u t i o n e f f e c t but by the pulmonary a r t e r i a l  distension.  B l o o d hematocrit and plasma p r o t e i n c o n c e n t r a t i o n would a l s o a f f e c t the f r e e water c l e a r a n c e .  In has been  d e s c r i b e d t h a t when plasma p r o t e i n c o n c e n t r a t i o n and hemar o c r i t are lowered by d i l u t i n g the b l o o d , u r i n e volume and f r e e water clearance are i n c r e a s e d .  This e f f e c t i s  thought  135 t o be caused by p h y s i c a l f a c t o r changes i n s i d e the kidney as a r e s u l t of the d i l u t i o n , p o s s i b l y gradual washout of the c o n c e n t r a t i o n gradient i n the r e n a l medulla and i s not connected w i t h ADH.  In a l l the u r i n e c o l l e c t i o n experiments,  i n c l u d i n g the r e s u l t from the i s o l a t e d kidneys and c o n t r o l experiments f r e e water clearance rose s t e a d i l y over the e n t i r e c o l l e c t i o n periods ( F i g . 19 > 20, 21) s i m i l a r t o b l o o d d i l u t i o n r e s u l t s obtained by C r a i g et a l (1966), N i z e t et a l (1968).  Since we can not d e t e c t changes i n the  f r e e water clearance i n any set of experiment r e l a t e d to pulmonary a r t e r y pouch d i s t e n s i o n we assume t h a t they are not r e l a t e d .  The r o l e of ADH i n t h i s case i s not c l e a r ,  f o r no d i r e c t measurement of the hormone was made, we can o n l y compare the known e f f e c t s of ADH w i t h our e x p e r i mental r e s u l t .  Changes i n plasma o s m o l a r i t y and l e f t  a t r i a l d i s t e n s i o n are proven mechanisms a f f e c t i n g the r e l e a s e of ADH.  In the experiments, the plasma o s m o l a r i t y  was monitored and found t o be steady and w i t h i n the p h y s i o l o g i c a l l e v e l f o r each i n d i v i d u a l experiment, t h e r e f o r e we can exclude e f f e c t of plasma o s m o l a r i t y on the r e l e a s e of ADH i n t h i s case.  Although the l e f t a t r i a l  pressure  was not recorded i n a l l of the experiments, i n a few p r e l i m i n a r y experiments where i t was, monitored we d i d not d e t e c t any changes.  The l e f t a t r i a l d i s t e n s i o n exp-  eriments of Ledsome et a l (1961), L y d t i n et a l (1964), Ledsome et a l (1968), Lawrance et a l (1973) showed d i s t i n c t i v e r i s e s i n f r e e water clearance corresponding t o the  136 d i s t e n s i o n , r e s u l t s from the present experiments do not bear any resemblance t o them.  Radioimmunoassay  experiments  by de Torrente et a l (1975) showed c o n c l u s i v e l y t h a t the l e f t a t r i a l d i s t e n s i o n i s a s s o c i a t e d w i t h a decrease i n plasma ADH c o n c e n t r a t i o n and a r i s e i n the f r e e water c l e a r ance.  Based on the f a c t t h a t the f r e e water clearance  p a t t e r n from the present experiments i s d i s t i n c t i v e l y d i f f e r ent from t h a t of the known e f f e c t s of ADH and the pulmonary a r t e r y pouch d i s t e n s i o n d i d not produce ; any corresponding changes, we concluded t h a t the r a t e of ADH r e l e a s e i s not a f f e c t e d by pouch d i s t e n s i o n . The pulmonary a r t e r y pouch d i s t e n s i o n r e f l e x i s a n e u r a l r e f l e x as evidenced by the absence o f systemic pressure changes a f t e r c u t t i n g the vagus nerves.  The i n c r e a s e  i n systemic v a s c u l a r r e s i s t a n c e o c c u r r i n g as a r e s u l t of the d i s t e n s i o n i s most l i k e l y due t o i n c r e a s e d sympathetic nervous a c t i v i t y .  The same sympathetic nervous a c t i v i t y  a c t i n g on the kidney may cause a r e d i s t r i b u t i o n of i n t r a r e n a l b l o o d f l o w i n f a v o r of the outer m e d u l l a .  Although such a  r e d i s t r i b u t i o n w i l l i n c r e a s e the r e n a l sodium e x c r e t i o n , i t s d f f e e t on the t o t a l r e n a l b l o o d f l o w and, r e s i s t a n c e may be unnoticeable.  Indeed our r e s u l t s showed no change i n r e n a l  r e s i s t a n c e i n response t o pulmonary a r t e r y pouch d i s t e n s i o n . The i s o l a t e d kidney experiments p r o v i d e d a b e t t e r view f o r the e f f e c t s of r e n a l nerve a c t i v i t y .  Compared w i t h the  i n t a c t r i g h t kidney o f the same a n i m a l , the i s o l a t e d kidney always showed a h i g h e r sodium e x c r e t i o n r a t e and f r e e water  137 clearance s i m i l a r t o B e r n e ' s 1952 r e s u l t s .  These d i f f e r e n c e s  between the two kidneys are most l i k e l y to be due to denerv a t i o n of the i s o l a t e d k i d n e y .  Although r e s u l t s from the  i n t a c t kidney experiments d i d not show how much o f the sodium e x c r e t i o n response i s mediated by the n e u r a l f a c t o r there i s a p o s s i b i l i t y t h a t such a mechanism does p l a y a r o l e . The sodium e x c r e t i o n p a t t e r n i n F i g , 12, 13 r e v e a l e d two d i s t i n c t s e c t i o n s i n periods I I  and I I I  may represent two d i f f e r e n t c o n t r o l mechanisms.  