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Gastric electrical activity : the effects of vagal section and vagal stimulation 1973

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GASTRIC ELECTRICAL ACTIVITY: THE EFFECTS OF VAGAL SECTION AND VAGAL STIMULATION by MORTON LAWRENCE DORAN M.D., U n i v e r s i t y of Toronto, 1964 A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of Surgery We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard The U n i v e r s i t y of B r i t i s h Columbia A p r i l , 1973 In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t of the requirements f o r an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be granted by the Head of my Depart- ment or by h i s r e p r e s e n t a t i v e s . I t i s understood th a t copying or p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be allowed without my w r i t t e n permission. Department of snrgpry The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada ABSTRACT The c u r r e n t enthusiasm f o r vagotomy as treatment f o r p e p t i c u l c e r d i s e a s e has been dampened by s e v e r a l problems, the most s e r i o u s of which i s r e c u r r e n t u l c e r a t i o n . As t h i s i s due i n most i n s t a n c e s t o incomplete v a g a l s e c t i o n , i t i s c l e a r t h a t the development of a r e l i a b l e method to assess completeness of vagotomy d u r i n g the course of surgery i s an e s s e n t i a l step toward r e d u c i n g the 10-15% i n c i d e n c e of r e c u r r e n t u l c e r . The problem has been approached by s t u d y i n g some of the g a s t r i c e f f e c t s of v a g a l s t i m u l a t i o n d u r i n g o p e r a t i o n . These i n c l u d e changes i n i n t r a g a s t r i c p r e s s u r e , a c i d s e c r e t i o n , and e l e c t r i c a l a c t i v i t y . The i n v e s t i g a t i o n as o u t l i n e d i n t h i s t h e s i s was aimed at de v e l o p i n g a r e l i a b l e , r e p r o d u c i b l e i n t r a - o p e r a t i v e method f o r a s s e s s i n g the completeness of vagotomy. The p l a n o f the experiment was e s s e n t i a l l y twofolds ( i ) t o determine whether complete vagotomy would a l t e r the g a s t r i c e l e c t r i c a l a c t i v i t y i n some r e p r o d u c i b l e manner such as would i n d i c a t e t h a t a l l v a g a l connec- t i o n s had been severed; ( i i ) t o d i v i d e one vagus nerve at the l e v e l of the eso- phageal h i a t u s , assess the e f f e c t on e l e c t r i c a l a c t i v i t y of s t i m u l a t i o n of i t s d i s t a l or p e r i p h e r a l end, and then s t i m u l a t e the c e n t r a l end with view t o e l i c i t i n g a response i n the e l e c t r i c a l a c t i v i t y v i a r e f l e x pathways through the brainstem, v a g a l n u c l e i , and along the remaining i n t a c t e f f e r e n t v a g a l f i b r e s these remaining f i b r e s would then be d i v i d e d , c e n t r a l s t i m u l a t i o n of e i t h e r v a g a l trunk repeated, and presumably the p r e v i o u s l y observed " c h a r a c t e r - i s t i c " response of the g a s t r i c e l e c t r i c a l a c t i v i t y would no l o n g e r be obtained, i n d i c a t i n g complete d i v i s i o n of a l l v a g a l f i b r e s , Vago-vagal r e f l e x responses to a f f e r e n t v a g a l s t i m u l a t i o n have been documented with r e s p e c t to i n f l u e n c e on both g a s t r i c tone and s e c r e t i o n . One may reasonably expect to be able to demonstrate the e x i s t e n c e of a vago-vagal r e f l e x pathway where by one might a l t e r g a s t r i c e l e c t r i c a l a c t i v i t y by c e n t r a l or r e f l e x s t i m u l a t i o n of the a f f e r e n t v a g a l f i b r e s . G a s t r i c e l e c t r i c a l a c t i v i t y has been recorded, and the e f f e c t s of v a g a l s e c t i o n on t h i s e l e c t r i c a l a c t i v i t y have been ass e s s e d . The r e d u c t i o n i n the frequency of the b a s i c e l e c - t r i c a l rhythm (BER) observed f o l l o w i n g complete vagotomy, though of s i g n i f i c a n c e s t a t i s t i c a l l y , was found t o be caused as w e l l by o t h e r n o n - r e l a t e d f a c t o r s , and was i n any case of such a low o r d e r as to be of l i m i t e d v alue i n a s s e s s i n g any i n d i v i d u a l case. I t c o u l d t h e r e f o r e not be c o n s i d e r e d i n d i c a - t i v e of complete v a g a l s e c t i o n . The d i s o r g a n i z a t i o n of the BER observed f o l l o w i n g vagotomy was both temporary and i n c o n - s i s t e n t , and c o u l d not be i n t e r p r e t e d as pathognomonic of complete vagotomy. The observations recorded d u r i n g e l e c t r i c a l s t i m u l a t i o n of a f f e r e n t v a g a l f i b r e s have demonstrated the e x i s t e n c e of a i v vago-vagal r e f l e x pathway whereby g a s t r i c e l e c t r i c a l and motor a c t i v i t y can be modified by a f f e r e n t vagal s t i m u l a t i o n . These e f f e c t s are presumably conveyed v i a pathways through the c e n t r a l nervous system and along the i n t a c t e f f e r e n t vagal f i b r e s . The e f f e c t s on g a s t r i c e l e c t r i c a l a c t i v i t y are n e i t h e r c o n s i s t e n t nor r e p r o d u c i b l e , whereas the e f f e c t s on g a s t r i c motor a c t i v i t y appear to be cons i d e r a b l y more r e l i a b l e . In the l i g h t of these observations, i t would seem more appropriate t o study the changes i n the c o n t r a c t i l e f o r c e of g a s t r o i n t e s t i n a l smooth muscle sub- sequent t o a f f e r e n t vagal s t i m u l a t i o n i n the search f o r a method to assess completeness of vagotomy during the course of surgery. The development of such a t e s t w i l l be a major f a c t o r i n pre- v e n t i n g t h i s form of treatment from f a l l i n g i n t o d i s r e p u t e because of a continued high r a t e of re c u r r e n t u l c e r a t i o n . TABLE OF CONTENTS Page Chapter One 1 I n t r o d u c t i o n 1 S e c t i o n I . I n t r a g a s t r i c Pressure 1 S e c t i o n I I . A c i d S e c r e t i o n 3 S e c t i o n I I I . G a s t r i c E l e c t r i c a l A c t i v i t y 7 A. H i s t o r y 8 B. E l e c t r i c a l Recording 9 C. The B a s i c E l e c t r i c a l Rhythm: I t s O r i g i n and Pro p a g a t i o n 11 D. A c t i o n P o t e n t i a l s 15 E. C o o r d i n a t i o n of G a s t r i c P e r i s t a l s i s 16 F. Pacemaker Dominance 18 G. R e l a x a t i o n O s c i l l a t o r s 19 S e c t i o n IV. F a c t o r s Which I n f l u e n c e G a s t r i c E l e c t r i c a l A c t i v i t y 24 A. I n f l u e n c e of Drugs 24 B. I n f l u e n c e of Hormones 29 C. Mechanical and Me t a b o l i c F a c t o r s 30 D. Neural I n f l u e n c e s 32 S e c t i o n V. Vagal Pathways and E f f e c t s on G a s t r i c C o n t r a c t i l e A c t i v i t y 35 A. G a s t r o i n t e s t i n a l Receptors 36 B. A f f e r e n t Nerve Pathways 38 1. Vagal A f f e r e n t s 38 2. A f f e r e n t f i b r e s a s s o c i a t e d with sympathetic e f f e r e n t s 42 C. E f f e r e n t Nerve Pathways 43 1. I n t r o d u c t i o n 43 2. Vagal e f f e r e n t s 46 3. Sympathetic e f f e r e n t pathways 56 D. C e n t r a l I n t e g r a t i o n of Autonomic Nerve Pathways 57 v i Page S e c t i o n VI. The Gastroduodenal J u n c t i o n 60 S e c t i o n V I I . The Small I n t e s t i n e 66 S e c t i o n V I I I . Human BER 68 Chapter Two Methods of I n v e s t i g a t i o n 70 1. The P l a n of the Experiment 70 2. Group I . Recording of the BER: the e f f e c t of v a g a l s e c t i o n and v a g a l s t i m u l a t i o n u s i n g sodium t h i o - p e n t a l a n a e s t h e s i a 71 3. Group I I . E f f e c t of the o p e r a t i v e procedure on BER 7^ 4. Group I I I . E f f e c t of v a g a l s t i m u l a - t i o n on BER, u s i n g c h l o r a l o s e - urethane a n a e s t h e s i a 75 5. Group IV. Conduction v e l o c i t y of the BER 76 6. Group V. E f f e c t of p e n t a g a s t r i n on BER before and a f t e r vagotomy 76 Chapter Three R e s u l t s and D i s c u s s i o n 78 1. Group I . Recording of the BER: the e f f e c t of v a g a l s e c t i o n and v a g a l s t i m u l a t i o n u s i n g sodium t h i o - p e n t a l a n a e s t h e s i a 78 2. Group I I . E f f e c t of the o p e r a t i v e procedure on BER 82 3. Group I I I . E f f e c t of v a g a l s t i m u l a - t i o n on BER, u s i n g c h l o r a l o s e - urethane a n a e s t h e s i a 82 4. Group IV. Conduction v e l o c i t y of the BER 87 5. Group V. E f f e c t of p e n t a g a s t r i n on BER before and a f t e r vagotomy 87 v i i Page Chapter Four 90 Summary and Conclusions 90 Tables 94 Figures 98 B i b l i o g r a p h y 108 LIST OF TABLES Table I B a s i c e l e c t r i c a l rhythm before and a f t e r vagotomy Table I I The e f f e c t of laparotomy and time on the BER Table I I I The e f f e c t of p e n t a g a s t r i n on the BER before and a f t e r vagotomy v i i i Page 95 96 97 i x LIST OF FIGURES Page F i g u r e 1. B a s i c e l e c t r i c a l rhythm (BER) recorded a t antrum. V a r i a t i o n s i n c o n f i g u r a t i o n of the e l e c t r i c a l p o t e n t i a l i n the r e s t i n g s t a t e . Demonstration of a s s o c i - ated a c t i o n p o t e n t i a l s . 99 F i g u r e 2. A l t e r a t i o n s i n the BER f o l l o w i n g v a g a l d i s s e c t i o n and d i v i s i o n . 100 F i g u r e 3. The e f f e c t on BER of a f f e r e n t and e f f e r e n t v a g a l s t i m u l a t i o n b e f o r e and a f t e r complete v a g a l s e c t i o n (sodium t h i o p e n t a l a n a e s t h e s i a ) . 101 F i g u r e 4. BER f o l l o w i n g complete vagotomy and esophageal t r a n s e c t i o n , 102 F i g u r e 5. The e f f e c t of d i s s e c t i o n and d i v i s i o n of the c e r v i c a l vagus nerves on the BER. 103 F i g u r e 6. The e f f e c t on BER of a f f e r e n t and e f f e r e n t v a g a l s t i m u l a t i o n b e f o r e and a f t e r complete v a g a l s e c t i o n ( c h l o r a - lose-urethane a n a e s t h e s i a ) . 104 F i g u r e 7. The e f f e c t on BER of a f f e r e n t v a g a l s t i m u l a t i o n before and a f t e r complete v a g a l s e c t i o n ( c h l o r a l o s e - u r e t h a n e a n a e s t h e s i a , s t i m u l u s i s o l a t o r ) . 105 F i g u r e 8. A. B i p o l a r r e c o r d i n g of BER, demon- s t r a t i n g conduction v e l o c i t y of the p a c e s e t t e r p o t e n t i a l before and a f t e r vagotomy. B. BER recorded w i t h h i g h a m p l i f i c a t i o n and s h o r t time c o n s t a n t . 106 F i g u r e 9. The e f f e c t on BER of a p e n t a g a s t r i n i n f u s i o n , before and a f t e r complete v a g a l s e c t i o n . 107 X ACKNOWLEDGEMENTS Many people have shown i n t e r e s t and concern i n the pre- p a r a t i o n and day-to-day work of t h i s p r o j e c t , and t h e i r con- t r i b u t i o n s have been both valuable and much appreciated. Dr. R.C, Harrison's enthusiasm and perseverance i n the search f o r a r e l i a b l e i n t r a o p e r a t i v e method to assess the complete- ness of vagotomy has been the major stimulus i n i n i t i a t i n g t h i s i n v e s t i g a t i o n . His support and encouragement throughout the course of the study, despite c r i t i c i s m from s k e p t i c s , has and w i l l continue t o ensure t h a t even though the search f o r such a t e s t has not concluded, the problem w i l l not be allowed to remain unanswered. My a p p r e c i a t i o n i s a l s o extended to Mr. Jan Van Den Broek and h i s s t a f f , who have g r e a t l y f a c i l i - t a t e d the experimental work of t h i s p r o j e c t by operating a very e f f i c i e n t , congenial animal research l a b o r a t o r y . In any i n v e s t i g a t i o n of t h i s type, there i s perhaps one person w i t h - out whom the p r o j e c t could not f u n c t i o n . I am th e r e f o r e par- t i c u l a r l y indebted t o Mr. Ken Pope f o r h i s continued help i n s o l v i n g the many t e c h n i c a l problems encountered throughout the study, i n c l u d i n g the design and maintenance of the stimu- l a t i n g and reco r d i n g equipment so indispensable to t h i s type of i n v e s t i g a t i o n . 1 CHAPTER ONE INTRODUCTION The c u r r e n t enthusiasm f o r vagotomy with an a s s o c i a t e d drainage procedure as treatment f o r p e p t i c u l c e r d i s e a s e has been dampened by s e v e r a l problems, the most s e r i o u s of which i s r e c u r r e n t u l c e r a t i o n . T h i s i s due i n most i n s t a n c e s to incomplete i n t e r r u p t i o n of the parasympathetic i n n e r v a t i o n t o the stomach. When one c o n s i d e r s t h a t the r e s u l t s obtained from p o s t - o p e r a t i v e assessment of completeness of vagotomy as measured by i n s u l i n - i n d u c e d hypoglycemia or maximum s t i m u l a t e d 70 a c i d s e c r e t i o n are o f t e n e q u i v o c a l , and t h a t these t e s t s are l i m i t e d i n value by v i r t u e of t h e i r b e i n g p o s t - o p e r a t i v e , i t i s c l e a r t h a t the development of a r e l i a b l e , r e p r o d u c i b l e method f o r determining the completeness of vagotomy d u r i n g the course of surgery i s an e s s e n t i a l step toward r e d u c i n g the 10-15% i n c i d e n c e of r e c u r r e n t u l c e r a t i o n . T h i s problem has been approached by s t u d y i n g some of the g a s t r i c responses t o v a g a l s t i m u l a t i o n d u r i n g o p e r a t i o n . These i n c l u d e changes i n i n t r a g a s t r i c p r e s s u r e , a c i d s e c r e t i o n , and e l e c t r i c a l a c t i v i t y . SECTION I . INTRAGASTRIC PRESSURE The e l e c t r i c a l s t i m u l a t i o n t e s t as d e s c r i b e d by Burge, 2-^' i n which p l a t i n u m e l e c t r o d e s a p p l i e d t o the esophagus e f f e c t v a g a l s t i m u l a t i o n , depends on e l i c i t i n g an i n c r e a s e i n i n t r a - g a s t r i c p r e s s u r e upon s t i m u l a t i o n of i n t a c t e f f e r e n t v a g a l 2 motor f i b r e s , and r e d u c t i o n of t h i s pressure when c o n t i n u i t y of these f i b r e s has been i n t e r r u p t e d . This t e s t depends on the premise t h a t s t i m u l a t i o n of e f f e r e n t vagal motor f i b r e s to the stomach causes an increase i n i n t r a g a s t r i c pressure. Notwithstanding the f a c t that t h i s method i s cumbersome i n i t s a p p l i c a t i o n , the premise upon which i t i s based i s at variance w i t h the observations of Harper, ' who noted a decrease i n i n t r a g a s t r i c pressure subsequent to s t i m u l a t i o n of vagal e f f e r e n t s . In both i n s t a n c e s , the observations were i n i t i a l l y recorded i n c a t s , using s i m i l a r but not i d e n t i c a l e l e c t r i c a l s t i m u l a t i o n c h a r a c t e r i s t i c s of v o l t a g e , impulse d u r a t i o n , and impulse frequency. The discrepancy i n these observations may be accounted f o r i n p a r t by Martinson's s e r i e s of i n v e s t i g a - t i o n s ^ ' ^ " 8 5 which have demonstrated i n cats the existence of both e x c i t a t o r y and i n h i b i t o r y v a g al e f f e r e n t s , d i f f e r e n - t i a t e d by graded vagal s t i m u l a t i o n ? "low t h r e s h o l d " e x c i t a t o r y f i b r e s responding to short d u r a t i o n impulses, causing increased tone and c o n t r a c t i l i t y , and "high t h r e s h o l d " i n h i b i t o r y f i b r e s responding to longer d u r a t i o n impulses, causing a decrease i n i n t r a l u m i n a l pressure and r e d u c t i o n i n c o n t r a c t i l e f o r c e pre- dominantly i n the corpus and fundus, but not i n the antrum. The p o i n t to be made here i s t h a t the r e s u l t s may d i f f e r , depending on the stimulus parameters and at what l o c a t i o n i n t r a g a s t r i c pressure i s measured. These f a c t o r s would tend to lend somewhat l e s s credence to the v a l i d i t y and r e l i a b i l i t y of the e l e c t r i c a l s t i m u l a t i o n t e s t as described by Burge. 3 The d e t e r m i n a t i o n of the e f f e c t of e f f e r e n t motor nerve s t i m u l a t i o n may a l s o he i n f l u e n c e d by the f a c t t h a t most of the v a g a l f i b r e s a t the l e v e l of the diaphragm are a f f e r e n t f i b r e s , and t h a t the r e l a t i v e l y few e f f e r e n t f i b r e s which are s t i m u l a t e d , though having an e f f e c t on smooth muscle tonus, may i n f a c t have l i t t l e or no e f f e c t on s e c r e t i o n . I n v e s t i g a t i o n i n c a t s 1 has demonstrated t h a t a t the diaphragmatic l e v e l , 90% of the 31f000 v a g a l f i b r e s are s m a l l , myelinated a f f e r e n t f i b r e s , 2-4 u i n diameter. The remaining 10% of f i b r e s are l a r g e r diameter e f f e r e n t s w i t h t h e i r c e l l bodies i n the c e n t r a l nervous system; these e f f e r e n t f i b r e s synapse d i r e c t l y with neurones of the myenteric p l e x u s e s . Hence th e r e i s an enormous d i s c r e p a n c y between the number of nerve c e l l s i n the myenteric pl e x u s e s (20-30 m i l l i o n ) and the 3,000 v a g a l e f f e r e n t f i b r e s . S i m i l a r s t u d i e s i n r a b b i t s - ^ r e v e a l a comparably low percentage of v a g a l f i b r e s a t the diaphragmatic l e v e l which are e f f e r e n t motor i n f u n c t i o n . SECTION I I . ACID SECRETION A second approach t o t h i s problem e n t a i l s i n t r a o p e r a t i v e pH mapping of the g a s t r i c mucosa, and a s s e s s i n g completeness of vagotomy by demonstrating a l k a l i n i t y of the e n t i r e p a r i e t a l c e l l mass. T h i s method has m e r i t i n t h a t i t can a c c u r a t e l y i n d i c a t e complete d e n e r v a t i o n of the p a r i e t a l c e l l s . However, i t d e a l s with only one of the two major mechanisms of v a g a l i n f l u e n c e on g a s t r i c s e c r e t i o n , s p e c i f i c a l l y the v a g a l e x c i t a t i o n of the p a r i e t a l c e l l mass. I t does not i n d i c a t e vagal denervation of the antrum, and t h e r e f o r e does not r u l e out the p o s s i b l e 27 delayed r e l e a s e of a n t r a l g a s t r i n . G r i f f i t h and h i s colleagues have c l e a r l y demonstrated the concept of segmental i n n e r v a t i o n of the stomach by combining e l e c t r i c a l s t i m u l a t i o n and n e u t r a l red dye to v i s u a l i z e the extent of g a s t r i c s e c r e t i o n . ^ 9 They have demonstrated a p r o g r e s s i v e l y decreasing overlap of i n n e r v a t i o n as one stimu- l a t e s v a gal f i b r e s s u c c e s s i v e l y from the l e v e l of the esophageal plexus to t h a t of the t e r m i n a l g a s t r i c branches. G r i f f i t h has demonstrated t h a t s t i m u l a t i o n of one vagal f i b r e cannot i n f l u - ence the e n t i r e g a s t r i c mucosa v i a connections w i t h i n Meissner's submucosal plexus, but t h a t s t i m u l a t i o n of any f i b r e which i n n e r - vates the antrum can, by way of a n t r a l r e l e a s e of g a s t r i n , cause a delayed, g e n e r a l i z e d s e c r e t i o n of the p a r i e t a l c e l l mucosa. Even though a v a g a l l y denervated p a r i e t a l c e l l mass would be l e s s responsive t o endogenous g a s t r i n , w i t h reduced a c i d s e c r e t i o n , pH mapping would not n e c e s s a r i l y i n d i c a t e t h a t the antrum had been denervated. F a i l u r e to achieve r e d u c t i o n i n b a s a l a c i d output a f t e r a s e l e c t i v e vagotomy may be due to vagal i n n e r v a t i o n v i a the undisturbed hepatic branch of the a n t e r i o r v a g a l trunk, w i t h f i b r e s reaching the antrum along the course of the r i g h t g a s t r i c a r t e r y . A l t e r n a t i v e l y , i n n e r v a t i o n may occur v i a parasympathetic f i b r e s emerging wi t h t h o r a c i c d o r s a l s p i n a l r o o t s . Hypersecretion f o l l o w i n g s e l e c t i v e vago- tomy may be a t t r i b u t e d to t h i s c i r c u i t o u s a n t r a l i n n e r v a t i o n w i t h the subsequent delayed a n t r a l r e l e a s e of g a s t r i n ; the 5 delayed e f f e c t of t h i s g a s t r i n on the p a r i e t a l c e l l s may not be detected by i n t r a o p e r a t i v e pH mapping. There are other f a c t o r s to be considered i n pH mapping of the g a s t r i c mucosa. The a c i d - a l k a l i n e j u n c t i o n i s not always a p r e c i s e l y defined zone of t r a n s i t i o n , but may i n f a c t extend across a distance of one centimetre. The antrum may not be u niformly a l k a l i n e , rendering i t d i f f i c u l t f o r the pH assay to a c c u r a t e l y demarcate the extent of a n t r a l mucosa. There i s an i nverse r e l a t i o n s h i p between the s i z e of the antrum and that of the p a r i e t a l c e l l mass; a small antrum i s u s u a l l y t o be found i n a p a t i e n t w i t h an uncomplicated duodenal u l c e r and high a c i d p r o d u c t i o n , as compared w i t h a l a r g e a l k a l i n e area i n a p a t i e n t w i t h e i t h e r a g a s t r i c u l c e r or a duodenal u l c e r 27 complicated by p y l o r i c o b s t r u c t i o n . Incomplete denervation of the antrum (or incomplete removal of a n t r a l mucosa during gastrectomy) w i l l t h e r e f o r e r e s u l t i n continued g a s t r i n pro- d u c t i o n , w i t h the r i s k of r e c u r r e n t u l c e r a t i o n . This f a c t o r w i l l be of g r e a t e r s i g n i f i c a n c e i n p a t i e n t s w i t h duodenal u l c e r than i n those w i t h an uncomplicated g a s t r i c u l c e r , as the l a t t e r have l e s s g a s t r i n production and g e n e r a l l y a s m a l l , a trophied p a r i e t a l c e l l mass. The concept of segmental i n n e r v a t i o n may account f o r the a n a t o m i c a l l y incomplete but "adequate" vagotomy.