which When the  pulmonary a r t e r i a l pouch pressure was i n c r e a s e d i n p e r i o d  II  t h e r e was a f a s t i n c r e a s e i n the systemic pressure and sodium e x c r e t i o n r a t e , the response was observable w i t h i n minutes and was maintained throughout the e n t i r e d i s t e n s i o n period.  Because of the f a s t nature of the response we  propose>) t h a t i t i s the r e s u l t of hemodynamic changes !  sub-  sequent to the i n c r e a s e i n systemic a r t e r i a l p r e s s u r e , as has been d i s c u s s e d .  When the pulmonary a r t e r i a l  was lowered i n p e r i o d I I I ,  pressure  as expected,the systemic a r t -  e r i a l pressure a l s o lowered back t o the p r e - d i s t e n s i o n l e v e l , however the sodium e x c r e t i o n r a t e remained e l e v a t e d , i n f a c t i t continued t o r i s e .  I f the sodium r e a b s o r p t i o n i n the  r e n a l t u b u l e s were c o n t r o l l e d by the r e n a l p e r f u s i o n p r e s sure a l o n e , r e t u r n i n g the systemic a r t e r i a l pressure t o the c o n t r o l l e v e l should a l s o b r i n g the sodium e x c r e t i o n r a t e back t o the c o n t r o l l e v e l i n p e r i o d I.  F a i l u r e to  r e t u r n t o the c o n t r o l l e v e l i n d i c a t e d a second f a c t o r other than the r e n a l p e r f u s i o n pressure e x e r t i n g an o v e r r i d i n g  138 e f f e c t on the sodium e x c r e t i o n r a t e .  To p o s t u l a t e a humoral  f a c t o r whose plasma c o n c e n t r a t i o n i s a f f e c t e d by pulmonary a r t e r y pouch d i s t e n s i o n , the humoral f a c t o r a l t e r i n g r e n a l sodium e x c r e t i o n r a t e would e x p l a i n the sodium e x c r e t i o n pattern.  A c e r t a i n amount of time i s r e q u i r e d before the  c i r c u l a t i n g l e v e l of a hormone can be a l t e r e d .  Suppose a  hormone which enhances sodium e x c r e t i o n i s r e l e a s e d by the pulmonary a r t e r y pouch i t i s l o g i c a l t o expect the c i r c u l a t i n g l e v e l of the hormone t o remain h i g h f o r a p e r i o d a f t e r the pouch pressure was r e l e a s e d .  As l o n g as the plasma  c o n c e n t r a t i o n of the hormone i s h i g h the u r i n a r y sodium e x c r e t i o n r a t e w i l l remain h i g h such as the case i n P i g . 12 and 13. Aldosterone i s the f i r s t candidate considered f o r producing the e l e v a t e d sodium e x c r e t i o n r a t e .  The pulmonary  a r t e r y pouch d i s t e n s i o n i s f o l l o w e d by an i n c r e a s e i n s y s temic a r t e r i a l pressure and r e n a l p e r f u s i o n p r e s s u r e .  The  exact mechanism c o n t r o l l i n g the r e l e a s e o f r e n i n i s not known.  I t i s g e n e r a l l y b e l i e v e d t h a t a r i s e i n the r e n a l  p e r f u s i o n pressure w i l l i n h i b i t the r e l e a s e o f r e n i n i n t o the c i r c u l a t i o n .  I t f o l l o w s t h a t the plasma c o n c e n t r a t i o n  of a n g i o t e n s i n and aldosterone w i l l a l s o decrease.  The  r e l a t i o n between the systemic pressure and r a t e of r e l e a s e of r e n i n i s not c l e a r , but asris.e in-.the.: 'systemic a r t e r i a l :  pressure i n t h i s case of about 10-12 mm Hg i s u n l i k e l y to cause a t o t a l c e s s a t i o n of r e n i n r e l e a s e .  Also the h a l f -  l i f e of the aldosterone a l r e a d y i n the c i r c u l a t i o n i s a t  139 l e a s t t h i r t y minutes l o n g which i s too l o n g t o account f o r the response p a t t e r n .  Potassium i s another i n d i c a t o r f o r  changes i n plasma aldosterone l e v e l .  When plasma aldosterone  c o n c e n t r a t i o n drops potassium e x c r e t i o n r a t e w i l l decrease i n a s s o c i a t i o n w i t h a r i s e i n sodium e x c r e t i o n r a t e . Although we cannot expect t o see a q u a n t i t a t i v e r e l a t i o n s h i p between the sodium and potassium e x c r e t i o n r a t e , we do expect t o see a change i n the potassium e x c r e t i o n r a t e . t h i s i s not the case i n our r e s u l t s ( P i g . 18).  However, Pulmonary  a r t e r y d i s t e n s i o n i n c r e a s e s sodium e x c r e t i o n r a t e without a f f e c t i n g potassium e x c r e t i o n r a t e .  The p o s s i b i l i t y of a  " n a t r i u r e t i c hormone", as considered by Smith (1957)> being a f f e c t e d was i n v e s t i g a t e d f u r t h e r . The i s o l a t e d kidney p r e p a r a t i o n was perfused at constant pressure t h e r e f o r e i t a l l o w e d us t o observe the s o l e e f f e c t of the hormone without the p e r f u s i o n pressure effects.  Results from the r i g h t i n t a c t kidney showed an  i n c r e a s e i n osmolar c l e a r a n c e , sodium and potassium e x c r e t i o n r a t e s d u r i n g the pulmonary a r t e r y pouch d i s t e n s i o n p e r i o d ( P i g . 20).  A l l three v a r i a b l e s r e t u r n e d to the p r e -  d i s t e n s i o n l e v e l upon the r e l e a s e of the pouch p r e s s u r e . The response p a t t e r n c l e a r l y shows the e f f e c t of r e n a l p e r f u s i o n pressure because of the c l o s e r e l a t i o n s h i p w i t h the systemic a r t e r i a l p r e s s u r e .  