^ A s m a l l , delayed response to i n s u l i n hypoglycemia, though i n d i c a t i n g a t e c h n i c a l l y incomplete vagotomy, may i n f a c t be due to an i n - t a c t t e r m i n a l g a s t r i c branch to the fundus, w i t h minimal r i s k 6 of r e c u r r e n t u l c e r a t i o n . On the oth e r hand, a pronounced, e a r l y response t o i n s u l i n hypoglycemia would i n d i c a t e an i n - complete vagotomy wi t h inadequate p r o t e c t i o n a g a i n s t r e c u r r e n t u l c e r a t i o n . N o twithstanding the c r i t i c i s m l e v i e d a g a i n s t the pH mapping technique i n a s s e s s i n g the completeness of vagotomy, t h i s t o o l can be of s i g n i f i c a n t v a l u e i n upgrading the s u r g i c a l treatment of p e p t i c u l c e r d i s e a s e , and much can be s a i d i n i t s defence. C l i n i c a l s t u d i e s suggest there i s a hig h i n c i d e n c e of incomplete antrectomy i n p a t i e n t s who develop r e c u r r e n t u l c e r a - 4. t i o n f o l l o w i n g gastrectomy with or without a s s o c i a t e d vagotomy. T h i s group of p a t i e n t s shows a p e r s i s t e n t e l e v a t i o n of a c i d s e c r e t i o n which may be due e i t h e r t o an incomplete vagotomy, or t o r e s i d u a l a n t r a l t i s s u e with continued g a s t r i n p r o d u c t i o n . Drs. R.C. H a r r i s o n and J.L. S t o l l e r , i n the Department of Sur- gery a t the Vancouver General H o s p i t a l , have e v a l u a t e d the e f f e c t s on a c i d s e c r e t i o n (from Heidenhain pouches i n dogs) t h a t have r e s u l t e d from the d e l i b e r a t e performance of an i n - complete antrectomy a s s o c i a t e d w i t h vagotomy. T h e i r r e s u l t s i n d i c a t e t h a t even a s m a l l p o r t i o n of r e s i d u a l antrum l e f t i n s i t u s i g n i f i c a n t l y a l t e r s the s e c r e t i o n from such a p r e p a r a t i o n , and suggest t h a t i f antrectomy i s t o be performed i n a s s o c i a - t i o n w i t h vagotomy, i t must be complete. In order t o f a c i l i t a t e demarcation of the pr o x i m a l extent of the antrum, they have de- v i s e d a method whereby f o l l o w i n g m i l d histamine s t i m u l a t i o n , the a c i d - a l k a l i n e j u n c t i o n can be i d e n t i f i e d - b y means of a 7 wandering pH s e n s i t i v e e l e c t r o d e i n t r o d u c e d p e r o r a l l y i n t o the stomach. Best r e s u l t s are l i k e l y t o be obtained i n duodenal u l c e r p a t i e n t s w i t h a c t i v e p a r i e t a l c e l l a c t i v i t y , though the a l k a l i n e a r e a i n g a s t r i c u l c e r p a t i e n t s with low a c i d s e c r e t i o n can be adequately mapped as w e l l . In i n t e r p r e t a t i o n of these r e s u l t s , one must r e c o g n i z e t h a t the terms " a l k a l i n e area" and "antrum" are not n e c e s s a r i l y synonymous. Though "antrum" i s intended to designate the g a s t r i n p r o d u c i n g area of the stomach, the a l k a l i n e a r e a i n a p a t i e n t w i t h s i g n i f i c a n t g a s t r i t i s may w e l l have extended i n t o an area p r e v i o u s l y occupied by a c t i v e p a r i e t a l c e l l s . T h i s newly e s t a b l i s h e d a l k a l i n e a r e a p r e - sumably does not produce g a s t r i n . Coupled with the o b s e r v a t i o n t h a t the antrum i s not n e c e s s a r i l y u n i f o r m l y a l k a l i n e , the pH assay may not always i n d i c a t e p r e c i s e l y how much stomach to r e s e c t i n o r d e r to ensure the complete removal of a l l a n t r a l t i s s u e (and thus remove the source of g a s t r i n ) , without extending the r e s e c t i o n too f a r p r o x i m a l l y . Moreover, the pH assay can- not s o l v e the problem which may a r i s e from g a s t r i n r e l e a s e from more d i s t a l s i t e s i n the i n t e s t i n a l t r a c t , though the s i g n i f i - cance of t h i s s m a l l amount of g a s t r i n as a cause of p e r s i s t e n t h y p e r s e c r e t i o n i s as y e t undetermined. SECTION I I I . GASTRIC ELECTRICAL ACTIVITY A t h i r d approach t o the problem of d e v e l o p i n g an i n t r a - o p e r a t i v e t e s t t o assess completeness of vagotomy has been to study the e l e c t r i c a l a c t i v i t y of the stomach; more s p e c i f i c a l l y , 8 to study changes i n e l e c t r i c a l a c t i v i t y "before and a f t e r vago- tomy, and the e f f e c t of both a f f e r e n t ( r e f l e x ) and e f f e r e n t v a g a l s t i m u l a t i o n on t h i s e l e c t r i c a l a c t i v i t y , A. H i s t o r y S e v e r a l i n v e s t i g a t i o n s serve as landmarks of h i s t o r i c a l i n t e r e s t i n the development of t h i s approach. The o r i g i n and c o n t r o l of g a s t r i c p e r i s t a l s i s has been s t u d i e d by v a r i o u s t e c h - n i q u e s , i n c l u d i n g d i r e c t v i s u a l i z a t i o n of the stomach, i n t r a - g a s t r i c p r e s s u r e r e c o r d i n g , and v i s u a l i z a t i o n by means of c o n t r a s t media and f l u o r o s c o p y . With the development of the concept of the c a r d i a c pacemaker, the stomach was examined f o r the presence of a s i m i l a r mechanism. E a r l y i n v e s t i g a t i o n sug- gested t h a t pacemaker-like t i s s u e i n the l e s s e r curve g a n g l i a , i n neuromuscular t i s s u e at the gastroesophageal j u n c t i o n , or i n the w e l l - d e v e l o p e d l e s s e r curve myenteric p l e x u s may be r e s - p o n s i b l e f o r c o o r d i n a t i n g g a s t r i c p e r i s t a l s i s . In 1922, Alvarez-^ d e s c r i b e d a slow, rhythmic e l e c t r i c a l a c t i v i t y o c c u r r i n g i n g a s t r i c muscle. These " a c t i o n c u r r e n t s " were reco r d e d con- s t a n t l y i n the g a s t r o i n t e s t i n a l t r a c t , even i n the absence of obvious c o n t r a c t i l e a c t i v i t y . ' J Using i s o l a t e d muscle s t r i p s from v a r i o u s areas of the stomach, he demonstrated t h a t the f r e - quency of the rhythmic a c t i v i t y was h i g h e s t i n the p r o x i m a l stomach, and lowest i n the d i s t a l stomach. He suggested t h a t h. a pacemaker was p r e s e n t i n the r e g i o n of the c a r d i a , and t h a t these e l e c t r i c a l c u r r e n t s were propagated a b o r a l l y along the stomach. A l v a r e z suggested t h a t these s p r e a d i n g c u r r e n t s may 9 coordinate mechanical and chemical f u n c t i o n s of the stomach which had p r e v i o u s l y been a t t r i b u t e d t o hormones and n e u r a l pathways. On the b a s i s of these observations, A l v a r e z i n t r o - duced the "electroenterogram" to the study of g a s t r o i n t e s t i n a l m o t i l i t y and i t s e l e c t r i c a l counterpart. Though he was not able t o d i f f e r e n t i a t e between what are now termed the b a s i c e l e c t r i c a l rhythm and a c t i o n p o t e n t i a l s , he nevertheless i n t r o - duced one more parameter of study t o t h i s f i e l d of i n v e s t i g a t i o n . B. E l e c t r i c a l Recording The concepts of m o t i l i t y should be based on the measure- 14 ment of v a r i a b l e s which c o n t r i b u t e to c o n t r a c t i l i t y . A c t i v a - t i o n of muscle f i b r e s i s accompanied by e l e c t r i c a l charges across the surface of t h e i r membranes and i n the surrounding e x t r a c e l l u l a r f l u i d . These i n v i v o b i o e l e c t r i c a l phenomena, as portrayed i n the enterogram, can supplement data obtained from manometry, r a d i o l o g y , and other standard methods of e v a l u - a t i o n of m o t i l i t y . There are three types of b i o e l e c t r i c phenomena which occur i n the GI t r a c t . They may be c l a s s i f i e d according t o the method of r e c o r d i n g : ( i ) transmembrane p o t e n t i a l s , which are voltage changes across a s i n g l e c e l l membrane of an i s o l a t e d t i s s u e ; t h i s type of p o t e n t i a l would be d e t e c t a b l e , f o r ex- ample, by i n s e r t i n g a microelectrode i n t o a s i n g l e smooth muscle c e l l ; p o t e n t i a l s from s p e c i f i c muscle l a y e r s may be recorded i n t h i s f a s h i o n ; 10 ( i i ) transmucosal p o t e n t i a l s , i n d i c a t i n g voltage change across a mucosal surf a c e ; ( i i i ) surface or e x t r a c e l l u l a r p o t e n t i a l s , which c o n s i s t of voltage changes across t i s s u e surfaces or e x t r a - c e l l u l a r f l u i d as recorded by e x t e r n a l l y a p p l i e d e l e c t r o d e s ; surface e l e c t r o d e s r e g i s t e r the mean of p o t e n t i a l s generated by many c e l l s exposed to the re c o r d i n g t i p . The electroenterogram described by Alvarez i s an example of surface p o t e n t i a l r e c o r d i n g , as are the ECG and EEG. E x t r a c e l l u l a r r e c o r d i n g e n t a i l s the use of e x t e r n a l e l e c - trodes which serve as connectors between a designated r e g i o n of b i o l o g i c a l t i s s u e and an a m p l i f y i n g and r e c o r d i n g device. To record i n a monopolar f a s h i o n , one ele c t r o d e i s placed i n con- t a c t w i t h the t i s s u e under i n v e s t i g a t i o n , and a reference e l e c - trode i s placed i n an area of low e l e c t r i c a l a c t i v i t y . Though other b i o l o g i c a l generators may l i e i n the path of the voltage being measured, and may thus c o n t r i b u t e to the p o t e n t i a l d i f f e r ' ence recorded, these unwanted p o t e n t i a l s are u s u a l l y randomly o r i e n t a t e d , and tend t o cancel each other out. The c o n f i g u r a - t i o n of the p o t e n t i a l recorded i s i n f l u e n c e d by many p h y s i c a l 14 20 f a c t o r s ; ' i n c l u d e d among the f a c t o r s t o be considered are the amount of pressure exerted by the e l e c t r o d e , the degree of p e n e t r a t i o n of the ele c t r o d e i n t o the t i s s u e , the s i z e of the rec o r d i n g t i p , the amount of e l e c t r o l y t e between the electro d e and the a c t i v e t i s s u e , the development of connective t i s s u e 11 beneath the el e c t r o d e during the course of long-term r e c o r d i n g , the propagation of the p o t e n t i a l s , and the s i n k r e l a t i o n s v i a low- r e s i s t a n c e pathways to d i s t a n t s o u r c e s . 1 0 0 Surface recordings of e l e c t r i c a l p o t e n t i a l from the gastro- i n t e s t i n a l t r a c t of i n t a c t animals have s e v e r a l d i s t i n c t advan- t a g e s , 1 2 ' ^ 1 0 0 ( i ) the p r e p a r a t i o n i s p h y s i o l o g i c a l ; ( i i ) m u l t i p l e t e s t s may be c a r r i e d out i n the same animal under v a r i a b l e c o n d i t i o n s , or over a pro- longed p e r i o d ; ( i i i ) many areas of the GI t r a c t can be explored s i m u l - taneously i n the same p r e p a r a t i o n ; ( i v ) a c t i v i t y can be recorded from a l o c a l i z e d area; (v) the r e c o r d i n g u n i t does not obstruct the bowel lumen, and does not act as an abnormal stimulus to mucosal r e f l e x e s ; ( v i ) the e l e c t r i c a l event i s a more s e n s i t i v e parameter than i s i n t r a l u m i n a l pressure f o r monitoring motor a c t i v i t y . C. The Basi c E l e c t r i c a l Rhythm; I t s O r i g i n and Propagation Research over the years has more a c c u r a t e l y defined the e l e c t r i c a l a c t i v i t y of the stomach as comprising two types of 4 T p o t e n t i a l v a r i a t i o n . J The r e p e t i t i v e " a c t i o n c u r r e n t s " r e - corded by A l v a r e z are now described as a rhythmic, omnipresent e l e c t r i c a l d e p o l a r i z a t i o n w i t h a c h a r a c t e r i s t i c t r i p h a s i c 12 ( p o s i t i v e , negative, p o s i t i v e ) c o n f i g u r a t i o n , designated the b a s i c e l e c t r i c a l rhythm, or BER. " B a s i c " i n d i c a t e s the per- s i s t e n t or fundamental property of the event; " e l e c t r i c a l " l k describes the type of phenomenon; "rhythm" denotes p e r i o d i c i t y . The BER has two components; a f a s t i n i t i a l d e p o l a r i z a t i o n , and a slow, p l a t e a u - l i k e d e p o l a r i z a t i o n which f o l l o w s . I t i s a c y c l i c a l a l t e r a t i o n of r e s t i n g p o t e n t i a l of smooth muscle c e l l s which renders the muscle a l t e r n a t e l y r e l a t i v e l y e x c i t a b l e and a b s o l u t e l y r e f r a c t o r y . ^ Synonymous terms f o r the BER i n c l u d e i n i t i a l p o t e n t i a l , slow wave, pa c e s e t t e r p o t e n t i a l (PP), and e l e c t r i c a l c o n t r o l a c t i v i t y . J The BER o r i g i n a t e s i n bundles of l o n g i t u d i n a l muscle l o - cated at the j u n c t i o n of the proximal and middle t h i r d s of the g r e a t e r curvature of the s t o m a c h , a n d i s propagated c a u d a l l y along the l o n g i t u d i n a l muscle f i b r e s to the antrum and to the l e s s e r curve by f i b r e s which sweep up from the g r e a t e r curve. The p o t e n t i a l i s propagated as a continuous sheath along the muscle w a l l , such th a t i t i s at the same phase i n any circum- f e r e n t i a l c r o s s - s e c t i o n of the stomach at any one p o i n t i n t i m e . 1 ^ ^ Anatomical s t u d i e s of the g a s t r i c musculature"^ 0 r e v e a l a confluence of l o n g i t u d i n a l muscle bundles on both a n t e r i o r and p o s t e r i o r aspects of the upper t h i r d of the g r e a t e r curve. From t h i s r e g i o n , the muscle bundles r a d i a t e i n m u l t i p l e arcs along the g r e a t e r curve to the antrum, and across to the l e s s e r curve. In the d i s t a l antrum, l o n g i t u d i n a l muscle bundles from 13 the g r e a t e r curve continue over the l e s s e r curve, and j o i n s i m i l a r bundles from the opposite s i d e . In the prox i m a l t h r e e - f o u r t h s of the stomach, the r a d i a t i n g f i b r e s from the g r e a t e r curve terminate b e f o r e r e a c h i n g the s u p e r i o r margin of the l e s s e r c u r v e . An assessment of p a r t i a l t r a n s e c t i o n of these muscle bundles a t v a r i o u s l e v e l s has demonstrated t h a t a narrow b r i d g e of muscle a l o n g the g r e a t e r curve (Z0%> of the circum- f e r e n c e ) i s s u f f i c i e n t t o m a i n t a i n normal e l e c t r i c a l c o n t i n u i t y and entrainment i n the segment of the stomach d i s t a l t o the t r a n s e c t i o n , i n d i c a t i n g t h a t the g r e a t e r curve i s c o n s i d e r a b l y more important i n g a s t r i c c o n d u c t i o n than are other areas of the stomach, i n c l u d i n g the l e s s e r curve. The p a u c i t y of l o n g i - t u d i n a l muscle on the prox i m a l t h r e e - f o u r t h s of the l e s s e r curve e x p l a i n s the absence of slow wave a c t i v i t y and condu c t i o n i n t h i s r e g i o n . Each i n i t i a l p o t e n t i a l extends over a s p e c i f i c segment of stomach w a l l , and may be d e s c r i b e d as having a wave or c y c l e l e n g t h . The segment of stomach (or bowel) beneath each c y c l e of t h i s p o t e n t i a l r e p r e s e n t s a p h y s i o l o g i c a l motor segment.-^' ^ The BER or p a c e s e t t e r p o t e n t i a l determines the dimensions of t h i s segment, and c o n t r o l s i t s motor a c t i v i t y . Rate of pro- p a g a t i o n of the BER i n c r e a s e s as the antrum i s approached, with r a t e s r a n g i n g from 0.1 cm. per second i n the corpus t o 2-4 cm. pe r second i n the t e r m i n a l a n t r u m , ^ C y c l e l e n g t h i s equal t o v e l o c i t y / f r e q u e n c y ; t h e r e f o r e , as the v e l o c i t y of p r o p a g a t i o n i n c r e a s e s , the c y c l e l e n g t h i n c r e a s e s p r o p o r t i o n a t e l y , and hence 14 the l e n g t h of the u n d e r l y i n g motor segment i s a l s o i n c r e a s e d . T h i s r a p i d spread of d e p o l a r i z a t i o n over the e n t i r e antrum i s r e s p o n s i b l e f o r i t s behaviour as a motor u n i t . The BER has a r a t e or frequency which i s constant and s p e c i e s s p e c i f i c (4-5 c y c l e s p er minute i n dogs, 3 c y c l e s per minute i n man). The t r i p h a s i c complex occupies 1.5-2,5 seconds, and i s f o l l o w e d k o by a r e f r a c t o r y p e r i o d of j u s t l e s s than three seconds. J 4 46 ^ o P r o p a g a t i o n i s f a c i l i t a t e d by n e x a l c o n n e c t i o n s , J * ' J ' which are areas of f u s i o n of a d j a c e n t c e l l membranes. The nexus p r o v i d e s a d i r e c t e l e c t r i c a l c o n n e c t i o n between c e l l i n t e r i o r s without i n t e r v e n i n g e x t r a c e l l u l a r space, while m a i n t a i n i n g c e l l u l a r i n t e g r i t y . Contiguous c e l l s p r o v i d e simultaneous c u r r e n t sources and c u r r e n t s i n k s , a l l o w i n g e l e c t r o t o n i c spread 20 21 from one c e l l membrane to another. ' The smooth muscle c e l l s behave e l e c t r i c a l l y as though t h e i r i n t e r i o r s were con- nected, and e l e c t r o t o n i c spread of c u r r e n t occurs between c e l l s much as c u r r e n t i s propagated a l o n g an axon. The c e l l membranes at s i t e s of n e x a l connections are exposed to h i g h potassium and low c a l c i u m c o n c e n t r a t i o n s , are d e p o l a r i z e d , and thus p r o v i d e low r e s i s t a n c e pathways f o r c u r r e n t flow. C o n t r o v e r s y has surrounded the o r i g i n of the BER. Most evidence f a v o u r s a myogenic r a t h e r than a neurogenic o r i g i n . ^ F a c t o r s which support t h i s concept i n c l u d e : ( i ) the i n a b i l i t y of n e u r o t r o p i c drugs t o a l t e r the BER; ( i i ) a t h e o r e t i c a l i n a b i l i t y of the s m a l l mass of neuro- genic elements of the g a s t r o i n t e s t i n a l t r a c t t o generate a p o t e n t i a l of the magnitude of the BER; 15 ( i i i ) the absence of the BER i n hypomuscular areas of the GI t r a c t , f o r example, the gastroduodenal j u n c t i o n ; ( i v ) c y c l i c a l e l e c t r i c a l phenomena are generated i n the l o n g i t u d i n a l but not the c i r c u l a r muscle l a y e r s of the GI t r a c t . D. A c t i o n P o t e n t i a l s The BER has been designated the " e l e c t r i c a l c o n t r o l a c t i - v i t y " as i t c o n t r o l s the appearance of the "response a c t i v i t y " , c o n t r a c t i o n . T h i s i s r e p r e s e n t e d e l e c t r i c a l l y as a second de- p o l a r i z a t i o n f o l l o w i n g the i n i t i a l or p a c e s e t t e r p o t e n t i a l (PP), and i s c h a r a c t e r i z e d by a more prolonged (4-8 seconds) n e g a t i v e d e f l e c t i o n , upon which may be superimposed a s e r i e s of f a s t e r 43 4"5 " s p i k e s " , J % T h i s "second p o t e n t i a l " immediately precedes c o n t r a c t i l e a c t i v i t y ( u s u a l l y by 0.5 seconds) as observed v i s u a l l y or measured e i t h e r kymographically or with s t r a i n gauges. Each BER c y c l e or motor segment has a s s o c i a t e d with i t only one b u r s t of "second" or " a c t i o n p o t e n t i a l s " , and thus only one band of c o n t r a c t i n g f i b r e s . The BER f i x e s the maximum frequency of c o n t r a c t i o n , and i t s caudal m i g r a t i o n s y n c h r o n i z e s and c o o r d i n a t e s the c o n t r a c t i o n , determining the v e l o c i t y of i t s p r o p a g a t i o n and the width of the c o n t r a c t i n g band. The frequency of c o n t r a c t i o n can t h e r e f o r e not exceed the frequency of the BER. During the f a s t i n g s t a t e , a c t i o n p o t e n t i a l s (AP's) occur i n a s s o c i a t i o n w i t h approximately 25% of BER c y c l e s . 1 ^ ' ^ 1 T h i s percentage i s markedly i n c r e a s e d d u r i n g f e e d i n g , and d u r i n g 16 3*5 37 43 91 the a d m i n i s t r a t i o n of v a r i o u s drugs. J % J ( ' J ' 7 The a c t i o n or " s p i k e " p o t e n t i a l , u n l i k e the BER, i s not propagated more 43 than a few m i l l i m e t r e s i n e i t h e r d i r e c t i o n . J A c t i o n p o t e n t i a l s have "been d i r e c t l y c o r r e l a t e d with con- t r a c t i l e a c t i v i t y as measured by i n c r e a s e i n i n t r a l u m i n a l p r e s s u r e . However, a measurement of i n t r a l u m i n a l p r e s s u r e r e c o r d s a change due t o the mean e f f e c t of a l l muscle l a y e r s , and does not i n d i c a t e w i t h i n which l a y e r the c o n t r a c t i l e a c t i - v i t y o r i g i n a t e s . By means of s t r a i n gauges o r i e n t a t e d so as to r e c o r d s i m u l t a n e o u s l y the c o n t r a c t i l e a c t i v i t y of both l o n g i - t u d i n a l and c i r c u l a r muscle, i t has been demonstrated t h a t the a c t i o n p o t e n t i a l s are a s s o c i a t e d w i t h c i r c u l a r muscle c o n t r a c - 14 t i o n . The number and amplitude of AP's are d i r e c t l y p r o - p o r t i o n a l to e i t h e r the change i n i n t r a l u m i n a l p r e s s u r e or the c o n t r a c t i l e f o r c e as measured wi t h s t r a i n gauges; t h i s would tend t o c o n f i r m t h a t a c t i o n p o t e n t i a l s are myogenic i n o r i g i n . F u r t h e r evidence i n support of the myogenic o r i g i n of these p o t e n t i a l s i s found i n the rhythmic c o n t r a c t i o n which occurs i n muscle c e l l s of the c h i c k amnion, which i s devoid of 88 nerve f i b r e s . T h i s o b s e r v a t i o n would i n d i c a t e t h a t spon- taneous c o n t r a c t i o n need not be neurogenic i n o r i g i n , E. C o o r d i n a t i o n of G a s t r i c P e r i s t a l s i s C o ordinated g a s t r i c p e r i s t a l s i s depends on the p a c e s e t t e r p o t e n t i a l sweeping i n a rhythmic p a t t e r n from i t s o r i g i n t o the p y l o r u s . I t s y n c h r o n i z e s the g a s t r i c musculature by p r o v i d i n g a s u i t a b l e e l e c t r i c a l framework through which g a s t r i c s t i m u l i 17 71 may act to a l t e r motor a c t i v i t y , ' and r e g u l a t e s the maximum frequency of c o n t r a c t i o n . The p a c e s e t t e r p o t e n t i a l s o r i g i n a t e i n the l o n g i t u d i n a l muscle l a y e r , and are propagated e l e c t r o n i c a l l y i n t o the c i r - c u l a r muscle l a y e r . The p h y s i o l o g i c a l conducting u n i t s con- s i s t of bundles of 100-300 muscle f i b r e s (and a s s o c i a t e d con- n e c t i v e t i s s u e ) i n p a r a l l e l which connect the two l a y e r s . ^ ' 1 0 0 The band of d e p o l a r i z a t i o n t h a t spreads to the c i r c u l a r l a y e r then i n t e r a c t s w i t h such l o c a l f a c t o r s as a c e t y l c h o l i n e , the i n t r a m u r a l nerve plexuses and perhaps other e x c i t a t o r y t r a n s - m i t t e r s to i n i t i a t e c o n t r a c t i l e a c t i v i t y . Whether the a c t i o n p o t e n t i a l s a c t u a l l y i n i t i a t e c o n t r a c t i o n or are e l e c t r i c a l d e p o l a r i z a t i o n s which simply p a r a l l e l con- t r a c t i o n i s undecided. The p a c e s e t t e r p o t e n t i a l may act s o l e l y by t r i g g e r i n g the r e l e a s e of a c e t y l c h o l i n e (Ach), or i t may s e n s i t i z e the g a s t r i c musculature to the e f f e c t s of Ach. The re l e a s e d Ach may i n i t i a t e the second d e p o l a r i z a t i o n or a c t i o n p o t e n t i a l , which i n t u r n r e s u l t s i n calcium r e l e a s e and subse- quent c o n t r a c t i o n . y Whether or not a c o n t r a c t i o n f o l l o w s the BER complex w i l l depend upon the s t a t e of s t r e t c h of the muscle, l o c a l hormone and t r a n s m i t t e r a c t i v i t y , and nerve impulses mediated v i a both i n t r i n s i c and e x t r i n s i c networks. The f a c t t h a t the l o n g i t u d i n a l and c i r c u l a r muscle l a y e r s c o n t r a c t simultaneously, and are able t o do so i n the absence of Meissner's p l e x u s , suggests that p e r i s t a l t i c a c t i v i t y i s 22 c o n t r o l l e d p r i m a r i l y by a myogenic phenomenon. Neural c o n t r o l 18 i s not a p r e r e q u i s i t e f o r p e r i s t a l s i s , and i s more modulating r a t h e r than commanding i n i t s r o l e . P e r i s t a l s i s can a l s o occur k<a i n the presence of t e t r o d o t o x i n , ^ which e l i m i n a t e s a l l n e u r a l a c t i v i t y . I t i s l i k e l y t h a t n e u r a l a c t i v i t y modulates the response t o slow wave d e p o l a r i z a t i o n by i n c r e a s i n g or d e c r e a s i n g the p r o b a b i l i t y of s p i k i n g d u r i n g the d e p o l a r i z e d phase of the BER complex. F. Pacemaker Dominance Exp e r i m e n t a l t r a n s e c t i o n of the stomach i n v a r i o u s planes and a t v a r i o u s l e v e l s has demonstrated not only the l o c a t i o n of the g a s t r i c pacemaker, but has supported the concept of dominance of h i g h e r order pacemakers."^' 1 0 ^ ' 1 0 ^ » 1 1 0 i f 0ne t r a n s e c t s the stomach d i s t a l t o the dominant pacemaker, the normal PP i s not propagated a c r o s s the s i t e of t r a n s e c t i o n , and a pacemaker with an i n h e r e n t l y slower r a t e i n the d i s t a l segment of the stomach w i l l assume pacemaking a c t i v i t y . The new, d i s t a l BER w i l l have a slower frequency, and may show both caudad and r e t r o g r a d e p r o p a g a t i o n and o c c a s i o n a l i r r e g u - l a r i t y due to i n t e r p o s e d p o t e n t i a l s from e c t o p i c f o c i of im- p u l s e g e n e r a t i o n . S i m i l a r l y , l o n g i t u d i n a l g a s t r i c b i s e c t i o n s e p a r a t i n g the g r e a t e r from the l e s s e r c u r v a t u r e causes the l e s s e r curve segment t o be no l o n g e r d r i v e n by the dominant g a s t r i c pacemaker. T h i s procedure a l s o r e s u l t s i n the develop- ment of a reduced BER frequency and an i r r e g u l a r i t y i n the BER due t o the appearance of m u l t i p l e e c t o p i c f o c i of pace- 73 making a c t i v i t y . J T h i s u n c o u p l i n g of e l e c t r i c a l a c t i v i t y 1 9 between the two segments i s only temporary, w i t h recovery o c c u r r i n g by two weeks. The re-establishment of c o u p l i n g has not been observed f o l l o w i n g h o r i z o n t a l t r a n s e c t i o n s t u d i e s , 1 0 ^ ' 1 0 ^ but the models i n each instance are not comparable inasmuch as the l o n g i t u d i n a l muscle bundles i n the h o r i z o n t a l t r a n s e c t i o n s t u d i e s have been d i v i d e d , whereas t h i s has not been done i n the b i s e c t i o n study. F o l l o w i n g h o r i z o n t a l t r a n s e c t i o n , the "permanently" lower BER frequency i s i n keeping w i t h the con- cept of a g r a d i e n t i n the rate of generation of the n a t u r a l or i n t r i n s i c p a c e s e t t e r p o t e n t i a l i n smooth muscle c e l l s of the 7 3 g a s t r o i n t e s t i n a l t r a c t . ' J The normal pacemaker on the proximal t h i r d of the g r e a t e r curve, having the f a s t e s t i n t r i n s i c frequency, e n t r a i n s the 7 3 1 1 0 l e s s e r curve and d i s t a l stomach.'-" The more d i s t a l stomach has a lower i n t r i n s i c PP frequency, but can accept and be d r i v e n by the f a s t e r orad pacemaker. The d i r e c t i o n of propagation of the PP i s determined by the s i t e of the group of c e l l s having the f a s t e s t frequency; propagation occurs from t h i s r e g i o n t o those w i t h slower inherent f r e q u e n c i e s . The smooth muscle c e l l s of the fundus and proximal corpus possess e l e c t r i c a l p r o p e r t i e s d i f f e r e n t from those of the r e - mainder of the stomach, as they n e i t h e r accept nor propagate 7 3 the c o r p o r a l PP.' V Lack of measurable rhythmic e l e c t r i c a l a c t i v i t y i n these areas supports t h i s o b s e r v a t i o n . 1 1 0 G. R e l a x a t i o n O s c i l l a t o r s In order t o elaborate on the mechanism of entrainment, i t 20 i s r e l e v a n t t o d i s c u s s the concept of r e l a x a t i o n o s c i l l a t o r s and t h e i r r o l e i n the e l e c t r i c a l c o n t r o l of g a s t r o i n t e s t i n a l m o t i l i t y . D % GI smooth muscle acts l i k e a matrix of l o o s e l y coupled r e l a x a t i o n o s c i l l a t o r s i n which p o t e n t i a l pacemaking f o c i o s c i l l a t e w i t h frequencies inherent to t h e i r s p e c i f i c l o c a l e i n the GI t r a c t . I n d i v i d u a l l o n g i t u d i n a l muscle c e l l s are capable of spontaneous slow wave generation. I n d i v i d u a l o s c i l l a t i n g u n i t s may be as small as one c e l l , o r , more l i k e l y , comprise a c o l l e c t i o n of c e l l s o s c i l l a t i n g i n phase. Coupling occurs v i a nexal contact or current flow i n the surrounding e x t r a c e l l u l a r f l u i d . Thus each c e l l or c e l l group can simultaneously c o n t a i n both a source and s i n k of c u r r e n t . An o s c i l l a t o r w i t h a higher n a t u r a l frequency can dominate, " p u l l i n " , or e n t r a i n lower frequency o s c i l l a t o r s such t h a t the l a t t e r tend t o accept the frequency of the f a s t e r o s c i l l a t o r . The r e l a x a t i o n p r o p e r t i e s of the lower frequency o s c i l l a t o r s 102 a l l o w t h i s modulation t o occur. This concept may be best it-i l l u s t r a t e d by reference to the conducting system of the h e a r t . The SA and AV nodes behave as coupled r e l a x a t i o n o s c i l l a t o r s , w i t h the SA node dominant, and the AV node tending t o " p u l l i n " towards the r a t e of the dominant node. The l e s s s t a b l e , lower frequency o s c i l l a t o r adopts a r a t e equal t o or some har- monic of the r a t e of the dominant o s c i l l a t o r . One can see how t h i s concept may be a p p l i e d t o the stomach and i n t e s t i n e , i n which each area has i t s own inherent r a t e of pacemaking a c t i v i t y 21 with a g r a d i e n t of frequency d e c r e a s i n g from p r o x i m a l to d i s t a l stomach, and from p r o x i m a l to d i s t a l s m a l l bowel. Proximal pacemakers i n each of these r e g i o n s of the GI t r a c t " p u l l i n " or e n t r a i n the more d i s t a l segments by c o u p l i n g of s e r i a l o s c i l l a t i n g pacemakers. The t r a n s e c t i o n and re-anastomosis experiments d e s c r i b e d i n the p r e v i o u s s e c t i o n 1 0 ^ * have demonstrated i n both stomach and s m a l l i n t e s t i n e a slower BER frequency i n the p o s t - anastomotic segments, with evidence of abnormal p r o p a g a t i o n secondary t o the emergence of e c t o p i c pacemakers no l o n g e r under the c o n t r o l of the f a s t e r , dominant pr o x i m a l pacemaker. T h i s i s , i n e f f e c t , an u n c o u p l i n g of the pacemakers. S i m i l a r e f f e c t s are observed f o l l o w i n g l o c a l trauma, l o c a l c o o l i n g , or l o c a l a n a e s t h e s i a a p p l i e d t o a c r o s s - s e c t i o n a l zone of stomach or bowel. These e f f e c t s are temporary, remaining f o r 71 p e r i o d s up t o two weeks. I t has been suggested t h a t c o u p l i n g of the pacemakers occurs such t h a t the o r i g i n a l BER frequency i s r e s t o r e d i n the post-anastomotic segment. An analogous s i t u a t i o n i s observed i n the h e a r t ; an a t r i a l pacemaker gener- ates the h i g h e s t frequency of a c t i v i t y , but the v e n t r i c l e i s capable of i t s own i n t r i n s i c rhythmic frequency i n the event of an AV c o n d u c t i o n b l o c k . T h i s s i t u a t i o n may a l s o be i n t e r p r e t e d as an u n c o u p l i n g of o s c i l l a t o r s , and may be temporary or perma- nent. C o r r e c t i o n of the AV b l o c k w i l l a l l o w r e c o u p l i n g of the o s c i l l a t o r s , and the dominant a t r i a l pacemaker w i l l assume e l e c t r i c a l c o n t r o l of the c a r d i a c muscle. 22 This concept i s important i n c o n s i d e r a t i o n of d i s o r g a n i z e d m o t i l i t y and delayed g a s t r i c emptying which so oft e n f o l l o w s vagotomy or g a s t r i c r e s e c t i o n . The proximal g a s t r i c pacemaker has the highest i n t r i n s i c frequency of o s c i l l a t i o n ; uncoupling of the d i s t a l stomach from the e l e c t r i c a l dominance of t h i s proximal pacemaker by g a s t r i c r e s e c t i o n and/or vagotomy may be a s i g n i f i c a n t f a c t o r i n the m o t i l i t y disturbances encountered a f t e r these p r o c e d u r e s . 1 1 0 As a c o r o l l a r y t o t h i s premise, i t may be p o s s i b l e to u t i l i z e t h i s model and apply e x t e r n a l o s c i l - l a t o r s t o the stomach t o overr i d e the u n d e s i r a b l e , a l t e r e d e l e c t r i c a l rhythm disturbances which occur f o l l o w i n g u l c e r surgery, much i n the same manner i n which c a r d i a c pacing over- r i d e s the undesirable arrythmias and conduction d i s o r d e r s f o l l o w i n g myocardial damage. ok, K e l l y and h i s co-workers' have a p p l i e d t h i s p r i n c i p l e to pacing the canine stomach e l e c t r i c a l l y . Using c u r r e n t s of 1-8 ma, and impulses of 0.1-2.0 seconds' d u r a t i o n a p p l i e d at 2-12 impulses per minute, he has demonstrated c o u p l i n g between the stimulus and the e x c i t a b l e t i s s u e s i n the g a s t r i c w a l l such t h a t the frequency of the PP corresponded e x a c t l y t o the f r e - quency of a p p l i e d s t i m u l a t i o n , w i t h subsequent suppression of the n a t u r a l g a s t r i c PP. The a r t i f i c i a l l y generated PP was propagated b i d i r e c t i o n a l l y , but was not observed i n the fundus. The v e l o c i t y of propagation was i d e n t i c a l i n both d i r e c t i o n s , and was of the same magnitude as th a t of the n a t u r a l PP. The n a t u r a l PP i n t h i s study had a mean frequency of 5.0 c y c l e s per 23 minute; t h i s c o u l d be i n c r e a s e d to 8.0 c y c l e s per minute, or decreased t o 4 . 2 c y c l e s per minute by v a r y i n g the frequency of a p p l i e d s t i m u l a t i o n . Beyond these l i m i t s , the n a t u r a l PP reappeared. P r e v i o u s attempts t o generate PP's and consequently con- t r o l g a s t r o i n t e s t i n a l a c t i v i t y have g e n e r a l l y met w i t h l i t t l e success and have c o n t r i b u t e d l i t t l e i n the way of c o n c r e t e r e s u l t s . V a r i e d s t u d i e s have demonstrated i n c r e a s e d g a s t r i c c o n t r a c t i l e a c t i v i t y and a s s o c i a t e d AP's f o l l o w i n g e x t e r n a l l y a p p l i e d e l e c t r i c a l s t i m u l a t i o n t o the stomach, but have not r e s u l t e d i n any p a r t i c u l a r success i n a l t e r i n g p o s t - o p e r a t i v e g a s t r o i n t e s t i n a l m o t i l i t y . ' y ' By d e l i v e r i n g e l e c t r i c a l s t i m u l i a t a frequency and w i t h a rhythm not u n l i k e t h a t of the n a t u r a l g a s t r i c pacemaker, K e l l y has been ab l e t o o v e r r i d e the n a t u r a l pacemaker and assume c o n t r o l of the pacemaking a c t i v i t y i n the stomach. Whether the e x t e r n a l s t i m u l i have a c t e d on neurones i n the i n t r a m u r a l plexuses or d i r e c t l y on the smooth muscle i t s e l f i s unknown. Frequency p u l l i n g between the s i t e of the e x t e r n a l s t i m u l u s and the s i t e of the n a t u r a l pace- maker oc c u r r e d i n such a manner t h a t the e x t e r n a l s t i m u l u s was a b l e , w i t h i n c e r t a i n d e f i n e d l i m i t s , t o c o n t r o l the n a t u r a l oh. pacemaker. T h i s i n v e s t i g a t i o n supports Nelsen's h y p o t h e s i s ' t h a t g a s t r o i n t e s t i n a l smooth muscle a c t s l i k e a m a t r i x of l o o s e l y coupled r e l a x a t i o n o s c i l l a t o r s i n which pacemaking s i t e s which o s c i l l a t e at the h i g h e s t frequency e n t r a i n or couple o t h e r areas of e l e c t r i c a l a c t i v i t y where the i n t r i n s i c f requen- c i e s are lower. 24 SECTION IV. FACTORS WHICH INFLUENCE GASTRIC ELECTRICAL ACTIVITY We may now consider the f a c t o r s which are known to i n f l u e n c e the BER and a c t i o n p o t e n t i a l s . These may be broadly c l a s s i f i e d as chemical, mechanical, and n e u r a l f a c t o r s . A. Influence of Drugs 1. A c e t y l c h o l i n e (Ach) S e v e r a l suggestions as to how the BER exerts c o n t r o l over c o n t r a c t i l e a c t i v i t y have already been o u t l i n e d . The PP may t r i g g e r the r e l e a s e of Ach, or may s e n s i t i z e the g a s t r i c muscu- l a t u r e to i t s e f f e c t s . Ach may, i n t u r n , i n i t i a t e a c t i o n po- t e n t i a l s , promote calcium r e l e a s e , and thus lead t o c o n t r a c t i o n , Ach r e l e a s e may a l s o be brought about by d i s t e n s i o n of the GI t r a c t , which a c t i v a t e s mechanoreceptors to set up nervous 44 lmpulses t h a t impinge on p o s t g a n g l i o n i c c h o l i n e r g i c nerves. A c e t y l c h o l i n e i s thought to be the sole t r a n s m i t t e r at both 93 pre- and p o s t g a n g l i o n i c c h o l i n e r g i c nerve endings. J Ach may o c c a s i o n a l l y cause a s l i g h t increase i n the ampli- 14 43 tude of the BER, * J but otherwise has no c o n s i s t e n t e f f e c t on i t s r a t e . Ach i n t h r e s h o l d doses i n j e c t e d i n t r a - a r t e r i a l l y ( i n t o the g a s t r o - e p i p l o i c v e s s e l s ) during the " s u s c e p t i b l e p e r i o d " ( a f t e r the r e f r a c t o r y p e r i o d of the i n i t i a l p o t e n t i a l ) w i l l produce or enhance a c t i o n p o t e n t i a l s . ^ I f i n j e c t e d at an i n a p p r o p r i a t e time (e.g. immediately a f t e r the absolute r e f r a c t o r y p e r i o d of 2.8 seconds, but w i t h i n 5 seconds of the 25 onset of the i n i t i a l p o t e n t i a l ) , i t w i l l r e s u l t i n a premature i n i t i a l p o t e n t i a l . ^ This premature PP w i l l he propagated both c a u d a l l y and i n a retrograde f a s h i o n . The retrograde propagation r e s u l t s i n the l o s s of the next expected normally propagated PP; the premature p o t e n t i a l c o l l i d e s w i t h the nor- mally expected PP, and the l a t t e r i s unable t o pass along the muscle which i s r e f r a c t o r y as a r e s u l t of the premature poten- t i a l . The r e s u l t i s an i r r e g u l a r i t y of the BER t h a t i s analo- gous i n i t s o r i g i n t o the compensatory pause which f o l l o w s a premature v e n t r i c u l a r c o n t r a c t i o n as recorded i n the ECG. 2. Atropine Atropine i n h i b i t s or a b o l i s h e s a c t i o n p o t e n t i a l s and con- t r a c t i l e a c t i v i t y by preventing a c e t y l c h o l i n e from e x e r t i n g h/O 43 98 i t s a c t i o n . • ' J* G e n e r a l l y , i t has no e f f e c t on the r a t e of the BER, though i t has on occasion been reported to decrease the amplitude of the i n i t i a l p o t e n t i a l s . - ^ * ^9 A t r o - pine does not a f f e c t the propagation of the BER, suggesting i n d i r e c t l y t h a t Ach i s not e s s e n t i a l f o r the production of i n i t i a l p o t e n t i a l s . High doses of atropine may, however, i n i - t i a t e r e p e t i t i v e b u r s t s of i n i t i a l p o t e n t i a l s , The p a t t e r n so described on the gastrogram has been l a b e l e d the "sympathetic 44 dominance p a t t e r n " ; t h i s phenomenon i s observed whenever there i s a dominance of sympathetic over parasympathetic a c t i v i t y . 3. Catecholamines Catecholamines i n t h r e s h o l d doses i n j e c t e d i n t r a - a r t e r i a l l y cause temporary i n h i b i t i o n of a c t i o n p o t e n t i a l s and c o n t r a c t i l e 26 37 42 43 a c t i v i t y . ' ' This e f f e c t has been demonstrated with both epinephrine and i s o p r o t e r e n o l , suggesting that there are two kinds of i n h i b i t o r y adrenergic receptors i n the stomach: alpha receptors i n the myenteric plexuses s t i m u l a t e d by norepinephrine, preventing the r e l e a s e of a c e t y l c h o l i n e , and beta receptors i n the smooth muscle c e l l s s t i m u l a t e d by i s o - p r o t e r e n o l , d i m i n i s h i n g the e f f e c t of Ach on the g a s t r i c muscu- 44 l a t u r e . Catecholamines i n low dosage do not a f f e c t the BER, except 14 37 by o c c a s i o n a l l y decreasing the amplitude of the p o t e n t i a l . ' •Jf Large dosage, however, r e s u l t s i n a s e r i e s of r e p e t i t i v e t r i - 39 phasic p o t e n t i a l s without c o n t r a c t i o n , ' and thus suppresses l o c a l c o n t r o l a c t i v i t y . I n i t i a l p o t e n t i a l s are t e m p o r a r i l y e l i m i n a t e d d i s t a l to the s i t e of l o c a l i n j e c t i o n , J J and e l e c t r i c a l a c t i v i t y which may be generated below the i n j e c t i o n s i t e i s propagated i n both caudad and retrograde d i r e c t i o n s . In other words, the muscle may be able to propagate pac e s e t t e r p o t e n t i a l s at a time when i t does not i n i t i a t e them. Moreover, the c a p a b i l i t y of g a s t r i c musculature to propagate p o t e n t i a l s i n both d i r e c t i o n s supports the concept of the e l e c t r o t o n i c spread of c u r r e n t ; the a b i l i t y to propagate p o t e n t i a l s b i d i r e c - t i o n a l l y i s incompatible w i t h a mechanism i n v o l v i n g chemical t r a n s m i s s i o n at synapses. The phenomenon described as the sympathetic dominance p a t t e r n i s due i n p a r t to a r e l a t i v e d e f i c i e n c y of a c e t y l c h o l i n e at the l e v e l of the smooth muscle c e l l s . This p a t t e r n r a d i c a l l y 27 d i s o r g a n i z e s the BER. I t i s of i n t e r e s t to note t h a t d e s p i t e the r a p i d r a t e of the p o t e n t i a l s , the minimum time i n t e r v a l between each p o t e n t i a l i s 2.8 seconds; t h i s i s i d e n t i c a l t o 43 the d u r a t i o n of the absolute r e f r a c t o r y p e r i o d . J S i m i l a r p a t t e r n s have been observed f o l l o w i n g l o c a l i n j e c t i o n of high doses of a t r o p i n e , morphine, and h i s t a m i n e . 4. Hexamethonium G a n g l i o n i c b l o c k i n g agents have no s p e c i f i c e f f e c t s on l 4 37 the BER. * J l However, both c o n t r a c t i l e and r e l a x a n t r e s - 98 ponses to v a g a l s t i m u l a t i o n are a b o l i s h e d by these drugs. T h i s hexamethonium-sensitive r e l a x a t i o n may be mediated v i a p r e g a n g l i o n i c v a g a l f i b r e s which synapse with g a n g l i o n c e l l s of a d r e n e r g i c neurones. 5. Morphine Morphine causes a s p a s t i c , non-propulsive i n c r e a s e i n con- t r a c t i l e a c t i v i t y and a c o r r e s p o n d i n g i n c r e a s e i n the frequency 14 42 and amplitude of a c t i o n p o t e n t i a l s . ' I t may cause a s l i g h t i n c r e a s e i n the amplitude of the i n i t i a l p o t e n t i a l s , but i t s e f f e c t on BER r a t e i s v a r i a b l e . The e f f e c t of morphine on c o n t r a c t i l e a c t i v i t y i s l i m i t e d to the c i r c u l a r muscle l a y e r . Despite the marked i n c r e a s e i n the frequency of AP's caused by morphine, a 1:1 r a t i o i s always maintained between the BER and the AP's. 6. Histamine and 5-hydroxytryptamine (5-HT) Histamine e x c i t e s c h o l i n e r g i c g a n g l i o n i c c e l l s presynap- 98 t i c a l l y , r e s u l t i n g i n an i n c r e a s e i n AP's and c o n t r a c t i l e 28 a c t i v i t y . I t a l s o has a d i r e c t e x c i t a t o r y e f f e c t on a n t r a l smooth muscle. 5-HT may be e i t h e r e x c i t a t o r y or i n h i b i t o r y on i n t r i n s i c c h o l i n e r g i c neurones, depending on the p r i o r kk degree of tonus m the smooth muscle c e l l s . 5-HT may a l s o 77 p l a y a r o l e i n v a g a l i n h i b i t i o n of c o n t r a c t i l i t y . N e i t h e r histamine nor 5-HT have c o n s i s t e n t e f f e c t s on the BER. 7 . S e r o t o n i n S e r o t o n i n causes an i n c r e a s e i n the amplitude of PP's, but a slowing of the BER frequency, and some d i s o r g a n i z a t i o n 37 i n i t s rhythm. 8. L o c a l a n a e s t h e t i c s P r o c a i n e or cocaine i n dosage s u f f i c i e n t t o p a r a l y s e a l l n e u r a l elements does not a p p a r e n t l y a f f e c t the BER, c o n f i r m i n g t h a t the i n i t i a l p o t e n t i a l i s not n e u r a l i n o r i g i n . - ^ ' ^ 9t B a r b i t u r a t e s A n a e s t h e s i a with sodium t h i o p e n t a l i n low dosage has no a p p r e c i a b l e e f f e c t on a c t i o n p o t e n t i a l s or on the r e s t i n g BER. With deeper a n a e s t h e s i a , sympathetic tone predominates and g a s t r o i n t e s t i n a l atony r e s u l t s . ^ ' ^ * ^ The e f f e c t s are l i m i t e d t o a decrease i n the i n c i d e n c e of a c t i o n p o t e n t i a l s , and a s i g n i f i c a n t l y decreased response of i n t r a g a s t r i c p r e s s u r e to v a g a l s t i m u l a t i o n . Halogen a n a e s t h e t i c s have s i m i l a r e f f e c t s . Though the e f f e c t of b a r b i t u r a t e s on the BER i s thought t o 29 be n e g l i g i b l e , one i n v e s t i g a t i o n 7 has r e p o r t e d a s i g n i f i c a n t i n f l u e n c e . Recordings from un a n a e s t h e t i z e d dogs demonstrated 29 a mean c y c l e d u r a t i o n of 12.2 t 0.55 seconds; dogs a n a e s t h e t i z e d with sodium t h i o p e n t a l recorded c y c l e d u r a t i o n s of 15.5 - 3*5 seconds. The p r o l o n g a t i o n of the BER c y c l e , and hence the slowing of the BER r a t e may have been due i n p a r t a t l e a s t t o the f a l l i n body temperature which accompanies a n a e s t h e s i a . B. I n f l u e n c e of Hormones 1. I n s u l i n I n s u l i n r e s u l t s i n a marked i n c r e a s e i n v e l o c i t y of pro- p a g a t i o n of the BER, and i n c r e a s e s the i n c i d e n c e of a c t i o n 71 p o t e n t i a l s . However, i t does not s i g n i f i c a n t l y a l t e r the 107 BER r a t e . The e x c i t a t o r y e f f e c t d e s c r i b e d i s v a g a l l y mediated. 2. G a s t r i n G a s t r i n has an e x c i t a t o r y e f f e c t on g a s t r i c musculature. I t has been shown to i n c r e a s e the BER frequency by 25-35%."^' ^ G a s t r i n causes a marked i n c r e a s e i n a n t r a l c o n t r a c t i l e a c t i - 44 v i t y v i a d i r e c t a c t i o n on smooth muscle r e c e p t o r s . I t can cause powerful c o n t r a c t i o n i n a t o t a l l y denervated g a s t r i c 107 pouch; ' t h i s e f f e c t i s not b l o c k e d by a n t i c h o l i n e r g i c s , l o c a l a n a e s t h e t i c s , or g a n g l i o n i c b l o c k i n g agents; nor i s i t p o t e n t i a t e d by a n t i c h o l i n e s t e r a s e s . The e f f e c t s of i n c r e a s e d c o n t r a c t i l e a c t i v i t y and the a s s o c i a t e d i n c r e a s e i n AP's occur w i t h a dosage comparable t o t h a t which w i l l produce a maximal 107 s e c r e t o r y response. Of i n t e r e s t however i s a r e c e n t i n v e s t i - g a t i o n - ^ which has demonstrated t h a t , d e s p i t e the i n c r e a s e i n c o n t r a c t i l e a c t i v i t y and a c t u a l f o r c e of c o n t r a c t i o n (measured wi t h s t r a i n gauges), g a s t r i c emptying time i s a c t u a l l y delayed 30 during the i n f u s i o n of p e n t a g a s t r i n at r a t e s v a r y i n g from 1-4 ugm/kg./hr. 3 . A l k a l i n i z a t i o n of the duodenum to a pH g r e a t e r than 8.2 r e s u l t s i n increased m o t i l i t y of a t o t a l l y denervated or autotransplanted g a s t r i c pouch, with corresponding increase i n 107 the incidence of a c t i o n p o t e n t i a l s . Whether t h i s i s due to suppression of an i n h i b i t o r y hormone such as enterogastrone, or to the production of an e x c i t a t o r y motor hormone i s u n c e r t a i n , 4. A humoral b r a i n f a c t o r ( J e f f e r s o n et al.^ 7""^* 7') may be a c t i v a t e d or r e l e a s e d by s t i m u l a t i o n of the c e n t r a l end of a d i v i d e d c e r v i c a l vagus nerve, r e s u l t i n g i n a r e f l e x increase i n g a s t r i c c o n t r a c t i l i t y . This matter w i l l be discussed f u r - t h e r i n a subsequent s e c t i o n . C. Mechanical and Metabolic Factors 1. Body temperature A f a l l of 10° C. i n body temperature decreases the f r e - quency of the BER by 50%',^* 3 7 the amplitude of the PP's and t h e i r v e l o c i t y of propagation are a l s o reduced. Conversely, these parameters are p r o p o r t i o n a t e l y increased f o l l o w i n g an increase i n body temperature. The slower BER provides an e l e c t r i c a l environment conducive to the appearance of e c t o p i c f o c i of e l e c t r i c a l impulse generation, thus rendering the rhythm i r r e g u l a r . This i s analogous to the appearance of e c t o p i c a t r i a l or v e n t r i c u l a r f o c i i n c a r d i a c muscle during periods of bradycardia. 31 2. Anoxia Anoxia r e s u l t s i n a p r o g r e s s i v e r e d u c t i o n i n the BER f r e - quency, w i t h decreased v o l t a g e and a p r o l o n g a t i o n of the r e - f r a c t o r y p e r i o d . However, d u r i n g the i n i t i a l stages of anoxia, c o n t r a c t i l e a c t i v i t y i s i n c r e a s e d . ^ S e l e c t i v e d e s t r u c t i o n of the i n t r i n s i c nerve plexus by l o c a l hypoxia r e s u l t s i n a lowered BER r a t e d i s t a l t o the Ik damaged segment. I t i s p o s t u l a t e d t h a t when the nerve plexus i s damaged, the smooth muscle generates an i n i t i a l p o t e n t i a l at i t s i n h e r e n t myogenic r a t e , a r a t e t h a t i s lower than t h a t of the i n t a c t bowel w a l l . One might conclude t h a t a f u n c t i o n a l myenteric p l e x u s r a i s e s the e x c i t a b i l i t y of the myogenic system so t h a t i t generates the PP at a f a s t e r frequency than i t s own n a t u r a l i n h e r e n t r a t e . 3. Trauma, i n the form of clamping or t r a n s e c t i o n of the antrum, r e s u l t s i n a temporary slowing of the BER frequency d i s t a l t o the s i t e o f the i n s u l t . V e l o c i t y of p r o p a g a t i o n i n the d i s t a l segment i s permanently reduced. D i s o r g a n i z a t i o n of the BER of the d i s t a l segment i s u s u a l l y observed f o r a v a r i a b l e p e r i o d , and r e s u l t s from the r e t r o g r a d e p r o p a g a t i o n of poten- t i a l s o r i g i n a t i n g i n the r e g i o n of the p y l o r u s . k. H y p e r v e n t i l a t i o n reduces both p a r i e t a l c e l l and muscular response to v a g a l s t i m u l a t i o n . I t may t h e r e f o r e be accompanied by a r e d u c t i o n i n the i n c i d e n c e of a c t i o n p o t e n t i a l s . I t p r o b a b l y has no e f f e c t on the BER. 32 Whether or not an a c t i o n p o t e n t i a l and c o n t r a c t i o n w i l l occur w i l l t h e r e f o r e depend not only on the a r r i v a l of a pro- pagated p a c e s e t t e r p o t e n t i a l , but on the l o c a l chemical and p h y s i c a l environment of the smooth muscle c e l l s , and whether kk t h i s environment i s r e c e p t i v e to i n i t i a t i n g response a c t i v i t y . L o c a l r e f l e x e s modulate the response by determining the quan- t i t i e s of t r a n s m i t t e r s and hormones to be r e l e a s e d , and thereby r e g u l a t e the balance between e x c i t a t i o n and i n h i b i t i o n . D. Neural Influences The v a g i may exert a c o n t r o l l i n g or s t a b i l i z i n g i n f l u e n c e over the g a s t r i c pacemaker. Vagotomy i n dogs has been shown to cause a temporary slowing of the BER frequency, a disorgan- 93 96 i z a t i o n of the r e g u l a r rhythm, 7 and a permanent slowing 71 of the caudad propagation of the BER. The reduced frequency and d i s o r g a n i z a t i o n are temporary, l a s t i n g on the average 5-10 days. One i n t e r p r e t a t i o n of these observations i s that vagotomy has removed a c o n t r o l l i n g i n f l u e n c e over the normal pacemaker, a l l o w i n g i t to assume i t s n a t u r a l slower r a t e . Since higher order pacemakers dominate, the lower i n t r i n s i c r a t e provides as already described an e l e c t r i c a l environment s u i t a b l e f o r the emergence of e c t o p i c f o c i of impulse generation; hence the d i s - organized BER w i t h m u l t i p l e conduction pathways and both caudad and retrograde ( a n t i p e r i s t a l t i c ) propagation. The p a t t e r n on the electrogastrogram i s somewhat analogous to the ECG p a t t e r n of slow a t r i a l f i b r i l l a t i o n w i t h superimposed m u l t i f o c a l pre- mature v e n t r i c u l a r c o n t r a c t i o n s . 