The d i l u t i o n e f f e c t on sodium  e x c r e t i o n was minimized by an a p p r o p r i a t e s t a b l i z a t i o n p e r i o d evidenced by the steady sodium e x c r e t i o n r a t e i n p e r i o d I,  One major d i f f e r e n c e of the sodium e x c r e t i o n r a t e  140 i n F i g . 20 from those i n F i g . 12, 13 i s the drop i n p e r i o d III  a f t e r the r e l e a s e of the pouch p r e s s u r e .  In F i g . 12 and  13, the continuous r i s e of the sodium e x c r e t i o n r a t e i n period III  encouraged us t o p o s t u l a t e a n a t r i u r e t i c hormone  as p a r t of the response, however, the same p a t t e r n i s absent from the r e s u l t s i n F i g . 20.  Without an assay technique  f o r the n a t r i u r e t i c hormone we can only speculate on the p o s s i b l e discrepancy between the d i f f e r e n t sets of e x p e r i ment*  The experiments shown on F i g . 12 and 13* were done  w i t h 2 l i t e r s of a r t i f i c a l p e r f u s a t e i n the r e s e r v o i r w h i l e those shown on F i g . 20 were done w i t h 3 l i t e r s .  The d i l u t i o n  caused by the p e r f u s a t e i s obvious, the question i s , can the e x t r a one l i t e r account f o r the d i f f e r e n t responses i n period III?  Not knowing the dosage response c h a r a c t e r ,  the question cannot be answered.  The i s o l a t e d kidney which  i s not a f f e c t e d by the changes i n systemic pressure  should  g i v e us a b e t t e r p i c t u r e of the a c t i o n of the hormone. F i g . 21 showed a r i s e i n the sodium e x c r e t i o n r a t e c o r r e s ponding approximately to the pulmonary a r t e r y d i s t e n s i o n and no change i n potassium e x c r e t i o n r a t e .  The sodium  response i s very l i k e l y to be caused by a humoral f a c t o r , however, s t a t i s t i c a l t e s t i n d i c a t e d t h a t the confidence l e v e l f o r the hypothesis t h a t there was a change i n sodium e x c r e t i o n r a t e i s g r e a t e r than 0.90 but l e s s than 0.95. The normal acceptable l e v e l of confidence i s when i t i s g r e a t e r than 0.95, i h t h i s case we f a i l e d t o prove t h a t t h e r e i s a s i g n i f i c a n t humoral f a c t o r r e g u l a t i n g the r e n a l sodium e x c r e t i o n .  Since the confidence l e v e l i s g r e a t e r  14-1  than 0.90 i t i s conceivable t h a t w i t h a b e t t e r experimental technique t o minimize the blood d i l u t i o n , the e f f e c t of a n a t r i u r e t i c hormone can be proved t o be s i g n i f i c a n t . In summary, the u r i n e c o l l e c t i o n experiments showed t h a t pulmonary a r t e r y pouch d i s t e n s i o n a f f e c t s u r i n a r y f u n ction.  Sodium e x c r e t i o n r a t e i s most s i g n i f i c a n t l y a f f e c t -  ed w h i l e potassium e x c r e t i o n r a t e i s n o t .  A major p a r t of  the response i s caused by an increased r e n a l p e r f u s i o n p r e s sure secondary t o the increase i n systemic a r t e r i a l pressure and a hormonal f a c t o r may a l s o be i n v o l v e d .  Aldosterone  i s an u n l i k e l y candidate because of the s t a b l e  potassium  e x c r e t i o n p a t t e r n i n the r e s u l t and the h a l f - l i f e of aldosterone.  A y e t unknown n a t r i u r e t i c hormone may be  i n v o l v e d , however, i t s existence was not proven.  The l e v e l  of ADH i s probably not changed by pulmonary a r t e r y pouch distension.  14-2  D.. A P o s s i b l e P h y s i o l o g i c a l Role Of The R e f l e x Response To Pulmonary A r t e r i a l D i s t e n s i o n The concept t h a t the body possess a mechanism which senses the f u l l n e s s of the blood stream and provokes a d i u r e t i c response through the kidney was f i r s t proposed by P e t e r s i n 1935•  Experimental v e r i f i c a t i o n s by i s q s m o t i c  expansion of blood volume were attempted by Borst  (194-8),  Zuidema, C l a r k e , Reeves, Gauer and Henry (1956) and many o t h e r groups, and i n d e e d , an i n c r e a s e d u r i n e f l o w was r e c o r d ed.  The term " f u l l n e s s " only gives a vague d e s c r i p t i o n of  the volume of a f l u i d i n r e l a t i o n w i t h the volume of the container.  For an e l a s t i c c o n t a i n e r l i k e the c a r d i o v a s c u l a r  beds, the p o t e n t i a l c a p a c i t y i s best d e s c r i b e d by a p r e s s u r e volume diagram and i t s " f u l l n e s s " d e f i n e d by the h y d r o s t a t i c pressure c r e a t e d by the b l o o d . Because of the w i d e l y d i f f e r e n t mechanical p r o p e r t i e s i n separate p a r t s of the c a r d i o v a s c u l a r bed, c l o s e r examination of i n d i v i d u a l s e c t i o n s r e v e a l e d i n t e r e s t i n g characters.  H i l l and Barnard (1897) s t r e s s e d the importance  of the d i f f e r e n t d i s t e n s i b i l i t i e s of the a r t e r i a l and venous systems.  They p o i n t e d out t h a t the r e l a t i v e l y s m a l l volume  necessary t o change the a r t e r i a l pressure over a wide range c o u l d e a s i l y be taken out of the capacious venous  system  w i t h only n e g l i g i b l e changes of venous p r e s s u r e .  