33 E a r l y i n v e s t i g a t i o n has suggested t h a t vagotomy r e s u l t s i n impaired g a s t r i c tone, weakened c o n t r a c t i o n s , d i s t u r b e d 71 88 93 p e r i s t a l s i s , and delayed emptying of s o l i d s . ' ' y : > Unsynchronized p e r i s t a l t i c waves, not coordinated i n time or d i r e c t i o n of propagation, would not provide adequate p r o p u l s i o n of s o l i d s , though the g e n e r a l i z e d increase i n tone could achieve normal or even a c c e l e r a t e d p r o p u l s i o n of the l i q u i d content of the stomach and thus account f o r the f r e q u e n t l y observed r a p i d " i n i t i a l emptying time" f o l l o w i n g vagotomy. The i n i t i a l emp- t y i n g of the f l u i d component of a meal i n t o the small bowel can 93 at times be so r a p i d as to be considered a form of dumping. J The major postvagotomy motor disturbance, however, i s r e t e n t i o n of the s o l i d p o r t i o n of a meal f o r hours or even days. I f the p a c e s e t t e r p o t e n t i a l does i n f a c t i n i t i a t e some change r e q u i r e d f o r the production of the a c t i o n p o t e n t i a l and subsequent con- t r a c t i o n , and thus coordinate c o n t r a c t i l e a c t i v i t y , the i r r e g u - l a r , d i s o r g a n i z e d BER w i t h the a s s o c i a t e d e q u a l l y d i s o r g a n i z e d a c t i o n p o t e n t i a l s so produced by vagotomy may w e l l account f o r the unsynchronized g a s t r i c p e r i s t a l t i c a c t i v i t y , g a s t r i c d i s - t e n s i o n , and delayed emptying which so o f t e n f o l l o w s vagotomy. The random d i s o r g a n i z a t i o n of the BER p e r s i s t s approximately one week; t h i s p e r i o d i s comparable to the d u r a t i o n of s i g n i - f i c a n t l y impaired g a s t r i c emptying and g a s t r i c d i l a t a t i o n ob- served f o l l o w i n g vagotomy i n humans. The e n t i r e concept i s analogous to the sequence of events observed f o l l o w i n g acute s p i n a l cord t r a n s e c t i o n , f o l l o w i n g which lower order r e f l e x . . . 10? a c t i v i t y t e m p o r a r i l y p r e v a i l s . ' 3 k ' Further evidence of vagal c o n t r o l over g a s t r i c e l e c t r i c a l 71 a c t i v i t y i s found i n the e f f e c t of i n s u l i n hypoglycemia. P r i o r t o vagotomy, i n s u l i n has been shown to cause an increased v e l o c i t y of propagation of the BER i n dogs, and a marked increase i n the incidence of AP's and c o n t r a c t i l e a c t i v i t y . Vagotomy abo l i s h e s t h i s e f f e c t of i n s u l i n induced hypoglycemia. In prevagotomized dogs, g a s t r i c i n s t i l l a t i o n of o i l slows propa- g a t i o n of the PP, and markedly diminishes the incidence of AP's; once again, vagotomy s u b s t a n t i a l l y diminishes and o c c a s i o n a l l y a b o l i s h e s t h i s e f f e c t of f a t on g a s t r i c e l e c t r i c a l a c t i v i t y . The o i l no longer reduces the incidence of AP's or c o n t r a c t i l e 71 a c t i v i t y . Both i n v e s t i g a t i o n s support the concept t h a t v a g a l l y mediated s t i m u l i exert some c o n t r o l over g a s t r i c e l e c - t r i c a l a c t i v i t y , and that vagotomy removes the c e p h a l i c phase of g a s t r i c m o t i l i t y i n the same manner as i t a b o l i s h e s the 93 c e p h a l i c phase of g a s t r i c s e c r e t i o n . J To pursue the problem of g a s t r i c i n h i b i t i o n by f a t , i t i s 107 l i k e l y t h a t both humoral and n e u r a l f a c t o r s are i n v o l v e d . ' Fat i n the upper small i n t e s t i n e , i n the presence of b i l e s a l t s and p a n c r e a t i c j u i c e , delays g a s t r i c emptying by i n h i b i t i n g g a s t r i c m o t i l i t y . This i n h i b i t i o n can occur i n both innervated and denervated stomach and i n an autotransplanted g a s t r i c pouch, suggesting that humoral f a c t o r s (enterogastrone) are i n v o l v e d . 1 0 7 However, p r o c a i n i z a t i o n of the i n t e s t i n a l mucosa abolishes the i n h i b i t o r y a c t i o n of f a t , and vagotomy s i g n i f i c a n t l y attenuates the i n h i b i t o r y response, as w e l l as p r o l o n g i n g i t s l a t e n c y . One 35 may conclude t h a t v a g a l l y dependent n e u r a l mechanisms are a l s o i m p l i c a t e d i n t h i s phenomenon. I t has been p o s t u l a t e d t h a t the i n h i b i t i o n by f a t i s i n i t i a t e d r e f l e x l y i n a f a s h i o n s i m i - l a r t o the i n i t i a t i o n of the e n t e r o g a s t r i c r e f l e x , and i s then perpetuated v i a the a c t i o n of c i r c u l a t i n g e n t erogastrone. The a c t i o n of p r o c a i n e i m p l i e s a l o c a l r e f l e x mechanism i n v o l v e d i n the r e l e a s e of enterogastrone; t h i s r e f l e x may be f a c i l i t a t e d or otherwise m o d i f i e d by v a g a l impulses. A s i m i l a r mechanism of c o n t r o l e x i s t s with r e s p e c t to g a s t r i n . The p a r t i c i p a t i o n of both n e u r a l and hormonal pathways p r o v i d e s a more complete e x p l a n a t i o n f o r the e f f e c t s of vagotomy on the g a s t r i c i n h i b i - t i o n by f a t . SECTION V. VAGAL PATHWAYS AND EFFECTS ON GASTRIC CONTRACTILE ACTIVITY Much of the work i n t r a c i n g v a g a l a f f e r e n t and e f f e r e n t pathways through the c e n t r a l nervous system has been accomplished by s t u d y i n g g a s t r i c tone and m o t i l i t y . Though the e f f e c t s of v a g a l s t i m u l a t i o n on g a s t r i c e l e c t r i c a l a c t i v i t y have not been s p e c i f i c a l l y s t u d i e d , i t i s p r o b a b l y j u s t i f i e d t o apply many of the concepts formulated by the study of m o t i l i t y t o the examina- t i o n of g a s t r i c e l e c t r i c a l a c t i v i t y , as the two parameters of study are c l o s e l y r e l a t e d . In o r d e r t h a t c o n t r a c t i o n s may serve a u s e f u l purpose, they must be c o o r d i n a t e d and brought i n t o harmony wi t h the needs of the organism, and must conform to a p a t t e r n which w i l l 36 serve the purposes of d i g e s t i o n . Regulation, of t h i s a c t i v i t y , whether i n the form of augmentation or i n h i b i t i o n , i s accom- p l i s h e d v i a l o c a l and c e n t r a l n e u r a l pathways, and v i a the e f f e c t s of c i r c u l a t i n g hormones. The only known d i r e c t i n n e r - v a t i o n of g a s t r i c smooth muscle c e l l s (except f o r a few post- g a n g l i o n i c sympathetics) i s v i a e f f e r e n t neurones i n the l o c a l i n t r i n s i c plexuses. These motor neurones c o n s t i t u t e the f i n a l common path i n a r e f l e x arc i n which the a f f e r e n t neurones are 107 a l s o l o c a t e d i n the same i n t r i n s i c plexuses. The long r e - f l e x arcs through the c e n t r a l nervous system are comprised of both vagal and sympathetic v i s c e r a l a f f e r e n t s plus t h e i r c o r r e s - ponding e f f e r e n t f i b r e s t r a v e l i n g i n the same nerves. The ex- t r i n s i c nerves do not i n f a c t innervate the g a s t r i c smooth muscle d i r e c t l y , but serve as connecting l i n k s between r e f l e x centres i n the CNS which are concerned w i t h r e g u l a t i n g g a s t r i c f u n c t i o n and the l o c a l r e f l e x centres i n the myenteric plexuses, through which the a c t i v i t y of the muscle i s coordinated. The v i s c e r a l e f f e r e n t nerve f i b r e s are i n r e a l i t y a f f e r e n t s to the l o c a l but d i f f u s e r e f l e x n e u r a l centres i n the v i s c e r a l organs. Thus, e x t r i n s i c n e u r a l i n f l u e n c e i s p r i m a r i l y d i r e c t e d at e i t h e r f a c i l i t a t i n g or i n h i b i t i n g the l o c a l axon r e f l e x e s mediated through the i n t r i n s i c myenteric network. A. G a s t r o i n t e s t i n a l Receptors Before d i s c u s s i n g the autonomic nerve pathways, i t i s rel e v a n t at t h i s p o i n t to b r i e f l y o u t l i n e the var i o u s gastro- i n t e s t i n a l receptors and i n d i c a t e the r o l e of the e x t r i n s i c nerves i n modifying t h e i r r e s p o n s e s . 1 0 7 3? 1. Osmoreceptors These are l o c a t e d i n the duodenal and upper j e j u n a l mucosa, and are s e n s i t i v e to osmotic f o r c e s . S o l u t i o n s having greater or l e s s e r a c t i v i t y than the osmolar c o n c e n t r a t i o n of blood plasma s t i m u l a t e these receptors w i t h r e s u l t a n t slowing of g a s t r i c emptying. The r o l e of the e x t r i n s i c autonomic net- work i n t h i s phenomenon i s u n c e r t a i n . 2. Hydrogen Ion Receptors These receptors are s i t u a t e d i n the upper i n t e s t i n a l mucosa, and operate w i t h a t h r e s h o l d of pH 2.0-3.5. A c i d i n the upper i n t e s t i n e i n h i b i t s g a s t r i c m o t i l i t y and delays gas- t r i c emptying. Recording from s i n g l e vagal f i b r e s , Iggo^^ has found t h a t the e l e c t r i c a l a c t i v i t y of the nerve i s increased when s o l u t i o n s w i t h a pH of l e s s than 3*0 or g r e a t e r than a pH of 8.0 are a p p l i e d t o the g a s t r i c mucosa. The f u n c t i o n of these g a s t r i c pH receptors i s unknown. 3. Other Chemoreceptors Amino a c i d s , products of p r o t e i n d i g e s t i o n , and peptones i n the upper i n t e s t i n e i n h i b i t g a s t r i c m o t i l i t y v i a n e u r a l pathways, probably v i a s p e c i f i c r e c e p t o r s . Fats and products of f a t d i g e s t i o n i n the upper i n t e s t i n e a l s o i n h i b i t g a s t r i c m o t i l i t y ; both enterogastrone and vagal pathways are i n v o l v e d i n t h i s phenomenon. 4. Mechanoreceptors Contact (pressure) receptors and s t r e t c h receptors are each present i n the g a s t r o i n t e s t i n a l t r a c t , and are i n v o l v e d i n 38 l o c a l r e f l e x e s which r e g u l a t e m o t i l i t y . S t r e t c h r e c e p t o r s i n the g a s t r i c w a l l , when s t i m u l a t e d , r e s u l t i n impulses d e t e c t - able i n a f f e r e n t v a g a l f i b r e s . These impulses i n f l u e n c e 64 97 111 m o t i l i t y v i a l o n g r e f l e x a r c s through the CNS. * Youmans has d e s c r i b e d an " i n t e s t i n o - i n t e s t i n a l " r e f l e x i n which over- d i s t e n s i o n o f a segment of i n t e s t i n e r e s u l t s i n g e n e r a l i z e d i n t e s t i n a l i n h i b i t i o n , presumably due t o s t i m u l a t i o n of s t r e t c h or t e n s i o n r e c e p t o r s . T h i s i n t u r n has an i n h i b i t o r y e f f e c t on g a s t r i c p e r i s t a l s i s . The s i t u a t i o n i s not c l e a r , however, when one attempts t o draw p a r a l l e l s between the r e f l e x e f f e c t s of s t i m u l a t i n g these r e c e p t o r s and the responses obtained by s t i m u l a t i o n of e x t r i n s i c nerves. I n t e g r a t i o n of l o c a l axon r e f l e x e s w i t h l o n g r e f l e x a r c s through the CNS probably p r o - v i d e s the most s u i t a b l e e x p l a n a t i o n f o r the r o l e assumed by the v a r i o u s mechanoreceptors. 5. M i s c e l l a n e o u s Receptors P a i n , thermal, and s p e c i a l sense r e c e p t o r s a l l have d i r e c t or i n d i r e c t e f f e c t s on g a s t r o i n t e s t i n a l m o t i l i t y . T h e i r e f f e c t s are mediated i n p a r t at l e a s t by t h e i r i n f l u e n c e on e l e c t r i c a l a c t i v i t y . Noxious s t i m u l i such as e x c e s s i v e muscular c o n t r a c - t i o n , mechanical trauma or chemical i n j u r y r e s u l t i n n o n - s p e c i f i c i n h i b i t i o n of v i s c e r a l f u n c t i o n . Body temperature has a l r e a d y been d i s c u s s e d i n s o f a r as i t a f f e c t s e l e c t r i c a l a c t i v i t y . ^ 7 B. A f f e r e n t Nerve Pathways 1. Vagal A f f e r e n t s A f f e r e n t v a g a l f i b r e s are concerned w i t h the autonomic 39 r e g u l a t i o n of g a s t r o i n t e s t i n a l f u n c t i o n . Pavlov, i n h i s account of the nervous r e g u l a t i o n of d i g e s t i o n , ' emphasized the importance of a discharge down e f f e r e n t vagal f i b r e s t o the abdominal v i s c e r a . This discharge was thought t o be a r e f l e x impulse i n i t i a t e d i n a "se c r e t o r y centre" i n the b r a i n stem f o l l o w i n g s t i m u l a t i o n of c e p h a l i c nerve endings which i n tu r n had been e x c i t e d by v i s c e r a l a f f e r e n t i n f l o w along the course of the abdominal v a g i (and sympathetics as w e l l ) . 88 Existence of t h i s r e f l e x was queried when McSwiney and 7 . . . Alvarez demonstrated that g a s t r i c s e c r e t i o n and m o t i l i t y could be a l t e r e d i n the absence of an e x t r i n s i c nerve supply. Nevertheless, s e v e r a l i n v e s t i g a t o r s have described the e f f e c t s of e l e c t r i c a l s t i m u l a t i o n of vagal a f f e r e n t f i b r e s , measured as a change i n the tonus or c o n t r a c t i l e a c t i v i t y of the g a s t r i c musculature. o Babkin and K i t e 7 have demonstrated i n h i b i t i o n of a n t r a l c o n t r a c t i l e a c t i v i t y f o l l o w i n g c e n t r a l ( r e f l e x ) s t i m u l a t i o n of one d i v i d e d c e r v i c a l vagus, the other nerve remaining i n t a c t . However, a s i m i l a r degree of a n t r a l i n h i b i t i o n was u s u a l l y ob- served f o l l o w i n g c e n t r a l s t i m u l a t i o n of femoral, s c i a t i c , or splanchnic nerves. The authors p o s t u l a t e d s e v e r a l mechanisms to account f o r t h i s i n h i b i t i o n s ( i ) depression of lower vagal centres i n the medulla, hypothalamus, or r e t i c u l a r substance; ( i i ) s t i m u l a t i o n of vagal i n h i b i t o r y neurones; ( i i i ) s t i m u l a t i o n of the sympatho-adrenal system. 40 The c e n t r a l pathways i n v o l v e d i n t h i s r e f l e x i n h i b i t i o n were thought t o i n c l u d e the c o r t e x , medulla, and hypothalamus. In these experiments, a chloralose-urethane anaesthetic mixture was used. This p a r t i c u l a r combination has been shown 9 54 to s t i m u l a t e vagal s e c r e t o r y centres i n the CNS, J and may l i k e w i s e s t i m u l a t e vagal motor centres i n the r e g i o n of the d o r s a l vagal nucleus and r e t i c u l a r substance. These e f f e c t s are a b o l i s h e d by vagotomy. The i n f l u e n c e of the anaesthetic agent may be of s i g n i f i c a n c e i n i n t e r p r e t a t i o n of the observa- . t i o n s as recorded by these i n v e s t i g a t o r s . co 9 7 TQ7 Harper and h i s c o l l e a g u e s ^ 7 ' ' have s t u d i e d the e f f e c t s of both a f f e r e n t and e f f e r e n t vagal s t i m u l a t i o n i n c a t s . Using square wave impulses of 0.1-10.0 m i l l i s e c o n d du- r a t i o n , 5-^0 V., a p p l i e d at 30-50 impulses per second f o r periods of 10-30 seconds, as w e l l as curare or high ( 0 3 ) s p i n a l cord s e c t i o n to e l i m i n a t e r e t c h i n g m o v e m e n t s , t h e y have demonstrated an increase i n a c i d and pepsin s e c r e t i o n upon s t i m u l a t i o n of the c e n t r a l end of one d i v i d e d vagus while the other vagus remained i n t a c t . C e n t r a l s t i m u l a t i o n of one d i v i d e d vagus r e s u l t e d i n an o v e r a l l decrease i n tone of the g a s t r i c musculature i n the m a j o r i t y (80%) of experiments, though there was evidence of s l i g h t superimposed c o n t r a c t i l e a c t i v i t y i n one-half of these cases. The o v e r a l l decrease i n tone out- l a s t e d the p e r i o d of s t i m u l a t i o n by up to 15-20 minutes. In the remaining 20% of experiments, there was no background de- crease i n tone, but only s l i g h t increase i n c o n t r a c t i l e a c t i v i t y 41 as measured by water manometry. The l a t e n t p e r i o d of t h i s response was 5-10 seconds. E f f e r e n t s t i m u l a t i o n of these same nerves using s i m i l a r s t i m u l a t i o n c h a r a c t e r i s t i c s a l s o r e s u l t e d i n enhanced a c i d and pepsin s e c r e t i o n , but p r i m a r i l y a strong c o n t r a c t i l e response of the g a s t r i c musculature. In approximately 50% of t h i s group, there was no l o s s of g a s t r i c tone; i n the remainder, the o v e r a l l l o s s of tone upon which the c o n t r a c t i o n s were superimposed was only s l i g h t and v a r i a b l e . Once again, the l a t e n t p e r i o d of t h i s response was 5-7 seconds. The e f f e c t of a f f e r e n t or r e f l e x s t i m u l a t i o n on g a s t r i c m o t i l i t y as described i n t h i s i n v e s t i g a t i o n was p r i m a r i l y i n h i - b i t o r y , whereas e f f e r e n t s t i m u l a t i o n was p r i m a r i l y e x c i t a t o r y . By way of c o n t r a s t , both a f f e r e n t and e f f e r e n t v a gal s t i m u l a - t i o n on i n t e s t i n a l m o t i l i t y was e x c i t a t o r y . F o l l o w i n g complete vagotomy, Harper demonstrated a pro g r e s s i v e increase i n g a s t r i c tone a s s o c i a t e d w i t h an increase i n spontaneous c o n t r a c t i l e a c t i v i t y . This could be i n t e r p r e t e d as a removal of the i n h i - b i t o r y e f f e c t s of the v a g i . The e n t i r e concept of vagal i n h i - b i t o r y f i b r e s w i l l be discussed i n more d e t a i l i n a subsequent s e c t i o n . Harper has t h e r e f o r e demonstrated t h a t vago-vagal r e f l e x e f f e c t s can be obtained by d i r e c t s t i m u l a t i o n of a f f e r e n t vagal f i b r e s , and th a t the s e c r e t o r y and motor changes as des- c r i b e d are a b o l i s h e d by complete vagotomy. J e f f e r s o n ^ " " ^ has demonstrated th a t e l e c t r i c a l s t i m u l a - t i o n of the c e n t r a l end of the c e r v i c a l vagus w i t h a l l vagal f i b r e s severed r e s u l t s i n g a s t r i c c o n t r a c t i o n l o c a l i z e d p r i m a r i l y 42 to the area of the c a r d i a and fundus. He suggests t h a t humoral f a c t o r s l i b e r a t e d from the CNS may be i m p l i c a t e d i n t h i s con- t r a c t i l e response. His i n v e s t i g a t i o n has a l s o put f o r t h e v i d - ence to suggest t h a t there are e x t r a v a g a l e f f e r e n t parasympa- t h e t i c f i b r e s which leave the s p i n a l cord between T^ and L 2 v i a d o r s a l and v e n t r a l r o o t s ; they t r a v e l to the stomach v i a the splanchnics and other as yet undetermined pathways, and 68 r e s u l t i n a c o n t r a c t i l e response. That t h e i r e f f e c t i s blocked by atropine suggests t h a t they are probably c h o l i n e r g i c . J e f f e r s o n ' s i n v e s t i g a t i o n suggests that complete i n t e r r u p t i o n of c h o l i n e r g i c impulses to the stomach cannot be achieved i n the dog by vagotomy. At the present time, one can only conclude t h a t i t i s d i f f i c u l t t o assess the s i g n i f i c a n c e of the c o n f l i c t i n g r e s u l t s obtained by e l e c t r i c a l s t i m u l a t i o n of a f f e r e n t vagal f i b r e s , p r i m a r i l y because the v a g i c o n t a i n a f f e r e n t s from so many un- r e l a t e d organs, and account f o r at l e a s t 90% of a l l vagal f i b r e s . 2. A f f e r e n t F i b r e s Associated w i t h Sympathetic E f f e r e n t s V i s c e r a l p a i n f i b r e s u s u a l l y accompany the sympathetic ~ nerves. A f f e r e n t s enter the s p i n a l cord v i a the d o r s a l roots of the lower t h o r a c i c nerves, u s u a l l y Tg_j2» though they may be found w i t h i n the range of T k - L 2 . ^ ' 1 0 7 Support f o r the existence of these a f f e r e n t pathways i s found i n Dragstedt's work i n the 1940*s. He has demonstrated that though vagotomy r e l i e v e s the p a i n of duodenal u l c e r , i n t r o d u c t i o n of a c i d i n t o *3 the stomach of a vagotomized subject can s t i l l e l i c i t p a i n , 52 i n d i c a t i n g t h a t an a f f e r e n t nerve pathway remains i n t a c t . C. E f f e r e n t Nerve Pathways 1. I n t r o d u c t i o n The autonomic nervous system r e g u l a t e s two types of g a s t r i c response: ( i ) pure tonus changes i n the form of c o n t r a c t i o n or r e l a x a t i o n ; ( i i ) augmentation or i n h i b i t i o n of rhythmic move- ments . The tonus of smooth muscle may be defined as "the r e s i s t a n c e of i t s substance to extension". The " a l l - o r - n o n e " law of s t r i a t e d muscle c o n t r a c t i o n does not apply t o p l a i n muscle. A s t a t e of tonus may be considered as a continued c o n t r a c t i o n , or as an i n h i b i t i o n or p a r t i a l l y i n h i b i t e d r e l a x a t i o n . From such an e q u i l i b r i u m , a s t a t e of f u r t h e r c o n t r a c t i o n or f u r t h e r r e l a x a t i o n can be obtained. I t i s a gross o v e r s i m p l i f i c a t i o n t o designate the vagus the motor nerve and the sympathetic the i n h i b i t o r nerve of the stomach. Sympathetic and parasympathetic networks each have 77 both e x c i t a t o r y and i n h i b i t o r y f u n c t i o n s . I t i s the purpose of the subsequent s e c t i o n s to o u t l i n e some of the e a r l y i n - v e s t i g a t i o n which has l e n t support to t h i s concept, and to r e - view more s p e c i f i c a l l y the r o l e of the e f f e r e n t pathways i n the r e g u l a t i o n of g a s t r o i n t e s t i n a l m o t i l i t y . k k Vagal e f f e r e n t f i b r e s reaching the stomach terminate i n 88 a r b o r i z a t i o n s around the neurones i n Auerbach's plexus. C e l l s of t h i s plexus i n t u r n innervate the smooth muscle c e l l s . With the exception of the few p o s t g a n g l i o n i c sympa- t h e t i c s , the e x t r i n s i c nerves do not d i r e c t l y innervate the g a s t r i c muscle f i b r e s , but serve r a t h e r as l i n k s between CNS centres and the myenteric plexuses; t h e i r i n f l u e n c e i s p r i m a r i l y 107 one of m o d i f i c a t i o n of l o c a l axon r e f l e x e s . I n v e s t i g a t i o n i n t h i s f i e l d has demonstrated over the years almost every conceivable combination of c o n t r a c t i o n and 98 r e l a x a t i o n i n response to e x t r i n s i c nerve s t i m u l a t i o n . The consensus, put simply, has been th a t g a s t r i c muscle, when st i m u l a t e d , i s more l i k e l y to c o n t r a c t i f f u l l y r e l a x e d , and t o r e l a x i f f u l l y c o n t r a c t e d . G e n e r a l l y , weak s t i m u l i have favoured c o n t r a c t i o n , and strong s t i m u l a t i o n has favoured 28 r e l a x a t i o n . The body and fundus appear more s u s c e p t i b l e to . . . . . 107 i n h i b i t i o n by vagal s t i m u l a t i o n than i s the antrum. ' I t has a l s o been observed t h a t the response to sympathetic s t i m u l a t i o n i s g e n e r a l l y not as dependent on the e x i s t i n g s t a t e of tonus as i s the response to vagal s t i m u l a t i o n . To elaborate on t h i s concept, i t can be s t a t e d that tonus i s dependent upon passage, of propagated disturbances over the p e r i p h e r a l p a r t of the neuromuscular mechanism, and t h a t the degree of tonus i s de- pendent upon the frequency of these propagated disturbances. When tonus i s h i g h , vagal s t i m u l a t i o n i s thought to decrease the frequency of the propagated disturbance t o an i n h i b i t o r y 45 value; when tonus i s low, the frequency of the propagation i s a l s o low, and vagal s t i m u l a t i o n w i l l r a i s e t h i s frequency t o e x c i t a t o r y v a l u e s . ^ ' o p McSwiney, i n h i s review of g a s t r i c i n n e r v a t i o n , comments that the immediate r e s u l t s of nerve s e c t i o n may not he of great p h y s i o l o g i c a l importance, as they are of b r i e f d u r a t i o n and are o f t e n i n d i s t i n g u i s h a b l e from the e f f e c t s of shock and anaesthesia. He c i t e s the i n h i b i t i o n of m o t i l i t y and l o s s of g a s t r i c tone f o l l o w i n g laparotomy as an example of t h i s con- cept, and suggests th a t the more remote e f f e c t s of nerve sec- t i o n are of g r e a t e r s i g n i f i c a n c e . His review of the subject t o 1931 concludes the f o l l o w i n g : ( i ) s e c t i o n of one vagus or of one splanchnic has no appreciable e f f e c t on g a s t r i c tone or m o t i l i t y ; ( i i ) complete vagal s e c t i o n r e s u l t s i n g a s t r i c d i l a - t a t i o n , decreased tonus, slow and weakened p e r i s t a l s i s , and delayed g a s t r i c emptying; ( i i i ) complete splanchnic s e c t i o n r e s u l t s i n a c c e l - erated g a s t r i c f u n c t i o n and e f f e c t s opposite to those of vagal s e c t i o n ; ( i v ) complete vagal plus splanchnic s e c t i o n r e s u l t s i n a sequence of events s i m i l a r t o , but l e s s pronounced than th a t which f o l l o w s complete vagotomy. 46 There are two stages i n the response which f o l l o w s vago- tomy. I n i t i a l i n h i b i t i o n and p a r e s i s i s fo l l o w e d by a gradual r e t u r n of f u n c t i o n . A f t e r a v a r i a b l e p e r i o d , the p e r i p h e r a l i n t r i n s i c nervous network assumes c o n t r o l of the e x t r i n s i c a l l y denervated stomach, supporting the premise t h a t the va g i (or the splanchnics) are not e s s e n t i a l to g a s t r i c f u n c t i o n , but are i n s t e a d modulating i n t h e i r r o l e . 2. Vagal E f f e r e n t s Vagal e f f e r e n t f i b r e s terminate i n r e l a t i o n to the c e l l s i n Auerbach's myenteric ple x u s , and are i n f l u e n t i a l i n modifying smooth muscle a c t i v i t y , e i t h e r by e x c i t i n g the ganglion c e l l s of the plexus t o discharge impulses over t h e i r axons, or by 107 i n h i b i t i n g or f a c i l i t a t i n g l o c a l r e f l e x e s . As an example, the t e m p o r a r i l y d i s t u r b e d g a s t r i c p e r i s t a l s i s f o l l o w i n g vago- tomy suggests t h a t the v a g i do have some r e g u l a t o r y i n f l u e n c e on l o c a l r e f l e x mechanisms. I t has been shown tha t vagal s t i m u l a t i o n can r e s u l t i n e i t h e r i n h i b i t i o n or augmentation of g a s t r i c c o n t r a c t i l e a c t i v i t y . As e a r l y as 1889» Openchowski described a " d i l a t o r nerve of the c a r d i a " , presumably a vagal f i b r e which, when r i g OO 1 1 0 s t i m u l a t e d , r e s u l t e d i n r e l a x a t i o n of the c a r d i a . 7 ' ' He described both c o n t r a c t i o n and r e l a x a t i o n of the c a r d i a f o l l o w i n g vagal s t i m u l a t i o n ; the response depended upon the stre n g t h and frequency of the e l e c t r i c a l s t i m u l u s . Wertheimer, 79 i n 1897» obtained r e f l e x i n h i b i t i o n of the g a s t r i c musculature by s t i m u l a t i n g the c e n t r a l end of the s c i a t i c nerve or of one 47 vagus nerve; t h i s i n h i b i t i o n was much l e s s f o l l o w i n g complete vagotomy. Wertheimer made reference to e a r l i e r work by Morat, i n France (1882), who apparently observed c e s s a t i o n of g a s t r i c m o t i l i t y on s t i m u l a t i o n of the c e n t r a l end of the vagus, and a t t r i b u t e d t h i s phenomenon to the i n f l u e n c e of vagal i n h i b i t o r y f i b r e s . Langley, i n 1898, described a r e l a x a t i o n of the upper p o r t i o n of the body of the stomach and the esophageal o r i f i c e 79 on p e r i p h e r a l s t i m u l a t i o n of the c e r v i c a l vagus. The g r e a t e r the tone of the s p h i n c t e r , the g r e a t e r the e f f e c t of vagal s t i m u l a t i o n . Langley suggested t h a t the decrease i n i n t r a - g a s t r i c and s p h i n c t e r i c pressures was due to a c t i v e r e l a x a t i o n of the c a r d i a c o r i f i c e , r a t h e r than an opening of the s p h i n c t e r by c o n t r a c t i o n of the l o n g i t u d i n a l muscle of the esophagus. At the same time, vagal s t i m u l a t i o n was observed to increase con- t r a c t i o n i n the r e g i o n of the p y l o r u s . In the presence of atropine s u f f i c i e n t to block the e x c i t a t o r y response, Langley noted a much g r e a t e r degree of r e l a x a t i o n f o l l o w i n g vagal stimu- l a t i o n than when atropine was not used. Langley's work has th e r e f o r e demonstrated both motor and i n h i b i t o r y vagal e f f e r e n t f i b r e s . Subsequent i n v e s t i g a t i o n i n 1911 by Gannon and Lieb confirmed Langley*s observations by demonstrating r e l a x a t i o n of the lower esophagus and c a r d i a f o l l o w i n g e l e c t r i c a l stimu- l a t i o n of the d i s t a l end of a d i v i d e d c e r v i c a l vagus nerve. They noted f u r t h e r t h a t swallowing was a s s o c i a t e d w i t h a r e - l a x a t i o n of what they termed the c a r d i a c s p h i n c t e r . The fundus k8 was observed t o r e l a x j u s t p r i o r to the a r r i v a l of the esophageal p e r i s t a l t i c wave; i . e . , j u s t a f t e r the onset of swallowing. Maximal r e l a x a t i o n c o i n c i d e d w i t h the a r r i v a l of the esophageal p e r i s t a l s i c wave, r e s u l t i n g i n an i n c r e a s e d g a s t r i c c a p a c i t y without a concomitant i n c r e a s e i n i n t r a - g a s t r i c p r e s s u r e . T h i s was i n t e r p r e t e d as a mechanism designed to a l l o w the swallowed m a t e r i a l to be r e c e i v e d i n t o the stomach with a minimal i n c r e a s e i n esophageal work, and was termed " r e c e p t i v e r e l a x a t i o n " . Repeated swallowing was a s s o c i a t e d with c o n t i n u e d r e l a x a t i o n of the c a r d i a and fundus. T h i s phenomenon i l l u s t r a t e d the concept of r e c i p r o c a l i n n e r v a t i o n of a n t a g o n i s t i c muscles, i n which opposing muscles a c t i n r e c i p r o c a l c o o p e r a t i o n . Vagotomy r e s u l t e d i n a b o l i t i o n of t h i s r e f l e x r e c e p t i v e r e l a x a t i o n , i n d i c a t i n g t h a t i t i s medi- ated by i n h i b i t o r y v a g a l e f f e r e n t f i b r e s . Hexamethonium a l s o a b o l i s h e s t h i s phenomenon. Cannon and L i e b a l s o noted motor e f f e c t s f o l l o w i n g e f f e r e n t v a g a l s t i m u l a t i o n . Low f r e q u e n c i e s and i n t e n s i t i e s of stimu- l a t i o n were a s s o c i a t e d w i t h e x c i t a t o r y e f f e c t s on the g a s t r i c musculature, whereas i n h i b i t i o n f o l l o w e d h i g h frequency, h i g h i n t e n s i t y s t i m u l a t i o n . Other i n v e s t i g a t o r s s t u d i e d the i n h i b i t o r y e f f e c t s of 109 e f f e r e n t v a g a l s t i m u l a t i o n . Veach, i n 1925, p o s t u l a t e d t h a t the i n h i b i t o r y e f f e c t s were due to an e xhaustion of the t r a n s m i s s i o n mechanism, s i m i l a r i n p r i n c i p l e to Wedensky i n h i - b i t i o n . McSwiney and Wadge^ 7 r e i t e r a t e d the concept t h a t the 49 response to e f f e r e n t v a g a l s t i m u l a t i o n was dependent upon the b a s a l tone of the stomach at the time of s t i m u l a t i o n . H a r r i s o n and McSwiney, i n 1936, suggested t h a t i n h i b i t o r y e f f e c t s were due to a d r e n e r g i c f i b r e s i n the v a g i , as i n h i b i t i o n was not 98 a b o l i s h e d by a t r o p i n e . Paton and Vane' were proponents of t h i s view, c l a i m i n g t h a t they c o u l d achieve i n h i b i t i o n of g a s t r i c m o t i l i t y on v a g a l s t i m u l a t i o n only i n the presence of a t r o p i n e , and t h a t the i n h i b i t o r y e f f e c t was a b o l i s h e d by sym- 54 p a t h o l y t i c drugs. E l i a s s o n , i n 1952, e l i c i t e d g a s t r i c i n h i - b i t i o n f o l l o w i n g the s t i m u l a t i o n of the o r b i t a l r e g i o n i n the b r a i n stem of c a t s , and e s t a b l i s h e d t h a t t h i s response was conveyed v i a v a g a l e f f e r e n t s . T h i s response was no l o n g e r observed f o l l o w i n g the a d m i n i s t r a t i o n of a t r o p i n e . Needless t o say, these c o n f l i c t i n g , c o n t r a d i c t o r y r e s u l t s are c o n f u s i n g . More d e f i n i t i v e q u a n t i t a t i v e e v a l u a t i o n of these o b s e r v a t i o n s has been o f f e r e d by Martinson and h i s c o l - 66 81—8 5 leagues i n Sweden. ' ~ D Autonomic nervous c o n t r o l of smooth muscle i s e x e r t e d by a f i b r e d i s c h a r g e of r e l a t i v e l y low frequency, of the order of 1-4 impulses per second at r e s t , 8 ? and 8-10 impulses per second d u r i n g i n t e n s e e x c i t a t i o n . Veach has demonstrated an i n c r e a s e i n g a s t r i c m o t i l i t y f o l l o w i n g d i r e c t v a g a l s t i m u l a t i o n with impulse f r e q u e n c i e s of up t o 12 109 per second. J With f u r t h e r i n c r e a s e i n the frequency, or i n c r e a s e i n the s t r e n g t h of s t i m u l a t i o n a t h i g h e r f r e q u e n c i e s , i n h i b i t i o n r e s u l t e d , and Veach a t t r i b u t e d t h i s t o Wedensky i n - h i b i t i o n . As a l r e a d y d e s c r i b e d , McSwiney and Wadge claimed 50 t h a t the i n i t i a l tone of the muscle was the dominant f a c t o r i n determining whether vagal s t i m u l a t i o n would cause increased or decreased m o t i l i t y ; they observed i n h i b i t i o n i f the b a s a l tone were hig h , and augmented c o n t r a c t i l i t y i f b a s a l tone were low. By a p p l y i n g graded e f f e r e n t vagal s t i m u l a t i o n w i t h v a r i - a t i o n of impulse d u r a t i o n , v o l t a g e , and impulse frequency i n a 8 2 c o n t r o l l e d manner, Martinson has described frequency-response curves f o r changes i n g a s t r i c tone and s e c r e t i o n which suggest two groups of e f f e r e n t vagal f i b r e s : "low t h r e s h o l d " e x c i t a - t o r y f i b r e s responding to short d u r a t i o n ( l e s s than 0.2 msc.) impulses, causing increased tone and c o n t r a c t i l i t y , and "high t h r e s h o l d " i n h i b i t o r y f i b r e s responding to longer d u r a t i o n impulses (1 msc. or l o n g e r ) , r e s u l t i n g i n a r e d u c t i o n i n tone predominantly i n the corpus i n fundus, but not i n the antrum. The i n h i b i t o r y f i b r e s have l i t t l e i f any e f f e c t on the p y l o r i c r e g i o n , whereas the e x c i t a t o r y f i b r e s have t h e i r g r e a t e s t e f f e c t i n t h i s r e g i o n . The most pronounced e x c i t a t o r y responses occurred w i t h s t i m u l i of 0.1-0.2 msc. d u r a t i o n , 4-5 V, a p p l i e d at impulse frequencies of 8-10 impulses per second. The strength of the response increased w i t h an increase i n the r a t e of s t i m u l a t i o n up to 8-10 per second, and then l e v e l e d out; f u r t h e r i ncrease i n only the frequency of s t i m u l a t i o n d i d not f u r t h e r a l t e r the c h a r a c t e r of the response. This observation c o n f l i c t s w i t h t h a t of Veach which suggests t h a t an increase i n the frequency of s t i m u l a t i o n alone i s s u f f i c i e n t to e v e n t u a l l y change the response from e x c i t a t o r y t o i n h i b i t o r y . Veach 51 observed t h a t g a s t r i c m o t i l i t y could be i n h i b i t e d by i n c r e a s i n g e i t h e r the i n t e n s i t y or the frequency of vagal s t i m u l a t i o n . I t appears from Martinson* s work th a t i n h i b i t i o n appears only a f t e r a c e r t a i n t h r e s h o l d i n t e n s i t y of s t i m u l a t i o n i s reached, and then occurs whether the frequency of s t i m u l a t i o n i s high or low. C e r t a i n l y a high frequency s t i m u l a t i o n w i l l r e s u l t i n some depression of neurogenic i n f l u e n c e due to f a t i g u e i n some l i n k i n the n e u r o e f f e c t o r u n i t , provided t h a t the rat e of stimu- l a t i o n exceeds the c a p a c i t y of the system; t h i s , however, i s a 82 n o n - s p e c i f i c suppression of the e f f e c t o r response. Atropine a b o l i s h e s the e x c i t a t o r y response, but does not a f f e c t the i n h i b i t o r y response, i n d i c a t i n g t h a t the l a t t e r i s not c h o l i n e r g i c i n o r i g i n . Nor i s i t t r u l y adrenergic, as i t i s not a b o l i s h e d by sympatholytic drugs. The t h r e s h o l d f o r i n h i b i t i o n i s i d e n t i c a l before and a f t e r a b o l i t i o n of the e x c i t a - t o r y response by a t r o p i n e . The short l a t e n c y of the i n h i b i t o r y response (approximately f i v e seconds) i n d i c a t e s that i t must be n e u r a l i n o r i g i n , and that humoral f a c t o r s are not i n v o l v e d . The i n h i b i t i o n caused by vagal s t i m u l a t i o n has been a t t r i - buted by some to adrenergic f i b r e s i n the v a g i , or at l e a s t to some adrenergic mechanism.^ 1 However, the f a c t o r s as o u t l i n e d 8 3 below serve to d i f f e r e n t i a t e vagal from sympathetic i n h i b i t i o n : ( i ) v a g a l l y induced i n h i b i t i o n i s more potent, deve- lops more r a p i d l y , and has a s h o r t e r l a t e n c y (5 seconds v. 30 seconds) than i n h i b i t i o n i n - duced by sympathetic s t i m u l a t i o n u s i n g compar- able s t i m u l a t i o n parameters; the response to infused catecholamines is of even lesser degree than is the response to stimulation of sympa- thetic f i b r e s ; 7 7 , 8 1 (ii) the extremely short latency of the gastric inhi- bitory response to vagal stimulation indicates that humoral mechanisms, including the adrenal 81 medulla, are not involved; ( i i i ) vagal and sympathetic stimulation produce differing frequency-response relationships; the maximum response to vagal stimulation is achieved with lower impulse frequencies than those required to obtain a maximum response to sympathetic stimulation; (iv) vagal relaxation is of longer duration than that achieved by sympathetic stimulation; with maximal sympathetic or catecholamine induced inhibition, further relaxation can be achieved by subsequent vagal stimulation; (v) vagally induced inhibition is confined primarily to the corpus and fundus, whereas sympathetic stimulation inhibits the antrum as well; (vi) inhibition produced by stimulation of these opposing networks of the autonomic nervous system differs in its response to antagonistic drugs; sympathetic and catecholamine induced responses are abolished by guanethidine, whereas vagal relaxation is not affected by 53 e i t h e r alpha or "beta adrenergic b l o c k i n g agents; vagal r e l a x a t i o n i s p o t e n t i a t e d r a t h e r than decreased by a t r o p i n e , but i s 66 77 81 a b o l i s h e d by hexamethonium. ' The a b o l i t i o n of vagal r e l a x a t i o n by hexamethonium suggests that the mechanism i n v o l v e s a g a n g l i o n i c t r a n s m i s s i o n s t e p . ^ That atropine enhances the r e l a x a t i o n suggests that i t may act here at a g a n g l i o n i c l e v e l , r a t h e r than only at the periphery. I t appears that v a g a l l y induced g a s t r i c i n h i b i t i o n i s not medi- ated by an adrenergic mechanism, though there are i n f a c t adrenergic f i b r e s which enter the vagus w i t h i n the thorax and abdomen; t h e i r e f f e c t i s considered n e g l i g i b l e . ^ Sympathetic s t i m u l a t i o n at high s t i m u l a t i o n frequencies r e s u l t s i n i n h i b i - t i o n more on the b a s i s of a n o n - s p e c i f i c overflow of adrenergic t r a n s m i t t e r substance from v a s o c o n s t r i c t o r nerve endings than anything e l s e , accounting f o r the longer l a t e n c y and s h o r t e r 8 2 d u r a t i o n of the response. The l o n g - l a s t i n g s p e c i f i c r e l a x a - t i o n of the stomach on e x c i t a t i o n of high t h r e s h o l d vagal e f f e r e n t s i s mediated v i a p r e g a n g l i o n i c vagal f i b r e s which are n e i t h e r adrenergic nor s t r i c t l y c h o l i n e r g i c . The p e r i p h e r a l mechanism may i n v o l v e the l o c a l r e l e a s e of a s t a b l e , smooth 66 muscle r e l a x i n g t r a n s m i t t e r which i s more potent than the catecholamines, and i s e l i m i n a t e d at a slower rate.. E f f e c t s of t h i s type have not been described w i t h histamine, b r a d y k i n i n , s e r o t o n i n , or g a s t r i n , but i t has been suggested t h a t perhaps 5 -hydroxytryptamine may be i m p l i c a t e d i n the g a n g l i o n i c t r a n s - mission step of t h i s vagal i n h i b i t o r y p a t h w a y * ^ 5 k The c e p h a l i c phase of g a s t r i c s e c r e t i o n , mediated v i a the v a g i , r e s u l t s i n increased s e c r e t i o n of h y d r o c h l o r i c a c i d and pepsin. This i s an energy consuming process, r e q u i r i n g i n - creased "blood f l o w . The se c r e t o r y response i s achieved v i a s t i m u l a t i o n of high t h r e s h o l d f i b r e s , as i s g a s t r i c v a s o d i l a - t a t i o n which would provide the increased blood flow necessary f o r the s e c r e t o r y response. Martinson has proposed t h a t stimu- l a t i o n of these high t h r e s h o l d vagal e f f e r e n t s i n i t i a t e s a p h y s i o l o g i c , g a s t r i c p e r i p h e r a l response p a t t e r n comprised of the s e c r e t i o n of h y d r o c h l o r i c a c i d and pepsinogen, v a s o d i l a t a - t i o n , and r e l a x a t i o n of the corpus and fundus ( r e c e p t i v e r e l a x a - 84 85 t i o n ) i n a s s o c i a t i o n w i t h swallowing. ' The i n d i v i d u a l com- ponents of t h i s response p a t t e r n cannot be separated by means of the e l e c t r o p h y s i o l o g i c a l p r o p e r t i e s of the f i b r e s i n v o l v e d . At the same time, a n t r a l a c t i v i t y i s enhanced, wi t h e f f e c t i v e mixing and p r o p u l s i o n of the stomach contents. The r e l a t i v e fewness of e f f e r e n t vagal f i b r e s suggests t h a t though they i n i t i a t e the p a t t e r n of response, the f i n a l response i s governed by the f a r g r e a t e r number of neurones i n the myenteric plexuses, and probably by l o c a l hormone a c t i o n as w e l l . I t has been demonstrated t h a t r e p e t i t i v e s t i m u l a t i o n of nervous t i s s u e at high frequencies can r e s u l t i n increased r e s - 19 103 ponsiveness to subsequent s t i m u l a t i o n . 7 1 J Rapid, r e p e t i t i v e s t i m u l a t i o n i s thought t o cause a p e r s i s t e n t h y p e r p o l a r i z a t i o n of the ter m i n a t i o n s of the presynaptic or motor f i b r e s i n v o l v e d at the l e v e l of Auerbach's ple x u s , w i t h a consequent increase 55 i n the amount of t r a n s m i t t e r substance rele a s e d i n response to subsequent s t i m u l a t i o n . P o t e n t i a t i o n of g a s t r i c c o n t r a c t i o n i n response to e f f e r e n t vagal s t i m u l a t i o n has been achieved by- preceding a r e g u l a r t e s t stimulus (at f o r example 5-10 impulses per second) by a t h i r t y second p e r i o d of s t i m u l a t i o n using the same volt a g e and impulse d u r a t i o n , but a p p l i e d at a con s i d e r a b l y higher impulse frequency, of the order of 20-50 impulses per second. S i m i l a r p o t e n t i a t i o n of e f f e r e n t vagal s t i m u l a t i o n on i n t e s t i n a l c o n t r a c t i l i t y has a l s o been observed. P o t e n t i a t i o n of a f f e r e n t or r e f l e x vagal s t i m u l a t i o n was e f f e c t i v e i n i n c r e a s - i n g i n t e s t i n a l c o n t r a c t i l i t y f o l l o w i n g the r e g u l a r t e s t s t i m u l u s ; however, slow s t i m u l a t i o n of a f f e r e n t vagal f i b r e s had no s i g n i - f i c a n t e f f e c t on g a s t r i c c o n t r a c t i l i t y e i t h e r before or a f t e r the a p p l i c a t i o n of a p o t e n t i a t i n g s t i m u l u s . The increased response of i n t e s t i n a l (but not g a s t r i c ) muscle t o slow a f f e r - ent vagal s t i m u l a t i o n a f t e r a p o t e n t i a t i n g stimulus i s an ex- ample of p o t e n t i a t i o n mediated v i a an autonomic r e f l e x arc through the CNS. P o t e n t i a t i o n i s increased i n degree and d u r a t i o n when a l l vagal connections are severed. This has been i n t e r p r e t e d as being due t o the removal of the r e f l e x i n h i b i t i o n mediated v i a vagal a f f e r e n t s . P o s t - a c t i v a t i o n p o t e n t i a t i o n of e i t h e r a c i d or pepsin s e c r e t i o n has not been demonstrated, but perhaps t h i s could yet be achieved using d i f f e r e n t stimulus parameters. The p o t e n t i a t i o n i s produced by impulse frequencies (20- 50 per second) at which the va g a l f i b r e s may be expected t o 56 64 conduct. Iggo has recorded impulse frequencies of 30 per second i n non-myelinated vagal a f f e r e n t s i n c a t s . I t has a l - ready been noted t h a t i n c a t s , approximately 3»00° e f f e r e n t vagal f i b r e s are given the task of c o o r d i n a t i n g or at l e a s t modifying g a s t r o i n t e s t i n a l s e c r e t i o n and m o t i l i t y . This con- cept of p o t e n t i a t i o n and f a c i l i t a t i o n of c o n t r a c t i l e a c t i v i t y may account f o r the economic achievement of at l e a s t the motor f u n c t i o n s of the v a g i w i t h the r e l a t i v e l y small numbers of e f f e r e n t f i b r e s a v a i l a b l e , and i s a simple means of r e c o n c i l i n g the m u l t i p l i c i t y of a c t i o n s a t t r i b u t e d t o the e f f e r e n t v a g a l supply to the abdomen. 