To quote  t h e i r words, " t h a t the v a s c u l a r system i s so c o n s t r u c t e d as a discontinuous system i n order t h a t great changes of a r t e r i a l pressure may be brought about by v a s o c o n s t r i c t i o n  143 without any concomitant a l t e r a t i o n of venous o r pulmonary pressure."  To f u r t h e r analyse the d i s t r i b u t i o n of blood  volume and d i s t e n s i b i l i t y throughout the c i r c u l a t i o n , Gauer and Henry (1963) adapted the terms l o w - and h i g h - p r e s s u r e systems t o r e p l a c e the c l a s s i c a l anatomical d i s t i n c t i o n between the pulmonary v a s c u l a r bed and the g r e a t e r c i r c u lation.  The low-pressure system comprises the pulmonary  c i r c u l a t i o n , r i g h t h e a r t , and capacitance v e s s e l s of the systemic c i r c u l a t i o n and the high-pressure system c o n s i s t s of the a r t e r i a l c i r c u l a t i o n .  The estimated e l a s t i c r e s i s -  tance of the systemic a r t e r i e s i s 100 t o 200 times t h a t of the r e s t of the c i r c u l a t i o n and they c o n t a i n only 10-20 percent of the t o t a l blood volume (Gauer and Henry, 1963; Gauer, Henry and Behn, 1970).  About 80 percent of the c i r c u l a t i n g  b l o o d volume i s contained i n the v a s t capacious venouspulmonary c i r c u l a t i o n . Because of the r e l a t i v e l y s m a l l volume and h i g h e l a s t i c resistance f l u i d  dynamic e q u i l i b r i u m i n the h i g h -  pressure system r e s t s e n t i r e l y on f l o w r e s i s t a n c e and the f u n c t i o n of the c a r d i a c output.  I t i s w e l l i l l u s t r a t e d , by  s t o p p i n g the heart f o r 3 t o 4 b e a t s , during t h a t t i m e , the a r t e r i a l pressure w i l l have f a l l e n t o almost 30 mm Hg, w h i l e the 3 t o 4 s t r o k e volumes which have run o f f i n t o the low-pressure system w i l l have caused an i n c r e a s e of pressure of no more than a few centimeters water (Gauer, 1960). W i t h i n the low-pressure system, f u r t h e r f u n c t i o n a l s u b d i v i s i o n i n t o i n t r a t h o r a c i c and capacitance v e s s e l compartments  144 can be made.  Making use of s p i r o g r a p h i c , plethsmographic  and X-ray s t u d i e s S j o s t r a n d (1953a, 1953b), Gauer (1955), Gauer and Zuidema (1961) showed t h a t great q u a n t i t i e s of b l o o d can be interchanged f r e e l y between the two compartments. A c c e l e r a t i o n on a l a r g e c e n t r i f u g e d i s p l a c e s blood i n t o the dependent r e g i o n of the body.  A f t e r the a c c e l e r a t i o n has  ceased, blood rushes back i n t o the pulmonary c i r c u l a t i o n w i t h i n seconds (Gauer and Zuidema, 1961).  The pulmonary c i r -  c u l a t i o n a c t s as an important r e s e r v o i r which a l l o w s the l e f t v e n t r i c l e t o a d j u s t immediately t o v a r y i n g loads independent of changes of venous r e t u r n .  The pulmonary bed a l s o  serves  as an overflow r e s e r v o i r f o r b l o o d . As mentioned e a r l i e r , the f u l l n e s s of the blood stream mediated r e n a l f u n c t i o n .  B o r s t (194-8) viewed the  o l i g u r i a f o l l o w i n g hemorrhage, as w e l l as the d i u r e s i s f o l l o w i n g b l o o d t r a n s f u s i o n as a volume r e g u l a t o r y mechanism f o r the maintenance of an adequate c a r d i a c output.  Although  i t i s d i f f i c u l t t o exclude the changes i n r e n a l f u n c t i o n as a simple change i n f i l t r a t i o n , a v a i l a b l e evidence suggests the e x i s t e n c e of r e f l e x mechanisms u s i n g i n t r a v a s c u l a r mechanoreceptors which are s t i m u l a t e d by an expansion or c o n t r a c t i o n of the blood volume t o induce changes of r e n a l function.  In order t o l o c a l i z e s e n s i t i v e zones w i t h i n the  c i r c u l a t i o n where these mechanoreceptors may e x i s t , a number of authors have compared the e f f e c t of various maneuvers which change the d i s t r i b u t i o n of the body f l u i d and influence urine flow.  X-ray s t u d i e s i n man by l e n n , O t i s ,  14-5 Rahn, Chadwick and Hegnauer (194-7), K i l b u r n and S i e k e r (1960) i n d i c a t e d displacement of b l o o d i n t o the thorax w i t h negat i v e pressure b r e a t h i n g and a d e p l e t i o n of b l o o d under p o s i t i v e pressure b r e a t h i n g .  High p o s i t i v e pressure b r e a t h -  i n g i s accompanied by a n t i d i u r e s i s , a n t i n a t r i u r e s i s and f a l l i n osmolar clearance s i m i l a r t o t h a t found i n hemorrhage (Drury, Henry and Goodman, 194-7; Murdaugh, S i e k e r and M a n f r e d i , 1969).  On the other hand, negative pressure b r e a t h -  i n g u s u a l l y produces an i n c r e a s e i n f r e e water clearance and i n some cases n a t r i u r e s i s ( S i e k e r , Gauer and Henry, 1954-; \ S u r t s h i n , Hoeltzenbein and White, 1955; B o y l a n , and Antkowiak, 1959; Hulet and S m i t h , 1959; Pabst and Gauer, 1959).  