3. Sympathetic E f f e r e n t Pathways Sympathetic v i s c e r a l e f f e r e n t f i b r e s a l s o c o n s i s t of low t h r e s h o l d e x c i t a t o r y f i b r e s which are c h o l i n e r g i c and probably synapse at the myenteric plexus l e v e l , and high t h r e s h o l d i n h i - b i t o r y f i b r e s which are probably adrenergic, and synapse i n the 107 sympathetic g a n g l i a . Kure has described myelinated e f f e r e n t f i b r e s emerging i n the d o r s a l s p i n a l roots from l e v e l s T k-L 2, passing through the p r e v e r t e b r a l g a n g l i a without synapse, and 7R 88 reaching the stomach v i a the g r e a t e r splanchnic nerves. * These e x c i t a t o r y sympathetic f i b r e s have been shown to be c h o l i n e r g i c , as response to t h e i r s t i m u l a t i o n i s blocked by 107 a t r o p i n e . They have been termed " s p i n a l parasympathetics", and may be the same ex t r a v a g a l parasympathetic outflow a l l u d e d to i n J e f f e r s o n ' s w o r k . ^ 7 " ^ Splanchnic s t i m u l a t i o n g e n e r a l l y r e s u l t s i n g a s t r i c i n h i b i t i o n , but when the i n h i b i t o r y f i b r e s 5? are "blocked by the a p p l i c a t i o n of n i c o t i n e to the sympathetic g a n g l i a , splanchnic s t i m u l a t i o n has an e x c i t a t o r y a c t i o n , mediated presumably v i a the f i b r e s j u s t described. D. C e n t r a l I n t e g r a t i o n of Autonomic Nerve Pathways Experimental e l e c t r i c a l s t i m u l a t i o n s t u d i e s of the b r a i n have demonstrated l o c i i n many c e r e b r a l areas which have both 107 e x c i t a t o r y and i n h i b i t o r y i n f l u e n c e on g a s t r i c m o t i l i t y . These e f f e c t s are conveyed by sympathetic and parasympathetic v i s c e r a l e f f e r e n t f i b r e s , each of which c o n t a i n both e x c i t a t o r y and i n h i b i t o r y f i b r e s . They f u n c t i o n r e c i p r o c a l l y to regula t e m o t i l i t y by imposing a higher c o n t r o l . The e f f e c t s are guided by impulses which o r i g i n a t e i n v i s c e r a l and somatic receptors which respond to o s m o t i c a l l y a c t i v e substances, pH, pressure and muscle s t r e t c h , and by i n t r a c e r e b r a l i n p u t s . Somatic and v i s - c e r a l p a i n r e c e p t o r s , s p e c i a l sense r e c e p t o r s , and receptors i n v o l v e d w i t h emotional responses c o n t r i b u t e to i n i t i a t i n g these r e f l e x e s . The a f f e r e n t limb of each r e f l e x i s i n c o r - porated i n t o vagal and sympathetic a f f e r e n t s . E f f e r e n t impulses i n i t i a t e a c t i v i t y which w i l l best prepare the stomach f o r i t s f u n c t i o n s , and modify i t s ongoing a c t i v i t y i n accordance w i t h the needs of the organism as a whole. C o r t i c a l i n f l u e n c e i s f u n n e l l e d through the subcortex and brainstem. There are feed- back mechanisms at each l e v e l of c o n t r o l to provide f o r a h i e r - archy p e r m i t t i n g any given r e g i o n to e x h i b i t a dual r o l e i n i n f l u e n c i n g regions more c e n t r a l or more d i s t a l to i t , thus 58 securing homeostasis i n the r e g u l a t i o n of g a s t r i c m o t i l i t y . I n i n t e r p r e t a t i o n of these concepts, one must consider t h a t the response t o s t i m u l a t i o n of any given area i s r e l a t e d t o the species of animal s t u d i e d , the degree of tonus of the organ at the time of s t i m u l a t i o n , the stimulus parameters, the e f f e c t of anaesthesia, and many other f a c t o r s of t h i s nature. I t i s v a l i d t o compare the r e s u l t s of d i f f e r e n t s t u d i e s only i f these circumstances are taken i n t o c o n s i d e r a t i o n . E l i a s s o n ' has c o n c i s e l y described many of the i n t r a - c e r e b r a l pathways i n v o l v e d i n the r e g u l a t i o n of g a s t r i c m o t i l i t y . He has t r a c e d f i b r e s from each of the c o r t i c a l areas which i n - fluence c o n t r a c t i l e a c t i v i t y t o the r e g i o n of the a n t e r i o r commissure, thence to the thalamic n u c l e i and hypothalamus. F i b r e s pass from behind the diencephalon t o the corpora q u a d r i - gemina and r e t i c u l a r substance. Here the f i b r e s separate i n t o a p r i m a r i l y e x c i t a t o r y d o r s a l bundle and a p r i m a r i l y i n h i b i t o r y v e n t r a l bundle; both are then t r a c e d to the vagal n u c l e i . The medulla, which i s comprised i n p a r t from the d o r s a l motor nucleus of the vagus and the bulbar accessory nerves, r e c e i v e s f i b r e s from the nodose g a n g l i o n , which i s i n t u r n the s i t e of c e l l bodies of some of the v i s c e r a l a f f e r e n t f i b r e s from the abdominal c a v i t y . S t i m u l a t i o n of these v a r i e d regions has confirmed the con- cept t h a t the v a g i and sympathetics each c o n t a i n both e x c i t a t o r y and i n h i b i t o r y f i b r e s . With Martinson's i n v e s t i g a t i o n i n mind, i t i s l i k e l y t h a t the c o n f l i c t i n g r e s u l t s obtained by other 59 i n v e s t i g a t o r s f o l l o w i n g s t i m u l a t i o n of these pathways have been due to a mixed p e r i p h e r a l e f f e c t of simultaneous a c t i v a t i o n of both types of f i b r e s . The f o l l o w i n g examples serve to i l l u s t r a t e some of these 107 p r i n c i p l e s . A l l e f f e c t s on g a s t r i c m o t i l i t y f o l l o w i n g stimu- l a t i o n of the thalamus are abolished by b i l a t e r a l vagotomy or by a t r o p i n e , but not by splanchnic s e c t i o n . Thus, the g a s t r i c motor impulses e l i c i t e d by thalamic s t i m u l a t i o n are c a r r i e d by the v a g i . S t i m u l a t i o n of the d o r s a l column of anaesthetized dogs r e s u l t s i n an e x c i t a t o r y response, whereas v e n t r a l column s t i m u l a t i o n causes i n h i b i t i o n of g a s t r i c m o t i l i t y . This e f f e c t i s a b o l i s h e d by b i l a t e r a l splanchnicotomy, and suggests that motor pathways i n the d o r s a l r o o t s connect the splanchnics t o the medulla. J e f f e r s o n ' s work, described i n a previous s e c t i o n , has demonstrated an e x c i t a t o r y response to s t i m u l a t i o n of e i t h e r d o r s a l or v e n t r a l s p i n a l roots i n the r e g i o n from T^-L^; he has suggested that both ro o t s convey motor f i b r e s t o the stomach. This p a r t i c u l a r phenomenon i s not a b o l i s h e d by removal of e i t h e r the s t e l l a t e or c e l i a c g a n g l i a . J e f f e r s o n has a l s o observed g a s t r i c c o n t r a c t i o n upon s t i m u l a t i o n of the i s o l a t e d vagus nerve i n the thorax (s e c t i o n e d both i n the neck and above the d i a - 107 phragm); ' from t h i s observation he concludes th a t there are e f f e r e n t , e x t r a v a g a l motor f i b r e s to the stomach, c h o l i n e r g i c i n t h e i r a c t i o n , which leave the cord between T^ and L^, and reach the stomach v i a the splanchnics and perhaps other pathways as yet uncharted. F o l l o w i n g s e c t i o n of the v a g i and the s p i n a l 60 cord, s u p r a - s p i n a l s t i m u l a t i o n r e g i s t e r s no e f f e c t on g a s t r i c 77 m o t i l i t y . ' G e n e r a l l y , i n h i b i t o r y impulses, p a r t i c u l a r l y those i n i t i a t e d i n somatic a f f e r e n t s and those a s s o c i a t e d w i t h emo- t i o n a l disturbances, are conveyed v i a the sympathetic nerves. E x c i t a t o r y responses are g e n e r a l l y c a r r i e d i n the v a g i . Vagal i n h i b i t i o n i s concerned more w i t h s p e c i f i c i n h i b i t o r y r e f l e x e s , such as r e c e p t i v e r e l a x a t i o n . Thus a l l l e v e l s of the CNS have been shown by s t i m u l a t i o n and a b l a t i o n s t u d i e s to i n f l u e n c e g a s t r i c m o t i l i t y ; successive a b l a t i o n from higher t o lower l e v e l s of c o n t r o l i s g e n e r a l l y accompanied by increased m o t i l i t y . 1 0 ' ' ' I t i s evident t h a t the i n t e g r a t i o n of c o n t r o l of g a s t r i c m o t i l i t y and the as s o c i a t e d e l e c t r i c a l phenomena are complex. Once again, i t i s prudent to consider t h a t the response to s t i m u l a t i o n may be modified by the numerous f a c t o r s o u t l i n e d at the beginning of t h i s s e c t i o n ; i t i s th e r e f o r e d i f f i c u l t i f not impossible t o draw any sweeping or dogmatic conclusions i n t h i s f i e l d of study. SECTION VI. THE GASTRODUODENAL JUNCTION Though the major focus of t h i s review i s concerned wi t h g a s t r i c c o n t r a c t i l e and e l e c t r i c a l a c t i v i t y , the f u n c t i o n and c o n t r o l of the gastroduodenal j u n c t i o n i s r e l e v a n t to t h i s d i s c u s s i o n . The d e t a i l s of anatomical c o n t i n u i t y of the pylorus and duodenal cap are e s s e n t i a l to understanding the p o s s i b l e 61 i n t e g r a t i o n of f u n c t i o n of t h i s area. There are b a s i c a l l y three f u n c t i o n a l u n i t s to be considered: the pylorus and antrum operating as one u n i t ; the duodenal bulb above the en- trance of the common b i l e duct; and the duodenum proper below that l e v e l . C i r c u l a r muscle on e i t h e r side of the p y l o r i c r i n g i s discontinuous; however, approximately 20% of the l o n g i - t u d i n a l muscle f i b r e s from the antrum continue i n t o the duo- denum, p r i m a r i l y along the l e s s e r curve." 1" 0 The myenteric plexus, which remains l a r g e l y i n a s s o c i a t i o n with the l o n g i t u - tc-a d i n a l f i b r e s , i s a l s o p a r t l y continued i n t o the duodenum. J The outer subserous plexus c o n t a i n i n g vagal and sympathetic f i b r e s i s a l s o continuous across the p y l o r u s , but the degree of c o n t i n u i t y of the submucous plexus i s u n c e r t a i n . Duodenal e l e c t r i c a l a c t i v i t y i s c o n t r o l l e d by two separate pacemakers. The duodenal bulb has an e r r a t i c , i r r e g u l a r , low voltage BER; approximately 70% of BER c y c l e s are a s s o c i a t e d with a c t i o n p o t e n t i a l s and c o n t r a c t i l e a c t i v i t y . 1 0 This per- centage i s s u b s t a n t i a l l y higher than that which i s observed i n a s s o c i a t i o n w i t h the g a s t r i c or main duodenal p a c e s e t t e r po- t e n t i a l s . The main duodenal pacemaker i s s i t u a t e d at the l e v e l 14 of the common b i l e duct, but a s p e c i f i c , l o c a l i z e d pacemaker node has not as yet been i d e n t i f i e d . This pacemaker has an inherent frequency ( i n dogs) of 17-19 per m i n u t e , a n d i s propagated i n i t i a l l y at 20 cm. per second, with a p r o g r e s s i v e l y decreasing r a t e of propagation i n the more d i s t a l s m a ll bowel such t h a t i l e a l slow waves become independent of t h i s pacemaker 62 and o r i g i n a t e i n s t e a d w i t h i n the d i s t a l s m a l l bowel w a l l i t s e l f . 3 6 The duodenal pacemaker i s a f f e c t e d by f a c t o r s s i m i l a r t o those which have been d i s c u s s e d with r e f e r e n c e t o the g a s t r i c i k to R Q pacemaker. • J J * Vagotomy has no a p p r e c i a b l e e f f e c t on the duodenal BER. L o c a l i z e d duodenal h e a t i n g i n c r e a s e s the BER frequency, and may p r e c i p i t a t e e c t o p i c f o c i with r e t r o - grade c o n d u c t i o n o f p o t e n t i a l s . L o c a l i z e d c o o l i n g , t r a n s e c - t i o n , or clamping of the duodenum below the s i t e of the pace- maker decrease the BER frequency by i n t e r r u p t i n g c o n d u c t i o n 14 pathways. Duodenal pacemaker a c t i v i t y i n humans has been c o r r e l a t e d with t h y r o i d f u n c t i o n ; h y p e r a c t i v i t y 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 BER frequency; c o n v e r s e l y , a slowing of the BER i s 30-32 observed i n a s s o c i a t i o n w i t h decreased t h y r o i d f u n c t i o n . J The i n f l u e n c e of the t h y r o i d gland supports the view t h a t c e l l u l a r m e t abolic p r o c e s s e s are i n v o l v e d i n governing the slow wave frequency. D a n i e l J has r e c e n t l y compared the c o n t r o l a c t i v i t y or BER of the stomach wi t h t h a t of the duodenum, and has observed the f o l l o w i n g s i m i l a r i t i e s : ( i ) both a r i s e i n l o n g i t u d i n a l muscle, and are p r o- pagated e l e c t r o t o n i c a l l y i n t o the u n d e r l y i n g c i r c u l a r muscle; ( i i ) both are i n h e r e n t and spontaneous i n o r i g i n , and are not r e l a t e d to c o n t r a c t i l e a c t i v i t y ; a 63 higher i n t r i n s i c frequency i s found i n the proximal regions of each organ; ( i i i ) both e x h i b i t c o n t r o l over d i s t a l f r e q u e n c i e s , such t h a t the lower d i s t a l frequencies are " p u l l e d i n " or coupled to the higher proximal frequ e n c i e s ; ( i v ) both are s e n s i t i v e to i n h i b i t o r s of ATP^^-, i n d i c a t i n g a p o s s i b l e common mode of o r i g i n . - ' There were, however, appreciable d i f f e r e n c e s between the two PP's. Though the duodenal p o t e n t i a l i s capable of both caudad and retrograde propagation, i t does not demonstrate the f o l l o w i n g c h a r a c t e r i s t i c s t h a t are observed w i t h the g a s t r i c PP: ( i ) there i s no measurable r e f r a c t o r y p e r i o d f o l l o w i n g the duodenal slow wave; ( i i ) premature PP's cannot be induced by a c e t y l - c h o l i n e ; ( i i i ) catecholamines do not a b o l i s h the PP at e i t h e r l o c a l or d i s t a n t s i t e s . These observations suggest that perhaps the mechanisms under- l y i n g the i n i t i a t i o n of slow waves i n the stomach and duodenum are not i n f a c t i d e n t i c a l . Opinion v a r i e s as to the degree of c o o r d i n a t i o n between a n t r a l and duodenal a c t i v i t y . ^ 3 ' ^3 J+J W o u l d seem reasonable to suggest t h a t mechanisms e x i s t t o formulate a coordinated motor u n i t which would promote g a s t r i c mixing and emptying, and at the same time prevent duodenal r e f l u x . The g a s t r i c PP, 64 o r i g i n a t i n g i n the proximal g r e a t e r curve, sweeps down the g a s t r i c musculature w i t h i n c r e a s i n g v e l o c i t y , a t t a i n i n g a ra t e of 3- k cm. per second i n the antrum due to the g r e a t l y increased c o n d u c t i v i t y i n t h i s r e g i o n . The r a p i d progress of t h i s i n i t i a l d e p o l a r i z a t i o n permits the e n t i r e antrum to c o n t r a c t v i r t u a l l y simultaneously. The t e r m i n a l a n t r a l c o n t r a c t i o n so produced, i n c o n j u n c t i o n w i t h the c l o s e d , contracted p y l o r i c r i n g , i s w e l l designed f o r r e t r o p u l s i o n and thorough mixing of the 29 53 g a s t r i c chyme. J The frequency of the t e r m i n a l a n t r a l c o n t r a c t i o n i s r a t e - l i m i t e d by the frequency of the BER, The p y l o r i c r i n g musculature per se does not i n f l u e n c e r e s i s t a n c e to flow except i n a s s o c i a t i o n w i t h a n t r a l a c t i v i t y . I t i s not so much a s p h i n c t e r as p a r t of a pumping mechanism which regu- 53 l a t e s g a s t r i c e j e c t i o n of chyme i n t o the duodenum. J According t o many i n v e s t i g a t o r s , the g a s t r i c p a c e s e t t e r p o t e n t i a l continues as f a r as the connective t i s s u e septum between the antrum and duodenum, and there ceases. I t has been suggested t h a t t h i s "hypomuscular zone" acts as an e l e c t r i c a l l y s i l e n t i n s u l a t o r , and th a t there can be no e l e c t r o t o n i c spread of c u r r e n t through t h i s segment. However, some s t u d i e s have recorded o c c a s i o n a l evidence of duodenal e l e c t r i c a l a c t i v i t y i n the antrum, and r a r e l y a n t r a l e l e c t r i c a l a c t i v i t y i n the 43 duodenum. y These s t u d i e s have suggested t h a t the e l e c t r o t o n i c spread of current across t h i s j u n c t i o n occurs by way of the contiguous l o n g i t u d i n a l muscle f i b r e s . This observation lends support to the myogenic theory of o r i g i n and conduction of the 65 slow wave p o t e n t i a l . In view of the muscular and n e u r a l con- n e c t i o n s a c r o s s the gastroduodenal j u n c t i o n as o u t l i n e d above, i t i s d i f f i c u l t t o conceive of t h i s r e g i o n as an e l e c t r i c a l l y s i l e n t i n s u l a t o r . 2 53 A l l e n ' J J has p r o v i d e d evidence t o suggest a p o s s i b l e mechanism whereby a n t r a l and duodenal a c t i v i t y are i n t e r l o c k e d . Most work has shown t h a t there i s no c o n s i s t e n t temporal r e l a - t i o n s h i p between the a n t r a l and duodenal BER, or between a n t r a l and duodenal c o n t r a c t i o n s , i n e i t h e r f a s t e d or f e d animals (dogs). I n f a s t e d animals, there i s s i m i l a r l y no r e l a t i o n s h i p between duodenal a c t i o n p o t e n t i a l s (and a s s o c i a t e d c o n t r a c t i l e a c t i v i t y ) and the a n t r a l BER, However, i n f e d dogs, a r e l a - t i o n s h i p does e x i s t between the a n t r a l BER and duodenal con- t r a c t i o n i n which the a n t r a l BER suppresses a duodenal c o n t r a c - t i o n when a duodenal BER c y c l e begins synchronously with the onset of an a n t r a l BER c y c l e . Instead, the duodenal c o n t r a c - t i o n i s a s s o c i a t e d w i t h e i t h e r the second or t h i r d duodenal BER c y c l e f o l l o w i n g the onset of the a n t r a l BER c y c l e . The i n t e r l o c k i n g of a n t r a l and duodenal a c t i v i t y i s somehow brought i n t o p l a y f o l l o w i n g the i n g e s t i o n of f o o d . I n t e g r a t i o n may occur v i a e l e c t r i c a l impulses t r a n s m i t t e d w i t h i n the myenteric p l e x u s , v i a hormonal pathways, or v i a the stimulus of the g a s t r i c chyme e j e c t e d i n t o the duodenum. I t has a l s o been suggested t h a t because the duodenal BER i s u s u a l l y a 3 s i or 4:1 harmonic of the g a s t r i c BER, there may be a c o u p l i n g of the g a s t r i c and duodenal rhythms; the two pacemakers may func- t i o n as coupled r e l a x a t i o n o s c i l l a t o r s . J 66 With r e s p e c t t o s u r g i c a l a l t e r a t i o n of the gastroduodenal j u n c t i o n , an i n t e r e s t i n g concept has been put forward t o ex- p l a i n the e f f i c a c y of p y l o r o p l a s t y i n a s s o c i a t i o n with vagotomy. Vagotomy has been a s s o c i a t e d w i t h a d i s o r g a n i z e d BER d u r i n g the f i r s t p o s t o p e r a t i v e week, due t o the emergence of e c t o p i c f o c i of impulse g e n e r a t i o n . I t has been suggested t h a t p y l o r o p l a s t y may reduce the e x c i t a b i l i t y of e c t o p i c pacemakers i n the r e g i o n of the p y l o r u s which may have i n i t i a t e d randomly propagated p o t e n t i a l s . The net e f f e c t would be l e s s d i s o r g a n i z a t i o n of the BER than would occur without p y l o r o p l a s t y , and hence l e s s d i s t u r b a n c e of g a s t r i c p e r i s t a l s i s and improved g a s t r i c emptying k-3 io4 f o l l o w i n g vagotomy. J * SECTION V I I . THE SMALL INTESTINE From the p o i n t of view of comparison, the f o l l o w i n g s e c t i o n b r i e f l y o u t l i n e s some of the f e a t u r e s of s m a l l bowel motor and e l e c t r i c a l a c t i v i t y . There i s a g r a d i e n t of e l e c t r i c a l r h y t h m i c i t y p r o g r e s s i n g d i s t a l l y a l o n g the course of the s m a l l bowel, wi t h the dominant l 4 62 pacemaker l o c a t e d i n the second p a r t of the duodenum. ' BER frequency decreases p r o g r e s s i v e l y towards the ileum, a t which p o i n t the duodenal pacemaker no l o n g e r assumes c o n t r o l of 36 the e l e c t r i c a l a c t i v i t y . J The concept of segmental pacemakers c o l l e c t i v e l y forming a s e r i e s of coupled r e l a x a t i o n o s c i l l a t o r s p r o v i d e s the most p l a u s i b l e e x p l a n a t i o n f o r entrainment through- out the s m a l l bowel, and accounts f o r normal caudad p e r i - s t a l s i s . 6 2 ' 6? I n t e s t i n a l m o t i l i t y i s r e g u l a t e d by both e x t r i n s i c and i n t r i n s i c nerve pathways. The more prolonged l a t e n t p e r i o d of response, the r e l a t i v e p a u c i t y of nerve endings i n i n t e s - t i n a l versus g a s t r i c muscle, and the d i s p r o p o r t i o n a t e l y high number of impulses r e q u i r e d t o e f f e c t a response suggest t h a t e x c i t a t i o n or i n h i b i t i o n of i n t e s t i n a l smooth muscle r e s u l t s from a g e n e r a l i z e d d i f f u s i o n of t r a n s m i t t e r substance, r a t h e r than l i b e r a t i o n of the t r a n s m i t t e r at d i s c r e t e nerve endings i n the muscle substance. The i n t r i n s i c system i s much more r e a d i l y a c t i v a t e d i n 77 the small i n t e s t i n e than i n the stomach. ' The myenteric r e f l e x has been r e f e r r e d to as the "law of the i n t e s t i n e " as long ago as 1899 by B a y l i s s and S t a r l i n g . D* L o c a l stimu- l a t i o n of the i n t e s t i n e r e s u l t s i n e x c i t a t i o n above and i n h i - b i t i o n below the s i t e of s t i m u l a t i o n . R a d i a l s t r e t c h i n g of sensory receptors r a t h e r than increase i n transmural pressure i s the e f f e c t i v e s t i m u l u s . Transmission i n t h i s phenomenon i s c h o l i n e r g i c . The e x t r i n s i c i n n e r v a t i o n of the small i n t e s t i n e i s con- cerned w i t h the modulation of i n t r i n s i c r e f l e x e s . Both vagal and sympathetic f i b r e s may act i n e i t h e r an e x c i t a t o r y or i n - h i b i t o r y c a p a c i t y , depending on f a c t o r s analogous to those d i s - cussed w i t h reference to g a s t r i c m o t i l i t y . The sympathetic system i s e s s e n t i a l l y i n h i b i t o r y . I n h i - b i t o r y adrenergic alpha receptors are l o c a t e d i n the ganglion c e l l s i n n e r v a t i n g the smooth muscle, while i n h i b i t o r y beta 68 i k 7 7 receptors r e s i d e i n the smooth muscle f i b r e s themselves. ' S t i m u l a t i o n of sympathetic e f f e r e n t s g e n e r a l l y r e s u l t s i n i n h i - b i t i o n of i n t e s t i n a l tone and c o n t r a c t i l i t y , w i t h the most pronounced e f f e c t o c c u r r i n g i n the t e r m i n a l ileum. Vagal f i b r e s may be e i t h e r e x c i t a t o r y or i n h i b i t o r y i n t h e i r i n f l u e n c e . The e x c i t a t o r y e f f e c t s are more preva l e n t i n the upper small i n t e s t i n e , as the splanchnics have a g r e a t e r i n h i b i t o r y i n f l u e n c e i n the t e r m i n a l ileum. P o s t - a c t i v a t i o n p o t e n t i a t i o n of i n t e s t i n a l c o n t r a c t i l i t y f o l l o w i n g both a f f e r e n t 19 77 and e f f e r e n t vagal s t i m u l a t i o n has already been discussed. 7* 1 1 To summarize, the i n t r i n s i c n e u r a l pathways p l a y a more s i g n i f i c a n t r o l e i n the r e g u l a t i o n of i n t e s t i n a l m o t i l i t y than i n r e g u l a t i o n of g a s t r i c m o t i l i t y . The e x t r i n s i c nerves are p r i m a r i l y geared to f a c i l i t a t e or otherwise modify the i n t r i n s i c r e f l e x e s . SECTION V I I I . HUMAN BER The BER of the human stomach has been examined and recorded by means of p e r o r a l s u c t i o n e l e c t r o d e s i n contact w i t h the 90 g a s t r i c mucosa. I t c o n s i s t s of a t r i p h a s i c complex l a s t i n g 2.5-3.0 seconds, i s propagated at a v e l o c i t y of approximately 2 cm. per second i n the antrum, and has an inherent n a t u r a l frequency of three c y c l e s per minute. During the f a s t i n g s t a t e , approximately 25-30% of the BER c y c l e s are as s o c i a t e d w i t h ac- t i o n p o t e n t i a l s , which are represented e l e c t r i c a l l y by a burst of r a p i d spikes of unequal amplitude, beginning 3-4 seconds 69 a f t e r the onset of the BER complex, and l a s t i n g 3-6 seconds. The AP's are a s s o c i a t e d with g a s t r i c c o n t r a c t i l e a c t i v i t y . The electromyographic discharge of the a c t i o n p o t e n t i a l i s r e l a t e d both i n time and amplitude t o the pr e s s u r e wave 35 o recorded by e i t h e r a s t r a i n gauge or i n t r a l u m i n a l b a l l o o n . J 1 7 Duodenal BER has been recorded i n humans at a frequency 3 0 - 3 2 of 11.7 c y c l e s p e r minute. J There i s a descending g r a d i - ent o f BER frequency along the l e n g t h of the s m a l l i n t e s t i n e , w ith i l e a l r a t e s recorded a t 9.5 c y c l e s p e r minute. Human BER i s s e n s i t i v e t o temperature change i n a manner s i m i l a r to t h a t d e s c r i b e d f o r animals. I t i s a p p a r e n t l y not a f f e c t e d by f a s t i n g . The BER frequency has been shown to vary w i t h the a c t i v i t y o f the t h y r o i d gland; i n c r e a s e d BER frequency i s observed i n h y p e r t h y r o i d s t a t e s , and decreased r a t e s are 3 0 a s s o c i a t e d w i t h impaired t h y r o i d f u n c t i o n . I n s u l i n induced hypoglycemia has been shown to independently decrease the frequency of the BER. 70 CHAPTER TWO METHODS OF INVESTIGATION 1. The P l a n of the Experiment The p l a n of the experiment aimed at developing an i n t r a - o perative t e s t to assess the completeness of vagotomy was e s s e n t i a l l y twofold: ( i ) t o determine whether complete vagotomy would a l t e r the g a s t r i c e l e c t r i c a l a c t i v i t y i n some reproducible manner such as would i n d i c a t e that a l l vagal connec- t i o n s had been severed; ( i i ) to d i v i d e one vagus at the l e v e l of the esophageal h i a t u s , assess the e f f e c t on the e l e c t r i c a l a c t i v i t y of s t i m u l a t i o n of i t s d i s t a l or p e r i p h e r a l end, then s t i m u l a t e the c e n t r a l end w i t h view to e l i c i t i n g a response i n the e l e c t r i c a l a c t i v i t y v i a r e f l e x path- ways through the b r a i n stem and vagal n u c l e i , and hence down the remaining i n t a c t e f f e r e n t vagal f i b r e s ; the remaining f i b r e s would then be d i v i d e d , c e n t r a l s t i m u l a t i o n of e i t h e r vagal trunk repeated, and pre- sumably the p r e v i o u s l y observed " c h a r a c t e r i s t i c " response of the g a s t r i c e l e c t r i c a l a c t i v i t y would no longer be obtained, i n d i c a t i n g complete d i v i s i o n of a l l vagal f i b r e s . The r e f l e x pathway of vagal impulse t r a n s m i s s i o n through the c e n t r a l nervous system and g a s t r i c s e c r e t o r y and motor 71 responses t o a f f e r e n t v a g a l s t i m u l a t i o n have been adequately- documented i n the i n t r o d u c t o r y chapter of t h i s review. One may reasonably expect t h a t a c o r r e s p o n d i n g e f f e c t on g a s t r i c e l e c t r i c a l a c t i v i t y c o u l d a l s o be obtained v i a t h i s vago-vagal r e f l e x . To i n v e s t i g a t e these q u e s t i o n s , f i v e groups of animals were s t u d i e d . 2, Group I . Recording of the BER; the e f f e c t of v a g a l s e c t i o n and v a g a l stimu- l a t i o n u s i n g sodium t h i o p e n t a l a n a e s t h e s i a Twenty-six mongrel dogs weighing 15-25 kilograms were s t u d i e d i n acute experiments f o l l o w i n g an o v e r n i g h t f a s t . The animals were a n a e s t h e t i z e d w i t h sodium t h i o p e n t a l ( P e n t o t h a l , A b b o t t ) , and r e s p i r a t i o n was c o n t r o l l e d by the use of a B i r d Mark VII r e s p i r a t o r . A n t i c h o l i n e r g i c drugs were not adminis- t e r e d p r e - o p e r a t i v e l y . G a s t r i c e l e c t r i c a l a c t i v i t y was recorded by s e v e r a l methods. In the i n i t i a l t r i a l s , e l e c t r o d e s of both s t a i n l e s s s t e e l and s i l v e r w ire, 0.006-0.010 inches i n diameter, were implanted s u b s e r o s a l l y p e r p e n d i c u l a r to the long a x i s of the stomach. However, r e c o r d i n g s obtained i n t h i s manner were of u n s u i t a b l e q u a l i t y , and t h i s method was consequently abandoned. A l l e l e c - t r i c a l r e c o r d i n g s e v a l u a t e d i n both t h i s and subsequent groups of study were obtained u s i n g monopolar s i l v e r wire e l e c t r o d e s . The e l e c t r o d e t i p p r o j e c t e d 2 mm. from one s u r f a c e of a f l a t , d o u b l e - l a y e r e d T e f l o n d i s c . The s i l v e r wire e l e c t r o d e , w i t h the e x c e p t i o n of i t s t i p , was i n s u l a t e d by a T e f l o n sheath, and 72 was connected between the d i s c s to an i n s u l a t e d copper wire l e a d . The e n t i r e e l e c t r o d e assembly, again with the exception of the e l e c t r o d e t i p , was sealed w i t h epoxy r e s i n . The stomach was exposed through a m i d - l i n e laparotomy i n c i s i o n . The e l e c t r o d e d i s c s were sutured v i a d r i l l holes i n each of the f o u r corners to the s e r o s a l surface of the g r e a t e r curve of the stomach i n a s e r i a l f a s h i o n from the fundus to the t e r m i n a l antrum. I n s u l a t e d wire leads t r a n s m i t t e d the e l e c - t r i c a l s i g n a l to an a l t e r n a t i n g current a m p l i f i e r , which i n t u r n was l i n k e d to one channel of a r e c t i l i n e a r r e c o r d i n g system (Physiograph S i x - E & M Instruments). A time constant of 0.3 seconds was s e l e c t e d on the AG a m p l i f i e r . C a l i b r a t i o n was adjusted such t h a t a one m i l l i v o l t impulse was represented by a 15 mm. pen d e f l e c t i o n . A r e l a t i v e l y long time constant was chosen to a l l o w accurate r e c o r d i n g of the BER and evalua- t i o n of the temporal r e l a t i o n s h i p between the BER and any a s s o c i a t e d a c t i o n p o t e n t i a l s . Shorter time constants were found to deform or even e l i m i n a t e the BER complex ( F i g . 8 B ) . One disadvantage of the longer time constant r e l a t e d to the need to reduce the a m p l i f i e r g a i n i n order to avoid excessive d r i f t i n g of the b a s e l i n e . Shorter time constants and higher a m p l i f i c a t i o n allowed b e t t e r r e c o r d i n g of what were i n t e r p r e t e d as a c t i o n p o t e n t i a l s a s s o c i a t e d w i t h c o n t r a c t i l e a c t i v i t y , but the BER was so d i s t o r t e d as t o be u n i n t e r p r e t a b l e . The most s a t i s f a c t o r y recordings were obtained when the e l e c t r o d e s were i n f i r m contact w i t h serosa, but not p e n e t r a t i n g i t . E l e c t r o d e t i p s p e n e t r a t i n g the muscle or the g a s t r i c lumen produced r e c o r d i n g s which were unreadable because of extraneous e l e c - t r i c a l n o i s e . A f t e r r e c o r d i n g the b a s e l i n e BER, the vagus nerves were d i s s e c t e d a t the l e v e l of the esophageal h i a t u s , and were i s o - l a t e d by r e t r a c t i o n of adjacent s t r u c t u r e s . The t h o r a c i c c a v i t y was entered on a l l occasions t o f a c i l i t a t e i s o l a t i o n of a 3-k cm. segment of each nerve trunk. S t i m u l i t o both a f f e r e n t and e f f e r e n t v a g a l trunks were d e l i v e r e d by means of a s t a i n l e s s s t e e l b i p o l a r e l e c t r o d e f a s h i o n e d i n the form of a nerve hook. E l e c t r i c a l s t i m u l a t i o n was a p p l i e d i n the form of square wave impulses as d e l i v e r e d by the impulse g e n e r a t o r com- ponent of the Physiograph S i x system. The s t i m u l a t o r p r o v i d e d a range of impulse d u r a t i o n s (0.1, 0.5, and 2.0 m i l l i s e c o n d s ) , impulse f r e q u e n c i e s (2-200 impulses p e r second), and v o l t a g e s (0.1-130 v o l t s ) . In the i n i t i a l t r i a l experiments, s i n g l e v o l l e y impulses of v a r i o u s v o l t a g e s and impulse d u r a t i o n s were a p p l i e d , but these produced l i t t l e response. T h e r e a f t e r , s t i m u l i of v a r i e d g r a d a t i o n s were a p p l i e d f o r p e r i o d s of 60-120 seconds. Impulse d u r a t i o n s were v a r i e d on the b a s i s of the concept of the e x i s t e n c e of e x c i t a t o r y and i n h i b i t o r y f i b r e s Q "I Q j; as o u t l i n e d by Martin s o n . " D Most of the i n t e r p r e t a b l e r e s - ponses o c c u r r e d w i t h impulse d u r a t i o n s of 0,1 or 0.5 rase, a p p l i e d a t a frequency of 10 impulses p e r second. Low v o l t a g e s (5-20 V) produced minimal e f f e c t ; t h e r e f o r e , s t i m u l i of up t o 120 V, though u n p h y s i o l o g i c , were r e q u i r e d t o d e t e c t s i g n i f i - cant responses. 74 The BER was recorded i n a l l animals f o l l o w i n g the d i v i s i o n of one v a g a l trunk ( e i t h e r a n t e r i o r or p o s t e r i o r ) , and then f o l l o w i n g complete v a g a l s e c t i o n . F o l l o w i n g complete t r u n c a l vagotomy, the BER i n f i v e animals was f u r t h e r s t u d i e d under the f o l l o w i n g circumstances» ( i ) a f t e r esophageal t r a n s e c t i o n ; ( i i ) f o l l o w i n g r a p i d s a c r i f i c e of the animal by i n t r a - venous a d m i n i s t r a t i o n of potassium c h l o r i d e . D uring the course of s e v e r a l procedures, the r e g u l a r t e s t s t i m u l u s was preceded by a t h i r t y second p e r i o d of s t i m u l a t i o n u s i n g the same v o l t a g e and impulse d u r a t i o n as the t e s t stimulus i n q u e s t i o n , but a p p l i e d a t f r e q u e n c i e s of 5 0 - 1 0 0 impulses per s e c o n d . 6 0 ' 1 Q 3 The c e r v i c a l v a g i were d i s s e c t e d , d i v i d e d , and s t i m u l a t e d c e n t r a l l y and p e r i p h e r a l l y i n two dogs. The BER was examined before and d u r i n g s t i m u l a t i o n , and a f t e r complete c e r v i c a l vagotomy. 3 . Group I I . E f f e c t of the o p e r a t i v e procedure on BER A c o n t r o l group of s i x animals was s t u d i e d t o determine the e f f e c t of the o p e r a t i v e procedure per se on the r a t e of the BER. F i v e minute t r a c i n g s were recorded each f i f t e e n minutes over a two hour p e r i o d under o p e r a t i v e c o n d i t i o n s s i m i l a r to those which p r e v a i l e d . i n Group I . 75 k . Group I I I . E f f e c t of v a g a l s t i m u l a t i o n on BER, u s i n g c h l o r a l o s e - u r e t h a n e a n a e s t h e s i a A t h i r d s e r i e s of experiments was undertaken to take i n t o account the r e p o r t e d i n h i b i t o r y e f f e c t of b a r b i t u r a t e anaes- t h e s i a on the response of i n t r a g a s t r i c p r e s s u r e to v a g a l stimu- Q l a t i o n , as i t was c o n s i d e r e d t h a t t h i s i n h i b i t i o n might apply as w e l l to the v a g a l i n f l u e n c e on g a s t r i c e l e c t r i c a l a c t i v i t y . A mixture of c h l o r a l o s e and urethane was t h e r e f o r e used as a kg s u b s t i t u t e f o r sodium t h i o p e n t a l . A l p h a - c h l o r a l o s e (2 G.) was mixed wi t h urethane (10 G.) i n 100 cc of water, d i s s o l v e d by b o i l i n g , and a d m i n i s t e r e d i n t r a v e n o u s l y i n a dosage of 3*5 mg./kg. E l e c t r i c a l a c t i v i t y was recorded as d e s c r i b e d i n the d i s c u s s i o n of the f i r s t group of experiments, but i n t h i s s e r i e s , only a n t r a l e l e c t r o d e s were a p p l i e d . E l e c t r i c a l s t i m u l i to both a f f e r e n t and e f f e r e n t v a g a l trunks were d e l i v e r e d by the stimulus g e n e r a t o r a l r e a d y des- c r i b e d . Because of d i s t u r b i n g r e t c h i n g movements encountered upon c e n t r a l s t i m u l a t i o n of e i t h e r d i v i d e d v a g a l trunk i n the i n i t i a l f o u r animals s t u d i e d , s u c c i n y l c h o l i n e c h l o r i d e (Anectine, Dow) i n i n t e r m i t t e n t dosage of 20-30 mgm. was a d m i n i s t e r e d i n t r a v e n o u s l y t o c o u n t e r a c t t h i s e f f e c t . S t i m u l a t i o n i n the f o l l o w i n g twelve procedures was a p p l i e d w i t h the b i p o l a r s t a i n - l e s s s t e e l e l e c t r o d e employed i n Group I, u s i n g the same range of s t i m u l u s parameters o u t l i n e d i n t h a t s e c t i o n . In the remain- i n g t h i r t e e n animals s t u d i e d i n t h i s group, two i n n o v a t i o n s were i n t r o d u c e d . A s t i m u l u s i s o l a t o r ( T e k t r o n i x 2620) with a range of 0.01-30.0 m i l l i a m p e r e s was added to the s t i m u l a t o r component 76 w i t h the i n t e n t of ensuring p r e c i s e d e l i v e r y of the current s e l e c t e d by a u t o m a t i c a l l y compensating f o r any change i n the r e s i s t a n c e of the experimental model. A new, b i p o l a r phosphor- bronze s t i m u l a t i n g e l e c t r o d e w i t h broad, f l a t t e n e d contact surfaces was introduced f o r the purpose of minimizing heat damage to the nerve during s t i m u l a t i o n . The f l a t t e n e d sur- faces of the electro d e t i p s were designed t o permit the current to be d i s t r i b u t e d over a considerably longer segment of the nerve f i b r e . 5 . Group IV. Conduction v e l o c i t y of the BER Conduction v e l o c i t y of the BER was st u d i e d i n f o u r animals. E l e c t r i c a l a c t i v i t y was recorded i n a b i p o l a r f a s h i o n between two g a s t r i c e l e c t r o d e s s i t u a t e d 2 cm. and 5 cm. r e s p e c t i v e l y from the p y l o r u s . Conduction v e l o c i t y was examined before and a f t e r complete vagal s e c t i o n . E l e c t r i c a l s t i m u l a t i o n of a p e r i p h e r a l vagal trunk so d i s t o r t e d the BER that conduction v e l o c i t y during s t i m u l a t i o n could not be measured. 6• Group V. E f f e c t of p e n t a g a s t r i n on BER before and a f t e r vagotomy The e f f e c t of p e n t a g a s t r i n (Peptavlon, Ayerst) on g a s t r i c BER and c o n t r a c t i l e a c t i v i t y was examined i n e i g h t animals be- fo r e and a f t e r vagotomy. E l e c t r i c a l a c t i v i t y was recorded as o u t l i n e d f o r the i n i t i a l experimental groups. Baseline BER was recorded, and p e n t a g a s t r i n was then i n f u s e d continuously by means of a Harvard pump at a rat e of k ugm/kg./hr. Twenty 77 minutes a f t e r commencement of the i n f u s i o n , one vagus nerve ( e i t h e r a n t e r i o r or p o s t e r i o r ) was d i v i d e d at the l e v e l of the esophageal h i a t u s . The remaining vagal trunk was d i v i d e d a f t e r a f u r t h e r f i f t e e n minutes, and the i n f u s i o n was disc o n t i n u e d f i f t e e n minutes a f t e r complete vagal s e c t i o n . Random f i v e minute recordings at each stage of the procedure were examined to determine the e f f e c t on the BER. E l e c t r i c a l s t i m u l a t i o n of the d i v i d e d vagal tru n k s , u t i l i z i n g the new phosphorbronze el e c t r o d e and stimulus i s o l a t o r , was c a r r i e d out i n three a n i - mals dur i n g the course of p e n t a g a s t r i n i n f u s i o n . 78 CHAPTER THREE RESULTS AND DISCUSSION 1. Group I . Recording of the BER; the e f f e c t of vagal s e c t i o n and vagal stimu- l a t i o n u s i n g sodium t h i o p e n t a l anaesthesia Recordings from the fundus and proximal o n e - t h i r d of the corpus d i d not r e v e a l any evidence of rhythmical e l e c t r i c a l a c t i v i t y . I n i t i a l p o t e n t i a l s w i t h the gr e a t e s t amplitude were observed i n t r a c i n g s recorded over the antrum ( F i g . 1 ) . This observation i s i n agreement wi t h previous work which has l o - c a l i z e d the o r i g i n of the pa c e s e t t e r p o t e n t i a l t o the j u n c t i o n of the proximal and middle t h i r d s of the stomach." 1" 1 0 A c t i o n p o t e n t i a l s were recorded most oft e n at the antrum ( F i g . 1), and were f o l l o w e d immediately by v i s u a l l y observed c o n t r a c t i l e a c t i v i t y . Simultaneous r e c o r d i n g of i n t r a g a s t r i c pressure was not performed i n t h i s s e r i e s of experiments. As many as 50% of the PP's were f o l l o w e d by a c t i o n p o t e n t i a l s i n some of the animals s t u d i e d , p a r t i c u l a r l y a f t e r manipulation of the stomach. E l e c t r o d e s placed s e r i a l l y along e i t h e r the a n t e r i o r or p o s t e r i o r aspects of the gr e a t e r curve demonstrated i d e n t i c a l BER ra t e s throughout the le n g t h of the d i s t a l t w o-thirds of the organ. The mean frequency of the BER was c a l c u l a t e d from recordings i n twenty animals t o be 4.4l t 0.40 c y c l e s per minute (Table I ) . F o l l o w i n g d i v i s i o n of one vagal trunk ( e i t h e r a n t e r i o r or pos- t e r i o r ) , the mean frequency was 4.27 t 0.55 c y c l e s per minute. Complete vagotomy r e s u l t e d i n a mean frequency of 4.08 t 0.51 79 c y c l e s per minute. S t a t i s t i c a l a n a l y s i s (Wilcoxon's Signed Ranks) i n d i c a t e a s i g n i f i c a n t d i f f e r e n c e i n the BER frequency "before and a f t e r complete vagotomy (p < 0.002). The d i f f e r e n c e i n the BER frequency w i t h one vagus d i v i d e d as compared wi t h that f o l l o w i n g complete vagotomy i s a l s o of s i g n i f i c a n c e (p < 0.01). In f o u r animals, the BER became di s o r g a n i z e d f o l l o w i n g complete t r u n c a l vagotomy ( F i g . 2 ) . This d i s o r g a n i z a t i o n was temporary, r e v e r t i n g t o a r e g u l a r p a t t e r n i n most instances w i t h i n ten minutes. D i s o r g a n i z a t i o n of the BER was a l s o ob- served on s e v e r a l occasions f o l l o w i n g d i v i s i o n of only one vagal trunk ( F i g . 2); t h i s phenomenon was again only temporary. Sequences of desynchronized BER a l s o occurred spontaneously, perhaps due t o anoxia, change i n body temperature, anaesthesia, i n a d v e r t e n t t r a c t i o n on the d i s s e c t e d v a g i or on the stomach ( F i g . 2 ) , or h y p e r v e n t i l a t i o n . I t t h e r e f o r e appears that an i r r e g u l a r , d i s o r g a n i z e d BER i s by no means pathognomonic of complete v a g a l s e c t i o n . Previous reference was made to D a n i e l ' s observations which repo r t minor v a r i a t i o n s i n the amplitude of the BER complex 3 7 ko-hh secondary to the e f f e c t of various d r u g s . J < * The present study has demonstrated t h a t spontaneous changes i n the amplitude of the p a c e s e t t e r p o t e n t i a l are o f t e n observed w i t h i n r e l a t i v e l y short t r a c i n g s from the same ele c t r o d e ( F i g . 1 ) . These v a r i a - t i o n s were not apparently p r e c i p i t a t e d by any manipulation of the experimental model. I t i s d i f f i c u l t t o draw any f i r m 80 conclusions w i t h respect to f a c t o r s which may i n f l u e n c e the amplitude of the PP's, other than perhaps the firmness of contact or depth of p e n e t r a t i o n of the e l e c t r o d e t i p i n t o 14, 20 the serosa. ' E l e c t r i c a l s t i m u l a t i o n of the d i s t a l end of e i t h e r d i v i d e d vagal trunk, using s t i m u l i of 100-120 V, 0.1-0.5 msc. d u r a t i o n , a p p l i e d at 5-1° impulses per second f o r periods of 60-120 seconds, r e s u l t e d i n marked c o n t r a c t i l e a c t i v i t y of the antrum, a s e r i e s of AP's, and i n most instances an as s o c i a t e d disorgan- i z a t i o n of the BER f o r the d u r a t i o n of the s t i m u l a t i o n and up to 20-30 seconds t h e r e a f t e r ( F i g . 3K S t i m u l a t i o n of the c e n t r a l end of one d i v i d e d vagus ( e i t h e r a n t e r i o r or p o s t e r i o r ) w i t h the other trunk remaining i n t a c t had no demonstrable e f f e c t on the BER or c o n t r a c t i l e a c t i v i t y i n t h i s s e r i e s of e x p e r i - ments despite systematic v a r i a t i o n of v o l t a g e , impulse dura- t i o n , and impulse frequency across the f u l l range of c a p a b i l i t y of the s t i m u l a t o r a v a i l a b l e ( F i g . 3). Thus, the model as des- c r i b e d i n t h i s s e r i e s has not demonstrated the existence of a vago-vagal r e f l e x whereby one might a l t e r g a s t r i c e l e c t r i c a l a c t i v i t y or m o t i l i t y by c e n t r a l ( r e f l e x ) s t i m u l a t i o n of e i t h e r vagal trunk. F o l l o w i n g complete t r u n c a l vagotomy and esophageal t r a n - s e c t i o n , the BER remained unchanged i n the f i v e animals so stud i e d ( F i g , 4 ) . Rapid s a c r i f i c e of these animals by the intravenous a d m i n i s t r a t i o n of potassium c h l o r i d e (which caused c a r d i a c a s y s t o l e w i t h i n 10-15 seconds) d i d not a p p r e c i a b l y a l t e r 81 the BER i n the i n i t i a l few minutes post-mortem. F o l l o w i n g t h i s v a r i a b l e p e r i o d , the amplitude of the p o t e n t i a l s decreased, and some i r r e g u l a r i t y of rhythm was observed. One dog main- t a i n e d a r e g u l a r BER p a t t e r n w i t h a rat e i d e n t i c a l t o the pre- vagotomy r a t e f o r a f u l l twelve minutes a f t e r c a r d i a c stand- s t i l l . Attempts to ob t a i n an enhanced response of the BER t o e i t h e r a f f e r e n t or e f f e r e n t vagal s t i m u l a t i o n by preceding the r e g u l a r t e s t stimulus w i t h a t h i r t y second p e r i o d of high f r e - quency s t i m u l a t i o n were un s u c c e s s f u l . I t was not p o s s i b l e i n t h i s model t o confirm the p r i n c i p l e of p o s t - a c t i v a t i o n p o t e n t i - 19 a t i o n as a p p l i e d to g a s t r i c e l e c t r i c a l a c t i v i t y . In two animals, the c e r v i c a l v a g i were i s o l a t e d , d i v i d e d , and s t i m u l a t e d . S t i m u l a t i o n of the d i s t a l c e r v i c a l vagus (10- 50 V, 0.5-2.0 m s c , 10 impulses per second x 60-90 seconds) produced no e f f e c t on the BER. C e n t r a l s t i m u l a t i o n of one c e r v i c a l vagus while the other trunk remained i n t a c t r e s u l t e d only i n the c h a r a c t e r i s t i c r e t c h i n g movements, but no e f f e c t on the BER. Fo l l o w i n g complete c e r v i c a l vagal s e c t i o n i n one of the animals, a f i f t e e n minute p e r i o d of gross BER d i s o r - g a n i z a t i o n was observed ( F i g . 5). I n t e r e s t i n g l y , t r a c t i o n on the c e r v i c a l v a g i during d i s s e c t i o n but before d i v i s i o n of the nerve trunks r e s u l t e d i n t h i s same animal i n a prolonged s e r i e s of r e p e t i t i v e p o t e n t i a l s , perhaps an i l l u s t r a t i o n of the sympa- t h e t i c dominance p a t t e r n ( F i g . 5). 82 2. Group I I . E f f e c t of the operative procedure on BER A c o n t r o l group of s i x animals was examined to determine the e f f e c t of the operative procedure per se on the frequency of the BER (Table I I ) . More s p e c i f i c a l l y , t h i s i n v e s t i g a t i o n was designed to evaluate the combined e f f e c t s of time, anaes- t h e s i a , and change i n body temperature on the BER r a t e . Se- q u e n t i a l f i v e minute t r a c i n g s obtained at f i f t e e n minute i n t e r - v a l s over a two hour c o n t r o l procedure were examined. S t a t i s - t i c a l e v a l u a t i o n using a n a l y s i s of covariance and l i n e a r r e g r e s s i o n i n d i c a t e d a s i g n i f i c a n t slowing of the BER over the course of the two hour t e s t p e r i o d (p < 0 . 0 5 ) . Slopes f i t t e d f o r data obtained from each animal i n d i c a t e d t h a t the r a t e of r e d u c t i o n of the BER frequency was s i m i l a r i n each animal s t u d i e d (p = 0 . 0 1 ) . 3. Group I I I . E f f e c t of vagal s t i m u l a t i o n on BER, u sing chloralose-urethane anaesthesia The i n v e s t i g a t i o n t o t h i s p o i n t has not taken i n t o con- s i d e r a t i o n the reported i n h i b i t o r y e f f e c t of b a r b i t u r a t e anaes- t h e s i a on the g a s t r i c c o n t r a c t i l e response to v a gal s t i m u l a t i o n . As i t was considered t h a t t h i s i n h i b i t o r y e f f e c t may apply as w e l l to the response of e l e c t r i c a l a c t i v i t y , a f u r t h e r s e r i e s of acute experiments was undertaken, i n which a c h l o r a l o s e - urethane anaesthetic mixture was s u b s t i t u t e d f o r sodium t h i o -48 8 p e n t a l . C h l o r a l o s e , though depressing c o r t i c a l a c t i v i t y , i s thought to have an e x c i t a t o r y e f f e c t on s u b c o r t i c a l s t r u c - t u r e s , and may, v i a i t s a c t i o n on lower c e r e b r a l c e n t r e s , 83 Q p o t e n t i a t e g a s t r i c m o t i l i t y and s e c r e t i o n . ' A t o t a l of twenty-nine procedures was assessed i n t h i s s e r i e s . The s p e c i f i c e f f e c t of vagotomy on the frequency of the BER was not examined, as the i n v e s t i g a t i o n o u t l i n e d i n Groups I and I I has s a t i s f a c t o r i l y demonstrated th a t vagotomy has no c o n s i s t e n t , r e p r o d u c i b l e e f f e c t on the frequency of t h i s p o t e n t i a l . S u c c i n y l c h o l i n e a b o l i s h e d the r e t c h i n g movements caused by c e n t r a l r e f l e x s t i m u l a t i o n without a l t e r i n g the BER or g a s t r i c c o n t r a c t i l e responses t o e f f e r e n t vagal s t i m u l a t i o n . In t w e n t y - f i v e animals, both a f f e r e n t and e f f e r e n t vagal trunks were s t i m u l a t e d e l e c t r i c a l l y . I n the i n i t i a l twelve procedures (Group I I I A ) , e l e c t r i c a l s t i m u l a t i o n was a p p l i e d using the s t a i n l e s s s t e e l e l e c t r o d e as described f o r Group I . The remaining t h i r t e e n procedures (Group I I I B ) d i f f e r e d from the i n i t i a l twelve i n t h a t the stimulus i s o l a t o r and phosphor- bronze s t i m u l a t i n g e l e c t r o d e were introduced i n t o the e x p e r i - mental model. In Group I I I A , d i s t a l s t i m u l a t i o n of e i t h e r vagal trunk (whichever was d i v i d e d f i r s t ) u s u a l l y r e s u l t e d i n strong a n t r a l c o n t r a c t i o n s and oc c a s i o n a l upper j e j u n a l a c t i v i t y , and was accompanied by a marked d i s t o r t i o n of the BER complex f o r the d u r a t i o n of s t i m u l a t i o n and up t o 3°-60 seconds t h e r e a f t e r ( F i g . 6 ) . The la t e n c y of t h i s response was l e s s than f i v e seconds. The most pronounced e f f e c t s were achieved w i t h s t i m u l i of 100-120 V, 0.5-2.0 msc. d u r a t i o n , a p p l i e d at 10 impulses per second f o r periods of 60 seconds. 84 In nine of twelve t r i a l s of proximal or r e f l e x s t i m u l a t i o n of one d i v i d e d vagus w i t h the remaining vagus i n t a c t , an e f f e c t c o n s i s t i n g of s l i g h t to moderate a n t r a l and upper small "bowel c o n t r a c t i l e a c t i v i t y was observed a f t e r a v a r i a b l e l a t e n t p e r i o d of 30-40 seconds. The most pronounced e f f e c t s r e s u l t e d from s t i m u l i of 120 V, 0.5 msc. d u r a t i o n , a p p l i e d at 10 impulses per second f o r more prolonged p e r i o d s , up t o three minutes. In f i v e of the nine animals w i t h a p o s i t i v e c o n t r a c t i l e r e s - ponse, the BER was s i g n i f i c a n t l y d i s t o r t e d during the p e r i o d of s t i m u l a t i o n and f o r 40-60 seconds t h e r e a f t e r ( F i g . 6 ) . However, the d i s t o r t i o n of the BER was not observed w i t h every p e r i o d of proximal s t i m u l a t i o n i n the same animal. G e n e r a l l y , the i n - crease i n small bowel a c t i v i t y was more predominant than the a c t i v i t y of the antrum f o l l o w i n g proximal s t i m u l a t i o n . However, the observations of c o n t r a c t i l e a c t i v i t y were only s u b j e c t i v e impressions, and must be confirmed by measuring e i t h e r i n t r a - l u m i n a l pressure change or c o n t r a c t i l e f o r c e before assuming s i g n i f i c a n c e . In seven of the nine animals i n which c o n t r a c t i l e response (and o c c a s i o n a l BER d i s t o r t i o n ) had occurred on proximal stimu- l a t i o n of one d i v i d e d vagus, proximal s t i m u l a t i o n of e i t h e r v a g al trunk a f t e r s e c t i o n of the remaining vagus no longer pro- duced these e f f e c t s ( F i g . 