In these experiments the r e l e a s e of a hormone was  suspected because of the slow onset of the d i u r e s i s w i t h the i n i t i a t i o n of the pressure and i t s p e r s i s t e n c e a f t e r t e r m i n a t i o n of the maneuver (Gauer, Henry, S i d k e r and Wendt, 1951).  Also denervation of the kidney d i d not a b o l i s h the  e f f e c t s of negative pressure b r e a t h i n g ( S u r t s h i n , H o e l t z e n b e i n and White, 1955). The i n t r a t h o r a c i c blood volume can a l s o be a l t e r e d by water immersion.  R e s u l t s from s e v e r a l groups have demon-  s t r a t e d t h a t the h y d r o s t a t i c pressure gradient induced by head-out water immersion r e s u l t s i n a s i g n i f i c a n t r e d i s t r i b u t i o n of b l o o d volume ( A r b o r e l l u s , B a l l d i n , Lil<ja and l u n d g r e n , 1972; E p s t e i n , Duncan and Meek, 1973; Lange, Echt and Gauer, 1974-).  Lange,  In the study by Lange, Lange,  Echt and Gauer (1974-) a mean i n c r e a s e i n i n t r a t h o r a c i c  146 blood volume o f 700 ml and an increase i n heart volume of 180 ml was r e c o r d e d .  Consequent t o the expanded i n t r a t h o r a -  c i c volume, a l t e r a t i o n s i n f l u i d and e l e c t r o l y t e homeostasis were induced i n c l u d i n g a s i g n i f i c a n t n a t r i u r e s i s ,  diuresis,  s u p r e s s i o n o f the r e n i n - a l d o s t e r o n e a x i s and ADH r e l e a s e ( E p s t e i n , Duncan and Fishman, 1972; E p s t e i n , K a t s i k a s and Duncan, 1973; E p s t e i n , P i n s and M i l l e r , 1975).  It is  b e l i e v e d t h a t the "volume s t i m u l u s " i n c r e a s e d the stimulus t o r e c e p t o r s i n the i n t r a t h o r a c i c area and caused t h e r e n a l response.  By i n t r o d u c i n g c a t h e t e r s i n t o the r i g h t a t r i u m  and i n some cases the pulmonary a r t e r y , A r b o r e l i u s , B a l l d i n , L i l j a and Lundgren (1972) recorded an increase i n mean r i g h t a t r i a l and pulmonary a r t e r i a l pressure of 12 mm Hg d u r i n g water immersion.  The f i g u r e was obtained a f t e r  c o r r e c t i o n f o r the increase i n p l e u r a l pressure thus r e p r e s e n t s the t r u e transmural g r a d i e n t .  The i n c r e a s e d pulmonary  a r t e r i a l pressure was accompanied by an augmented pulse pressure and an increase i n both the c a r d i a c output and systemic a r t e r i a l  pressure.  S a l i n e s o l u t i o n i n f u s i o n i s another method t o i n c r e a s e the i n t r a t h o r a c i c blood volume. Rosenbaum and Rossmeisl  Strauss, Davis,  (1951), Levinsky and Lalone (1963),  r e p o r t e d n a t r i u r e s i s and water d i u r e s i s a f t e r s a l i n e infusion.  The r e n a l responses were d e s c r i b e d t o be s i m i l a r  t o those of water immersion.  Comparison of the r e s u l t s  from the two d i f f e r e n t maneuvers by E p s t e i n , P i n s , A r r i n g t o n , Denunzio and Engstrom (1975) i n d i c a t e s t h a t immersion  14-7  up t o the neck r e s u l t e d In a s i g n i f i c a n t n a t r i u r e s i s and k a l i u r e s i s which i s comparable t o t h a t induced by the acute i n f u s i o n of 2 l i t e r s of s a l i n e w h i l e the s u b j e c t i s i n the seated p o s i t i o n .  However, the mechanism t h a t caused the  r e n a l response was not known. The r e l a t i o n s h i p between a t r i a l d i s t e n s i o n and water d i u r e s i s i s w e l l known ( C a r s w e l l , Hainsworth and Ledsome, 1970; Gauer, Henry and Behn, 1970; Goetz, Hermeck, S l i c k and S t a r k e , 1970).  I t i s thought t h a t the d i l u t e  d i u r e s i s r e s u l t e d from a t r i a l d i s t e n s i o n i s mediated through ADH ( d e t a i l discussed e a r l i e r ) .  However, the a t r i a l r e f l e x  can only e x p l a i n p a r t of the r e n a l responses from s a l i n e i n f u s i o n and water immersion; the n a t r i u r e s i s i n p a r t i c u l a r i s s t i l l unaccounted f o r .  Increased sodium e x c r e t i o n as  p a r t of the pulmonary a r t e r y d i s t e n s i o n r e f l e x would e n l i g h t e n our knowledge on the body's responses t o "volume stimulus".  Our r e s u l t s i n d i c a t e an e f f e c t i v e hemodynamic  mechanism t o increase e x c r e t i o n of sodium.  In a d d i t i o n  t h e r e i s a p o s s i b i l i t y t h a t a yet unknown n a t r i u r e t i c hormone may a l s o be i n v o l v e d . O r d i n a r i l y , the pulmonary a r t e r i a l mean pressure i n man and dog averages o n e - f i f t h or o n e - s i x t h t h a t i n the systemic c i r c u l a t i o n (Cournand, 194-7; Nahas, V i s s c h e r , Mather, Haddy and Warner, 1954-).  However, there i s no  f i x e d r e l a t i o n s h i p between the pressure i n the two c i r c u i t s . In man, before the onset of s y s t o l e , the pulmonary a r t e r i a l pressure i s of the order of 7 t o 12 mm Hg; d u r i n g s y s t o l e  148 i t r i s e s a b r u p t l y to 20 to 30 mm Hg; the corresponding mean pressure i s of the order of 12 t o 15 mm Hg (Cournand, 1947; Dexter, Dow, Haynes, Whittenberger, F e r r i s , Goodale and Hellems, 1950).  For 95% of the p o p u l a t i o n , the range  of the mean pulmonary a r t e r i a l pressure i s from 11 t o 23 mm Hg ( M a r s h a l l , Helmholz and Wood, 1962).  In the dog,  Hamilton, Woodbury and Vogt,(1939) determined t h a t the p u l monary a r t e r i a l pressures tend t o be somewhat h i g h e r than i n a man, a mean pressure of 20 mm Hg i s not u n u s u a l .  In  some disease s t a t e s , the pulmonary a r t e r i a l pressure can become much h i g h e r .  Toor, Dulfano and Y a h i n i (1959) made  a d e t a i l e d study of p a t i e n t s w i t h pulmonary h y p e r t e n s i o n and others w i t h a o r t i c s t e n o s i s . w i t h f u n c t i o n a l group I I  In a group of 17 p a t i e n t s  and e a r l y I I I  a o r t i c s t e n o s i s (New  York Heart A s s o c i a t i o n C l a s s i f i c a t i o n ) mean pulmonary p r e s sure ranged from 32 t o 75 mm Hg.  One i n t e r e s t i n g r e s u l t  from the same study i s when compared w i t h another group o f 6 p a t i e n t s , who a l s o had group I I  and e a r l y I I I  aortic  s t e n o s i s but without pulmonary h y p e r t e n s i o n , a l l o t h e r hemodynamic values were n e a r l y e q u a l , i n c l u d i n g the sodium f i l t r a t i o n load.  Despite the l a c k of a s i g n i f i c a n t d i f f e r -  ence i n the f i l t e r e d sodium l o a d values between the two groups,the t u b u l a r r e j e c t i o n of sodium per minute, expressed as percent of sodium l o a d e x c r e t e d , i s s i g n i f i c a n t l y h i g h e r i n the group w i t h pulmonary h y p e r t e n s i o n .  This percentage  decreases i n yet a t h i r d group of 10 p a t i e n t s who had p u l monary h y p e r t e n s i o n but showing signs of heart f a i l u r e .  14-9 Extremely h i g h pulmonary a r t e r i a l pressures are sometimes seen i n some type of h e a r t d e f e c t s .  One study of 10 p a t i e n t s  w i t h t o t a l anomalous pulmonary venous connection recorded a h i g h pulmonary a r t e r y s y s t o l i c pressure of 119 mm Hg (Mars h a l l , Helmholz and Wood, 1962).  The f i g u r e s i n d i c a t e t h a t  the pressure range of 20-40 cm ^ 0 over which s i g n i f i c a n t changes i n systemic pressure were observed i s w e l l w i t h i n the p h y s i o l o g i c a l range.  Even the high pressure of 100 cm  H 0 (75 mm Hg) used i n some of the u r i n e experiments i s 2  not unknown under p a t h o l o g i c a l c o n d i t i o n s . The e x t r a c e l l u l a r f l u i d volume c o n s i s t s of the i n t e r s t i t i a l f l u i d space and the plasma volume.  They are  u s u a l l y i n an e q u i l i b r i u m s t a t e according to the h y d r o s t a t i c and osmotic pressure between the compartments.  Changes i n  the volume or the composition i n one w i l l a f f e c t the o t h e r , i n general the i n t e r s t i t i a l f l u i d space i s determined by the r a t e of c a p i l l a r y f i l t r a t i o n and r e a b s o r p t i o n (Gauer, Henry and Behn, 1970).  One c a t i o n of p a r t i c u l a r importance  i s sodium, because of the unique r e n a l p r o p e r t y to handle this ion.  Reinhardt and Behrenbeck (1967) i n v e s t i g a t e d  the e f f e c t of a l t e r e d sodium i n t a k e on the e x t r a c e l l u l a r f l u i d volume i n c h r o n i c dog experiments.  With h i g h s a l t  i n t a k e (1.7 to 14- mEq/kg per day) s a l t was r e t a i n e d and the e x t r a c e l l u l a r f l u i d volume went up.  A new e q u i l i b r i u m was  reached when the e x t r a c e l l u l a r volume reached 22 percent body weight.  With a sodium-poor d i e t (0.5 mEq/kg per d a y ) ,  the e x t r a c e l l u l a r f l u i d volume went down t o 16 percent of  150 the body weight w i t h i n 4- months.  These experiments demon-  s t r a t e d the dependence of the e x t r a c e l l u l a r f l u i d volume on s a l t metabolism. Changes i n e x t r a c e l l u l a r f l u i d volume w i l l event u a l l y a f f e c t the a r t e r i a l blood pressure through changes i n c a r d i a c output i n r e l a t i o n to the general p e r i p h e r a l resistance.  With the use of systems a n a l y s i s , t h i s mechanism  i s w e l l i l l u s t r a t e d by Guyton, Coleman, Cowley, Manning, Norman and Ferguson (1974-).  Short-term a r t e r i a l b l o o d  pressure c o n t r o l i s p r i m a r i l y a nervous f u n c t i o n , the a r t e r i a l baroreceptor b u f f e r i n g c i r c u i t behaves as a " p r o p o r t i o n a l negative feed-back" c o n t r o l system w i t h f i n i t e g a i n  (Warner  and Cox, 1962; Guyton, Coleman, Cowley, Manning, Norman and Ferguson, 1974-).  The c o n t r o l system c o n s i s t s of sensors  made up of a r t e r i a l baroreceptors which send a f f e r e n t s i g n a l s t o the c e n t r a l nervous system.  The s i g n a l s  are  i n t e g r a t e d by the c e n t r a l nervous system and transformed into efferent signals nervous systems.  i n the sympathetic and parasympathetic  The nervous s i g n a l s w i l l a c t on the e f f e c t -  ors and change the c a r d i a c f u n c t i o n o r modify the p e r i p h e r a l r e s i s t a n c e t o counteract the d i s t u r b a n c e .  