6 ) , suggesting t h a t the r e f l e x stimu- l a t i o n had i n f a c t i n i t i a t e d the responses observed v i a impulses conveyed through the c e n t r a l nervous system and along i n t a c t v a g a l e f f e r e n t s t o the stomach and small i n t e s t i n e . This would 85 seem to confirm the existence of a vago-vagal r e f l e x . I n the remaining two animals, however, proximal s t i m u l a t i o n of e i t h e r v a g al trunk f o l l o w i n g complete vagotomy r e s u l t e d i n increased small bowel motor a c t i v i t y , r a t h e r than a b o l i s h i n g the response. This may be i n t e r p r e t e d as due to e i t h e r a removal of vagal i n h i b i t o r y f i b r e s , or perhaps to s t i m u l a t i o n of sympathetic c h o l i n e r g i c e x c i t a t o r y e f f e r e n t s . 7 8 I n one animal, proximal s t i m u l a t i o n of the d i v i d e d a n t e r i o r vagus nerve w i t h the p o s t e r i o r trunk s t i l l i n t a c t produced no change i n the BER and no c o n t r a c t i l e a c t i v i t y . F o l l o w i n g com- p l e t e vagotomy, proximal s t i m u l a t i o n of e i t h e r v a gal trunk r e s u l t e d i n marked c o n t r a c t i l e a c t i v i t y of the upper small bowel, but no observable change i n the a n t r a l BER. D i s t a l s t i m u l a t i o n of e i t h e r trunk i n t h i s animal produced the c h a r a c t e r i s t i c strong a n t r a l c o n t r a c t i l e a c t i v i t y and d i s - t o r t i o n of the BER. In the remaining two animals of t h i s s e r i e s (Group I I I A ) , proximal s t i m u l a t i o n of one d i v i d e d vagus produced no change i n the BER, and no obvious c o n t r a c t i l e a c t i v i t y , though d i s t a l s t i m u l a t i o n was e f f e c t i v e i n e l i c i t i n g changes i n both. Proximal s t i m u l a t i o n of e i t h e r vagal trunk f o l l o w i n g complete vagotomy i n these two animals was a l s o i n e f f e c t i v e i n e l i c i t i n g any change i n BER or c o n t r a c t i l e a c t i v i t y . E f f e r e n t vagal s t i m u l a t i o n i n the animals i n c l u d e d i n Group I I I B g e n e r a l l y r e s u l t e d i n the same degree of BER d i s - t o r t i o n and a n t r a l c o n t r a c t i l e a c t i v i t y as occurred i n Group I I I A . In ten of t h i r t e e n animals, a f f e r e n t or r e f l e x s t i m u l a t i o n 86 of one d i v i d e d vagus (while the other vagus remained i n t a c t ) was accompanied by a v i s u a l l y observed increase i n a n t r a l and/or small bowel c o n t r a c t i l e a c t i v i t y . However, i n only three of these animals was there a d e f i n i t e , simultaneous change i n the BER p a t t e r n ( F i g . 7 ) . The most pronounced e f f e c t s were obtained using low i n t e n s i t y , low frequency s t i m u l i i n accordance w i t h Martinson's concept of low t h r e s - hold e x c i t a t o r y v a g a l f i b r e s . The most e f f e c t i v e s t i m u l i were of the order of 3-7 ma, 0.1 msc. d u r a t i o n , a p p l i e d at 5 im- pulses per second f o r periods of 60-120 seconds. Higher i n - t e n s i t y s t i m u l i g e n e r a l l y had l e s s pronounced e f f e c t s on con- t r a c t i l e a c t i v i t y . Preceding the t e s t stimulus w i t h t h i r t y second periods of high frequency s t i m u l a t i o n was not e f f e c t i v e i n p o t e n t i a t i n g the response to e i t h e r a f f e r e n t or e f f e r e n t s t i m u l a t i o n . Proximal s t i m u l a t i o n of one a f f e r e n t trunk was not a s s o c i a t e d w i t h any observable change i n BER or c o n t r a c t i l e a c t i v i t y i n the remaining three animals of t h i s group. F o l l o w i n g complete vagal s e c t i o n , proximal s t i m u l a t i o n of e i t h e r v a gal trunk using the same stimulus parameters no longer produced the e f f e c t s recorded above i n nine of the ten animals ( F i g . 7 ) . The one exception to t h i s p a t t e r n was an increase i n s m a ll bowel c o n t r a c t i l e a c t i v i t y f o l l o w i n g c e n t r a l vagal s t i m u l a t i o n , even though a l l vagal f i b r e s had been severed. Once again, the r e s u l t s tend to support the view t h a t g a s t r i c e l e c t r i c a l and motor a c t i v i t y can be a l t e r e d by r e f l e x stimu- l a t i o n of a f f e r e n t vagal f i b r e s . 87 4. Group IV. Conduction v e l o c i t y of the BER Conduction v e l o c i t y of the BER complex was s t u d i e d i n f o u r animals by r e c o r d i n g i n a b i p o l a r f a s h i o n from two adjacent a n t r a l e l e c t r o d e s ( F i g . 8A). The average c o n d u c t i o n v e l o c i t y was 2 cm. per second as measured over the antrum. The c o n d u c t i o n v e l o c i t y was not a l t e r e d s i g n i f i c a n t l y by d i - v i s i o n of e i t h e r one or both v a g i ( F i g . 8A). E l e c t r i c a l stimu- l a t i o n o f the d i s t a l v a g a l trunks so d i s t o r t e d the t r a c i n g s t h a t c o n d u c t i o n v e l o c i t y c o u l d not be measured. C e n t r a l stimu- l a t i o n of one d i v i d e d vagus, w i t h the oth e r trunk i n t a c t , d i d not a l t e r the condu c t i o n v e l o c i t y of the BER i n the animals s t u d i e d . 5. Group V. E f f e c t of p e n t a g a s t r i n on BER be f o r e and a f t e r vagotomy A f i n a l group of e i g h t animals was examined t o a s c e r t a i n the e f f e c t of a continuous p e n t a g a s t r i n i n f u s i o n on the BER f r e - quency and on g a s t r i c c o n t r a c t i l e a c t i v i t y . The r e c o r d i n g s ob- t a i n e d from s i x animals were s u i t a b l e f o r a n a l y s i s . The mean r e s t i n g BER frequency was c a l c u l a t e d a t 4.06 c y c l e s p e r minute. W i t h i n 15-30 seconds of the commencement of the p e n t a g a s t r i n i n f u s i o n , a n t r a l c o n t r a c t i l e a c t i v i t y i n c r e a s e d markedly, and continued a t t h i s heightened l e v e l f o r the d u r a t i o n of the i n - f u s i o n and u s u a l l y f o r 15-20 minutes t h e r e a f t e r . A c o r r e s - ponding i n c r e a s e i n the BER frequency was observed a f t e r the onset of p e n t a g a s t r i n i n f u s i o n i n a l l cases s t u d i e d , f o l l o w i n g a v a r i a b l e l a t e n t p e r i o d of 15-30 seconds ( F i g . 9). The i n c r e a s e d 88 BER frequency o u t l a s t e d the d u r a t i o n of the i n f u s i o n "by up to 40-45 minutes i n two animals observed f o r t h a t l e n g t h of time. The mean BER frequency d u r i n g the i n i t i a l stage of the i n f u s i o n , before the v a g i were d i v i d e d , was 5.45 c y c l e s per minute, an i n c r e a s e of Jkfo over the r e s t i n g r a t e (Table I I I ) . F o l l o w i n g d i v i s i o n of one vagus nerve, the mean frequency was 5.51 c y c l e s p e r minute; a f t e r complete vagotomy, the mean r a t e was 5«^5 c y c l e s per minute (Table I I I ) . The Jkfo i n c r e a s e i n BER frequency recorded d u r i n g penta- g a s t r i n i n f u s i o n i s i n accord with the s i m i l a r i n c r e a s e s des- 35 91 c r i b e d by C o o k e ^ and Monges. However, i t seems c l e a r t h a t t h i s e f f e c t i s not under v a g a l c o n t r o l , as no a p p r e c i a b l e change i n the BER frequency was observed f o l l o w i n g s e c t i o n of e i t h e r one or both v a g a l trunks ( F i g . 9). E l e c t r i c a l s t i m u l a t i o n of both a f f e r e n t and e f f e r e n t v a g a l trunks was s t u d i e d i n three animals d u r i n g the course of the continuous p e n t a g a s t r i n i n f u s i o n . P e r i p h e r a l s t i m u l a t i o n (5-10 ma, 0.1-0.5 m s c , 5-10 impulses per second f o r 60-120 seconds) c o n s i s t e n t l y r e s u l t e d , i n marked a n t r a l c o n t r a c t i l e a c t i v i t y and BER d i s t o r t i o n , as observed i n the p r e v i o u s experimental groups. C e n t r a l or r e f l e x s t i m u l a t i o n , however, produced only i n c o n s t a n t e f f e c t s on BER rhythm and a n t r a l c o n t r a c t i l i t y . Gross observa- t i o n s suggest t h a t p e n t a g a s t r i n at t h i s r a t e of i n f u s i o n (4 ugm/ kg./hr.) does not s i g n i f i c a n t l y p o t e n t i a t e the g a s t r i c c o n t r a c - t i l e response t o r e f l e x v a g a l s t i m u l a t i o n , though f i n e d i f f e r - ences c o u l d perhaps be de t e c t e d by measuring c o n t r a c t i l e f o r c e 89 w i t h s t r a i n gauges. I t t h e r e f o r e does not appear that the use of p e n t a g a s t r i n as an adjunct to p o t e n t i a t e vago-vagal r e f l e x a c t i v i t y w i l l be of any s i g n i f i c a n t value i n the search f o r a r e l i a b l e t e s t to assess the completeness of vagotomy. 90 CHAPTER FOUR SUMMARY AND CONCLUSIONS E l e c t r i c a l a c t i v i t y of the stomach has been recorded i n both monopolar and b i p o l a r f a s h i o n s from the g a s t r i c antrum, B a s i c e l e c t r i c a l rhythm (BER) was recorded b e f o r e and a f t e r vagotomy. A s i g n i f i c a n t r e d u c t i o n of the BER frequency was noted a f t e r complete vagotomy (p < 0.002), but not a f t e r the d i v i s i o n of only one v a g a l trunk. A l s o of s i g n i f i c a n c e was a slower BER frequency f o l l o w i n g complete vagotomy as compared with the r a t e with only one vagus d i v i d e d (p < 0.01). How- ever, the slowing of the BER as a r e s u l t of the e f f e c t s of the op e r a t i v e procedure i t s e l f ( e f f e c t of time, a n a e s t h e s i a , de- crease i n body temperature) was a l s o s i g n i f i c a n t when recorded over the course of a two hour p e r i o d (p < 0.05). T h e r e f o r e , i t i s not p o s s i b l e t o draw any d e f i n i t e c o n c l u s i o n s c o n c e r n i n g the s i g n i f i c a n c e of the reduced BER frequency which f o l l o w s com- p l e t e vagotomy. C e r t a i n l y one cannot c l a i m t h a t t h i s reduced r a t e i s i n d i c a t i v e of complete v a g a l s e c t i o n . Moreover, even i f the r e d u c t i o n i n BER frequency c o u l d i n f a c t be a t t r i b u t e d p u r e l y t o v a g a l s e c t i o n , the r e d u c t i o n observed i n t h i s i n v e s t i g a t i o n , though of s i g n i f i c a n c e s t a t i s t i c a l l y , i s of such a low order as t o be of ve r y l i m i t e d v a l u e i n the assessment of any i n d i v i d u a l case. On s e v e r a l o c c a s i o n s , a d i s o r g a n i z e d BER was observed f o l l o w i n g complete vagotomy. However, t h i s i r r e g u l a r i t y was 91 not only temporary, but c o u l d a l s o occur spontaneously, f o l l o w i n g d i v i s i o n of only one v a g a l trunk, or f o l l o w i n g t r a c t i o n on the v a g i . Hence i t i s c e r t a i n l y not pathogno- 93 monic of complete vagotomy, as has been suggested by Nelsen. J % Some i n v e s t i g a t o r s have r e p o r t e d t h a t the d i s o r g a n i z a t i o n of the BER f o l l o w i n g vagotomy i s not observed immediately, but develops on l y a f t e r a l a t e n t p e r i o d of s e v e r a l hours or even 71 days. T h i s may e x p l a i n why t h i s phenomenon was not observed more f r e q u e n t l y i n the p r e s e n t s e r i e s of acute experiments. I f d elay i n the onset of BER d i s o r g a n i z a t i o n i s the r u l e , t h i s p r i n c i p l e c o u l d not be a p p l i e d as a sound b a s i s f o r an i n t r a - o p e r a t i v e t e s t to assess the completeness of vagotomy. E l e c t r i c a l s t i m u l a t i o n of the p e r i p h e r a l or d i s t a l end of a d i v i d e d v a g a l trunk g e n e r a l l y r e s u l t e d i n a marked d i s t o r - t i o n of the BER and c o n s i d e r a b l e i n c r e a s e i n a n t r a l c o n t r a c t i l e a c t i v i t y . In the i n i t i a l experimental s e r i e s (Group I) u s i n g sodium t h i o p e n t a l a n a e s t h e s i a , i t was not p o s s i b l e t o e l i c i t a r e f l e x response i n g a s t r i c e l e c t r i c a l or motor a c t i v i t y by c e n t r a l s t i m u l a t i o n of one d i v i d e d vagus while the other v a g a l trunk remained i n t a c t . However, subsequent i n v e s t i g a t i o n sub- s t i t u t i n g a c h l o r a l o s e - u r e t h a n e mixture f o r sodium t h i o p e n t a l has suggested t h a t vago-vagal r e f l e x e f f e c t s can be achieved by means of a f f e r e n t v a g a l s t i m u l a t i o n . A l t e r a t i o n s i n g a s t r i c e l e c t r i c a l and c o n t r a c t i l e a c t i v i t y were produced by a f f e r e n t v a g a l s t i m u l a t i o n u s i n g low i n t e n s i t y , low frequency impulses (5 ma, 0.1 m s c , 5 impulses per second); the e f f e c t s were presumably mediated v i a pathways through the c e n t r a l nervous system and along the remaining i n t a c t e f f e r e n t v a g a l f i b r e s to the stomach. The r e p o r t e d p o t e n t i a t i n g e f f e c t of c h l o r a l o s e on the g a s t r i c response to v a g a l s t i m u l a t i o n may have been i n - o f l u e n t i a l i n a c h i e v i n g these r e s u l t s . N e v e r t h e l e s s , the r e - s u l t s do demonstrate the e x i s t e n c e of a vago-vagal r e f l e x path- way whereby one may modify g a s t r i c e l e c t r i c a l and c o n t r a c t i l e a c t i v i t y by s t i m u l a t i o n of a f f e r e n t v a g a l f i b r e s . The response of the BER to r e f l e x v a g a l s t i m u l a t i o n was very c o n v i n c i n g on s e v e r a l o c c a s i o n s , but u n f o r t u n a t e l y , t h i s response was by no means c o n s i s t e n t or r e p r o d u c i b l e . F a r more c o n s i s t e n t was the i n c r e a s e i n both a n t r a l and s m a l l bowel con- t r a c t i l e a c t i v i t y f o l l o w i n g a f f e r e n t v a g a l s t i m u l a t i o n . I t would t h e r e f o r e seem more a p p r o p r i a t e i n the l i g h t of these o b s e r v a t i o n s to conduct the s earch f o r a r e l i a b l e i n t r a o p e r a t i v e t e s t t o assess completeness of vagotomy by i n v e s t i g a t i o n of changes i n the c o n t r a c t i l e f o r c e of the g a s t r o i n t e s t i n a l smooth muscle subsequent to a f f e r e n t v a g a l s t i m u l a t i o n . On the other hand, i t does not appear t h a t f u r t h e r e v a l u a t i o n of e i t h e r the e f f e c t of vagotomy on the conduction v e l o c i t y of the BER or the e f f e c t of p e n t a g a s t r i n on e l e c t r i c a l a c t i v i t y b efore and a f t e r vagotomy w i l l c o n t r i b u t e very much of s i g n i f i c a n c e to the search at hand. What then are we l e f t with? The H o l l a n d e r i n s u l i n t e s t no doubt p r o v i d e s a reasonable guide as to who i s at r i s k of r e - c u r r e n t u l c e r a t i o n f o l l o w i n g vagotomy. The i n t r a o p e r a t i v e t e s t s 93 developed t o date have been n e i t h e r c o n c l u s i v e nor pathogno- monic of complete vagotomy. Perhaps complete parasympathetic denervation i s an impossible g o a l i n view of the ex t r a v a g a l c h o l i n e r g i c outflow v i a splanchnics and t h o r a c i c d o r s a l root g a n g l i a . Perhaps complete anatomic vagotomy i s not i n f a c t e s s e n t i a l f o r p r o t e c t i o n against r e c u r r e n t u l c e r ; support f o r t h i s concept can be found i n the incomplete but "adequate" vagotomy which occurs when only a t e r m i n a l g a s t r i c fundic branch remains undivided. Perhaps any of these t e s t s has as i t s major v i r t u e a stimulus t o the surgeon t o be more meticu- lous and e x a c t i n g i n h i s technique of performing vagotomy, knowing t h a t h i s work w i l l be put to the " a c i d " t e s t postopera- t i v e l y . Nevertheless, the development of such an i n t r a o p e r a t i v e t e s t w i l l be a major f a c t o r i n f i r m l y e s t a b l i s h i n g vagotomy as a v a l i d o peration i n the treatment of p e p t i c u l c e r disease, and w i l l help prevent t h i s method from f a l l i n g i n t o disrepute because of a continued high r a t e of re c u r r e n t u l c e r a t i o n . 9k TABLES 95 TABLE I BASIC ELECTRIC RHYTHM BEFORE AND AFTER VAGOTOMY BER ( c y c l e s per minute) Dog Vagi I n t a c t One vagus d i v i d e d Both v a g i d i v i d e d 1 3.95 3.13 2.76 2 4.13 4.47 4.11 3 4.57 4.56 4.54 4 4.21 4.17 3.99 5 4.83 4.72 4.95 6 4.78 4.36 4.05 7 4.13 , 4.05 3.76 8 4.51 3.79 3.91 9 4.93 4.65 4.16 10 3.97 4.07 4.19 11 4.77 4.43 4.57 12 4.75 3.60 3.84 13 4.46 4.21 3.75 14 3.91 4.03 3.74 15 4.44 4.12 4.01 16 4.42 4.13 3.95 17 4.20 4.37 3.93 18 3.57 3.65 3.60 19 5.20 5.60 5.00 20 4.40 5.20 4.75 mean 4.4l 4.27 4.08 standard ±0.40 ±0.55 ±0.51 d e v i a t i o n Each r e c o r d i n g represents the BER i n c y c l e s per minute, aver- aged over a randomly chosen f i v e minute sequence of re c o r d i n g . The d i f f e r e n c e i n the BER w i t h the va g i i n t a c t and tha t f o l l o w - i n g complete vagotomy was h i g h l y s i g n i f i c a n t (p < 0.002). The d i f f e r e n c e between the BER wit h one vagus d i v i d e d and tha t f o l l o w i n g complete vagotomy a l s o achieved s i g n i f i c a n c e (p<0.01). S t a t i s t i c a l a n a l y s i s performed by Wilcoxon's Signed Ranks Test. 96 TABLE I I THE EFFECT OF LAPAROTOMY AND TIME ON THE BER Dog BER ( c y c l e s per minute) at 15 minute i n t e r v a l s 0 15 30 45 60 75 90 105 120 1 4.88 4.?4 4.70 4.14 3.83 3.82 3.67 3.46 3.97 2 4.82 4.43 5.07 4.87 5.08 5.02 5.07 — — 3 4.95 4.62 4.54 3.65 4.00 3.87 3.93 3.85 4.20 4 4.12 4.29 4.21 3.96 3.80 3.90 3.94 4.04 3.69 5 4.34 4.42 4.52 4.68 4.79 4.71 4.29 4.21 4.08 6 3.88 4.12 4.20 4.54 3.69 4.39 4.10 mm mm 3.76 S t a t i s t i c a l e v a l u a t i o n u s i n g a n a l y s i s of covariance and l i n e a r r e g r e s s i o n i n d i c a t e s a s i g n i f i c a n t slowing of the BER over the two hour t e s t p e r i o d (p <0.05). Slopes f i t t e d f o r data obtained from each dog r e v e a l t h a t the r a t e of re d u c t i o n i n the BER ra t e i s s i m i l a r i n each animal s t u d i e d (p = 0.01). 97 TABLE I I I THE EFFECTS OF PENTAGASTRIN ON THE BER BEFORE AND AFTER VAGOTOMY Dog BER i n c y c l e s per minute Course of p e n t a g a s t r i n i n f u s i o n B a s e l i n e Vagi i n t a c t One vagus d i v i d e d Both v a g i d i v i d e d 1 3.76 5.20 5.30 5.50 2 4.04 5.06 5.20 5.20 3 4.34 5.66 5.60 5.60 4 3.80 5.56 5.40 5.52 5 3.80 5.28 5.54 4.88 6 4.60 5.94 6.00 6.02 mean 4.06 5.45 5.51 5.45 The e f f e c t of a continuous i n f u s i o n of p e n t a g a s t r i n (4 ugm./kg./hr.) on the BER of the canine stomach before and a f t e r vagotomy, P e n t a g a s t r i n r e s u l t e d i n a 34% increase i n the BER frequency. Vagotomy d i d not a l t e r t h i s e f f e c t . 98 FIGURES 99 BASIC ELECTRIC RHYTHM (BER) recorded at antrum; triphasic potential. BER note predominant negative deflection of triphasic potential. BER (antrum); note spontaneous variation in amplitude of triphasic potential. J l millivolt=15 Basic electrical rhythm with associated action potentials recorded at antrum. Figure 1. Basic e l e c t r i c a l rhythm (BER) recorded at antrum. V a r i a t i o n s i n c o n f i g u r a t i o n of the e l e c t r i c a l p o t e n t i a l i n the r e s t i n g s t a t e . Demonstration of asso- c i a t e d a c t i o n p o t e n t i a l s . 100 BER (antrum), with vagi intact. BER; effect of dissection of vagal trunks at esophageal hiatus BER with posterior vagus divided; note disorganized rhythm. BER following complete vagotomy; note further disorganization of rhythm. BER 30 minutes after complete vagal section - rapid BER. BER 2 minutes following complete truncal vagotomy; note delayed onset of spontaneous disorganization of BER. Figure 2. A l t e r a t i o n s i n the BER f o l l o w i n g v a g al d i s s e c t i o n and d i v i s i o n . 101 uHf. BER (antrum), vagi intact t 1 ' . t period of stimulation BER, anterior vagus divided; stimulation distal end of divided vagus. 120 V., 0.1 msc, 10 impulses/sec. for 60 sees.; period of stimulation * BER, anterior vagus divided; stimulation of central end divided vagus, 120 V., 0.1 msc, 10 impulses/sec, x 90"; note absence of effect on BER. note slight irregularity of BER BER, posterior vagus divided; stimulation of_central end of divided vagus 120 V., 0.1 msc, 10 impulses/sec, for 120 sees. Figure 3. The e f f e c t on BER of a f f e r e n t and e f f e r e n t vagal s t i m u l a t i o n before and a f t e r complete vagal s e c t i o n (sodium t h i o p e n t a l anaesthesia). BER (vagi intact) BER following complete vagotomy and esophageal transection Figure 4 . BER f o l l o w i n g complete vagotomy and esophageal t r a n s e c t i o n . BER (antrum), vagi intact Effect of dissection of cervical vagi on BER. 103 1 BER, following section of right cervical vagus. BER, following section of left cervical vagus- i.e. complete cervical vagotomy. BER 30 minutes after complete cervical vagotomy. Figure 5. The e f f e c t of d i s s e c t i o n and d i v i s i o n of the c e r v i c a l vagus nerves on the BER. 104 BER, Vagi intact; chloralose-urethane anaesthesia, with supplemental succinylcholine t t period of stimulation BER, anterior vagus divided; stimulation peripheral end of divided vagus; 120 V 0.5 msc, 10 impulses/second, for 60 seconds Strong antral contractions observed during stimulation .period of stimulation. BER,anterior vagus divided, stimulation central end of divided vagus 120 V, 2.0 msc, 10 impulses/second for 120 seconds Strong antral contractions observed during stimulation t t period of stimulation BER, both vagi divided/stimulation central end of divided anterior vagus. 120 V, 2.0 msc, 10 impulses/second x 60 seconds No contractile response in antrum. No change in BER. • • period of stimulation BER, both vagi divided; stimulation central end of divided posterior vagus, 120 V, 0.2 msc, 10 impulses/second x 60seconds. No contractile response in antrum. No change in BER Figure 6. The e f f e c t on BER of a f f e r e n t and e f f e r e n t vagal s t i m u l a t i o n before and a f t e r complete vagal s e c t i o n (chloralose-urethane anaesthesia). BER (antrum);Chloralose-urethane anaesthesia with succinylcholine. vagi intact. if—••X • 4 — " V - — l - ^ v ^ r ^ V ^ V V K N ' ^ ^ A r - — • — — ~ ^ \ ~ — — L—period of stimulation J BER, posterior vagus divided,-stimulation to central end of divided anterior vagus 7 ma, 0.1 msc, 5 impulses/sec. x90 sees . Strong antral contractions associated with stimulation after 45 sec. delay. —\f—|f—-Jf—--|f——\/^~\—t|f--u-|f--v-|f^~|r—-jr—\p- ^ p e r i o d of stimulation — ^ BER, both vagi divided; stimulation of central end of posterior vagus,- 7 ma, 0.1 msc, 5 impulses/sec, x 90 sees. No antral contractions. r— ( r ^ - A ^ ^ - V - ^ ^ * 1 ^ ^ — ^ H f ^ T - — ^ — — — ^ ^—period of stimulation—^ BER, both vagi divided,stimulation central end of anterior vagus; 7 ma, 0.1 msc, 5 impulses/sec.x 90 sees. No antral contractions. Figure 7. The_effect on BER of a f f e r e n t v a gal s t i m u l a t i o n before and a f t e r complete v a g a l s e c t i o n (chloralose-urethane anaesthesia, s t i m u l u s i s o l a t o r ) . 106 figure A BER (antrum), vagi intact. Bipolar recording with electrodes 3 cm. apart. Conduction velocity 1.6 cm./sec. BER, posterior vagus divided. Conduction velocity 1.6 cm./sec. _ |—, |[— | — | — , (|u_ I Ui. I— |u_ |(U- |u_ |u_- |L BER, both vagi divided.Conduction velocity 1.6 cm./sec. figure B BER recorded at antrum using a short time constant (0.03 sec.) and higher amplication (1 millivolt= 20 mm. deflection) Note distortion of BER. Figure 8. A. B i p o l a r r e c o r d i n g of BER, demonstrating conduction v e l o c i t y of the p a c e s e t t e r p o t e n t i a l before and a f t e r vagotomy. B. BER recorded w i t h high a m p l i f i c a t i o n and short time constant. i BER (antrum); vagi intact, chloralose—urethane anaesthesia BER frequency 3.8 cycles/minute BER during pentagastrin infusion at 4 ugm/kg/hr.,- vagi intact; BER frequency 5.2 cycles/minute BER; pentagastrin infusion,anterior vagus divided; BER frequency 5.3 cycles/minute. BER; pentagastrin infusion; posterior vagus divided— i.e.- complete vagal section,- BER frequency 5.3 cycles/minute. Figure 9. T-he e f f e c t on BER of a p e n t a g a s t r i n i n f u s i o n , before and a f t e r complete vagal s e c t i o n . o BIBLIOGRAPHY 109 BIBLIOGRAPHY 1. Agostoni, E., J.E. Chinnock, M. DeBurgh Daly, and J.C. Murray. F u n c t i o n a l and h i s t o l o g i c a l s t u d i e s of the vagus nerve and i t s branches to the heart, lungs, and abdominal v i s c e r a i n the c a t . J . P h y s i o l . (London) \T£_\ 182-205, 1957. 2. A l l e n , G.L., E.W. Poole, and C.F. Code. 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