The systemic  a r t e r i a l pressure w i l l be brought q u i c k l y back, c l o s e t o the r e f e r e n c e set p o i n t .  Because of the nature of the p r o p o r -  t i o n a l c o n t r o l system the a r t e r i a l pressure w i l l never go back t o the exact r e f e r e n c e set p o i n t unless the d i s t u r b ance i s removed.  The long-range l e v e l of a r t e r i a l blood  pressure can be increased or decreased as a r e s u l t of changes  151 i n three p o s s i b l e f a c t o r s : (a) the r a t e of f l u i d i n t a k e , (b) the a b i l i t y of the kidney t o excrete f l u i d , and (c) the r a t e of f l u i d l o s s by normal mechanisms (Ledingham, 1971). The kidneys a c t as a servo c o n t r o l l e r of the long-range l e v e l of a r t e r i a l blood p r e s s u r e .  They operate through  the f l u i d balance system (Coleman and Guyton, 1969) l i k e an " i n t e g r a l negative feed-back" c o n t r o l system w i t h i n f i n i t e g a i n (Guyton and Coleman, 1969; Guyton, Coleman, Cowley, Manning, Norman and Ferguson, 1974).  The sensors  of the system are mostly the low-pressure r e c e p t o r s i n the c a r d i o v a s c u l a r system.  A f f e r e n t s i g n a l s are a l s o sent to  the c e n t r a l nervous system t o be i n t e g r a t e d .  However, the  f i n a l output from the i n t e g r a t o r can be nervous s i g n a l s or a change i n the c i r c u l a t i n g l e v e l of some hormone.  They  a c t on the kidneys (the e f f e c t o r s ) to modify the r e n a l function.  The k i d n e y ' s a b i l i t y to c o n t r o l body f l u i d  e x c r e t i o n makes i t p o s s i b l e t o a t t a i n i n f i n i t e g a i n i n the c o n t r o l system thus e n a b l i n g i t to b r i n g the a r t e r i a l p r e s sure back e x a c t l y t o the r e f e r e n c e set p o i n t .  Many of the  a r t e r i a l blood pressure c o n t r o l systems known to a f f e c t a r t e r i a l blood pressure a c u t e l y , such as the a r t e r i a l b a r o r e c e p t o r c o n t r o l system, and the r e n i n - a n g i o t e n s i n system, a l s o have d i r e c t or i n d i r e c t e f f e c t on d i f f e r e n t aspects of the f l u i d balance system (Conway, 1966).  In some cases,  the two types of systems may have the same sensors, and the c l a s s i f i c a t i o n i s not a c l e a r cut matter.  I t i s the c o n -  t r i b u t i o n s of both the l o n g - and short-term c o n t r o l systems  152 on f l u i d balance through the kidneys t h a t a r t e r i a l pressure i s precisely regulated. Consider an i n c r e a s e d body f l u i d volume, such a s , shortly after f l u i d ingestion.  The expanded volume w i l l  b r i n g the e x t r a c e l l u l a r f l u i d volume i n t o a new e q u i l i b r i u m s t a t e , w i t h the i n t r a c e l l u l a r f l u i d volume, a c c o r d i n g to the o s m o l a r i t y of the ingested f l u i d .  E v e n t u a l l y the plasma  and i n t r a t h o r a c i c volume w i l l a l s o be i n c r e a s e d , and the a t r i a l and pulmonary a r t e r i a l pressures are expected t o r i s e . Consequently, an i n c r e a s e d c a r d i a c output and a r t e r i a l blood pressure f o l l o w .  There are s e v e r a l f r o n t s of defence i n the  body t o c o r r e c t the body f l u i d and a r t e r i a l pressure back t o normal.  The a r t e r i a l baroreceptors are the most f a s t a c t i n g  s h o r t - t e r m c o n t r o l mechanism a v a i l a b l e , i t w i l l b r i n g the a r t e r i a l pressure back very c l o s e to the r e f e r e n c e set p o i n t w i t h i n seconds v i a a neuro r e f l e x t o p r o t e c t the v i t a l organs. kidneys.  The long-term c o n t r o l systems a l l i n v o l v e the The osmolar receptors and the a t r i a l r e c e p t o r s  work v i a the r e g u l a t i o n of ADH.  When the plasma o s m o l a r i t y  decreases, the r e l e a s e of ADH i s i n h i b i t e d , and more water w i l l be e x c r e t e d .  An i n c r e a s e d a t r i a l pressure e x c i t e s the  a t r i a l r e c e p t o r s , which a l s o i n h i b i t s the r e l e a s e of ADH, and water d i u r e s i s r e s u l t s ( d e t a i l discussed e a r l i e r ) , t o r e s t o r e the body f l u i d volume t o normal.  As we have reviewed  e a r l i e r , maneuvers t o increase the i n t r a t h o r a c i c blood volume such as s a l i n e i n f u s i o n , water immersion or posture  change  from o r t h o s t a s i s t o a supine p o s i t i o n are connected w i t h  153 water d i u r e s i s plus n a t r i u r e s i s .  Present knowledge on ADH  c o n t r o l can only e x p l a i n the water d i u r e s i s phenomenon, we b e l i e v e t h a t r e s u l t s from the pulmonary a r t e r y experiments provide evidence f o r body f l u i d volume c o n t r o l through changes i n sodium e x c r e t i o n . When the pulmonary a r t e r i a l pressure i s e l e v a t e d , as the r e s u l t of an increased i n t r a t h o r a c i c b l o o d volume the systemic v a s c u l a r r e s i s t a n c e i s expected t o i n c r e a s e , as a r e s u l t of the pulmonary a r t e r i a l d i s t e n s i o n .  This  will  act t o magnify the e f f e c t of changes i n blood volume on b l o o d pressure not o n l y by an i n c r e a s e i n the c a r d i a c output but a l s o by m a i n t a i n i n g systemic v a s c u l a r r e s i s t a n c e .  The  hemodynamic changes brought about by the i n c r e a s e d a r t e r i a l pressure w i l l i n c r e a s e the sodium e x c r e t i o n r a t e and u r i n e f l o w of the k i d n e y s .  The u r i n e c o n t r o l system would f u n c -  t i o n , more e f f i c i e n t l y w i t h the i n c r e a s e d systemic a r t e r i a l pressure t o b r i n g the blood volume back to e q u i l i b r i u m faster.  As has been shown, when i n d i v i d u a l c a r d i o v a s c u l a r  beds were examined i t was found t h a t the r e n a l r e s i s t a n c e was not a f f e c t e d by pulmonary a r t e r y d i s t e n s i o n , but f o r the same d i s t e n d i n g p r e s s u r e , the h i n d - l i m b r e s i s t a n c e always i n c r e a s e d more than the general p e r i p h e r a l r e s i s t a n c e .  This  means t h a t f o r the same c a r d i a c output the r e s i s t a n c e changes would i n e f f e c t r e d i r e c t p a r t of the blood f l o w away from the h i n d - l i m b s i n f a v o r of the k i d n e y s , thus f u r t h e r i n c r e a s i n g the r e n a l sodium e x c r e t i o n r a t e .  154-  Renal e f f e c t s of pulmonary a r t e r y d i s t e n s i o n have been c l e a r l y demonstrated by the u r i n e c o l l e c t i o n experiments. There i s some evidence t h a t p a r t of the r e f l e x changes may be mediated by a yet unknown n a t r i u r e t i c hormone.  Since  no r e f l e x changes i n f r e e water clearance were observed i n the same experiments we must c o n s i d e r the i d e a of separate c o n t r o l systems f o r water and sodium e x c r e t i o n i n the i n t r a t h o r a c i c a r e a ; a t r i a l r e c e p t o r s a f f e c t i n g f r e e water c l e a r ance and the pulmonary a r t e r i a l baroreceptors a f f e c t i n g sodium e x c r e t i o n .  155 SUMMARY 1.  Evidence i s presented f o r the e x i s t e n c e of pulmonarya r t e r i a l baroreceptors.  2.  A p r e p a r a t i o n i s d e s c r i b e d u t i l i z i n g a constant f l o w , r i g h t h e a r t bypass which allowed p e r f u s i o n of an i s o l a t e d pouch of the pulmonary a r t e r i e s a t c o n t r o l l e d pressure.  3.  D i s t e n s i o n of an i s o l a t e d pulmonary a r t e r i a l pouch was a s s o c i a t e d w i t h an increase i n systemic v a s c u l a r resistance.  A marked i n c r e a s e i n v a s c u l a r r e s i s t a n c e  was demonstrated i n the perfused h i n d - l i m b s but no changes were observed i n a perfused i n n e r v a t e d k i d n e y . The changes i n v a s c u l a r r e s i s t a n c e were s t a t i s t i c a l l y s i g n i f i c a n t at a p h y s i o l o g i c a l range of pulmonary a r t erial 4-.  pressures.  D i s t e n s i o n of an i s o l a t e d pulmonary a r t e r i a l pouch was a l s o a s s o c i a t e d w i t h an increase i n u r i n a r y sodium e x c r e t i o n d u r i n g pouch d i s t e n s i o n .  C o n t i n u a t i o n of the  i n c r e a s e d sodium e x c r e t i o n a f t e r removal of the pouch d i s t e n s i o n suggested the p o s s i b i l i t y of r e l e a s e of a circulating "natriuretic factor". 5.  Experiments u s i n g animals w i t h one i n t a c t kidney and one kidney perfused and t o t a l l y i s o l a t e d , confirmed an i n c r e a s e i n sodium e x c r e t i o n from the i n t a c t kidney w i t h pulmonary a r t e r i a l d i s t e n s i o n but d i d not provide  156 support f o r the concept of a c i r c u l a t i n g " n a t r i u r e t i c factor". A p o s s i b l e p h y s i o l o g i c a l r o l e f o r the c a r d i o v a s c u l a r and r e n a l changes observed d u r i n g pulmonary a r t e r i a l d i s t e n sion i s discussed.  The l o c a t i o n of the pulmonary a r t -  e r i a l baroreceptors w i t h i n the h i g h l y d i s t e n s i b l e "low p r e s s u r e " system means t h a t the discharge from the r e c e p t o r s i s a f f e c t e d by changes i n c i r c u l a t i n g blood volume and i t s d i s t r i b u t i o n .  The hypothesis t h a t an  i n c r e a s e d discharge from pulmonary a r t e r i a l baroreceptors causes c i r c u l a t o r y : readjustments which r e s u l t i n an i n c r e a s e i n sodium e x c r e t i o n and thus promote the approp r i a t e m o d i f i c a t i o n of blood volume i s an a t t r a c t i v e one.  However, a p h y s i o l o g i c a l r o l e f o r the r e f l e x  responses d e s c r i b e d can not y e t be claimed on the b a s i s of t h i s work.  157 REFERENCES A n g e l l James, J . E . (1971)• The responses of a o r t i c a r c h and r i g h t s u b c l a v i a n baroreceptors to changes of n o n - p u l s a t i l e pressure and t h e i r m o d i f i c a t i o n byhypothermia. J . P h y s i o l . 214: 201-225. A r b o r e l i u s , M. , J R . , B a l l d i n , U.I., L i l j a , B. and Lundgren, C.E.G. (1972). Hemodynamic changes i n man d u r i n g immersion w i t h the head above w z t e r . Aerospace Med. 43: 592-598. 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