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Gastric electrical activity : the effects of vagal section and vagal stimulation Doran, Morton Lawrence 1973

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GASTRIC  ELECTRICAL A C T I V I T Y :  THE E F F E C T S OF VAGAL SECTION AND  VAGAL  STIMULATION  by MORTON LAWRENCE DORAN M.D.,  University  of Toronto,  1964  A THESIS SUBMITTED IN PARTIAL FULFILMENT  OF  THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in  the Department of Surgery  We  accept t h i s  required  The  thesis  as c o n f o r m i n g  t o the  standard  University  of B r i t i s h  April,  1973  Columbia  In presenting  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  r e q u i r e m e n t s f o r an advanced degree a t the U n i v e r s i t y o f B r i t i s h C o l u m b i a , I agree t h a t the L i b r a r y s h a l l make i t freely  a v a i l a b l e f o r r e f e r e n c e and s t u d y .  that permission f o r extensive  I f u r t h e r agree  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 g r a n t e d by t h e Head o f my D e p a r t ment o r by h i s r e p r e s e n t a t i v e s .  I t i s understood  that  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 s h a l l n o t be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n .  Department o f  snrgpry  The U n i v e r s i t y o f B r i t i s h Columbia Vancouver 8, Canada  gain  ABSTRACT The peptic the is  current  e n t h u s i a s m f o r vagotomy as t r e a t m e n t f o r  u l c e r disease  h a s b e e n dampened by s e v e r a l p r o b l e m s ,  most s e r i o u s o f w h i c h i s r e c u r r e n t u l c e r a t i o n . due i n most i n s t a n c e s  clear  t o incomplete  t h a t t h e development  completeness  step  recurrent  ulcer.  The  of a reliable  o f vagotomy d u r i n g  essential  vagal  toward r e d u c i n g  section, i t i s  method t o a s s e s s  the course  of surgery  effects  include  changes i n i n t r a g a s t r i c  electrical  of vagal  activity.  stimulation during pressure,  The i n v e s t i g a t i o n a s o u t l i n e d i n t h i s  operative  the completeness  (i)  method f o r a s s e s s i n g  reproducible  o f vagotomy.  t o d e t e r m i n e w h e t h e r c o m p l e t e vagotomy w o u l d gastric  electrical  activity  i n some  (ii)  phageal h i a t u s , assess  end,  the e f f e c t  on  a response  along  i n the e l e c t r i c a l  the remaining  or peripheral  t h e c e n t r a l end w i t h  r e f l e x pathways t h r o u g h t h e b r a i n s t e m , and  o f the eso-  electrical  of stimulation of i t s d i s t a l  and t h e n s t i m u l a t e  eliciting  connec-  severed;  t o d i v i d e one v a g u s n e r v e a t t h e l e v e l  activity  alter  reproducible  manner s u c h a s w o u l d i n d i c a t e t h a t a l l v a g a l t i o n s had b e e n  intra-  twofolds  o f t h e e x p e r i m e n t was e s s e n t i a l l y  the  These  a c i d s e c r e t i o n , and  a reliable,  plan  some o f t h e  operation.  t h e s i s was aimed a t d e v e l o p i n g  The  i s an  t h e 10-15% i n c i d e n c e o f  p r o b l e m h a s b e e n a p p r o a c h e d by s t u d y i n g  gastric  As t h i s  intact  view t o  activity via vagal  efferent vagal  nuclei, fibres  these  remaining  central and  f i b r e s would then  s t i m u l a t i o n of e i t h e r v a g a l trunk  response  of the g a s t r i c  w o u l d no  l o n g e r be  division  of a l l vagal  Vago-vagal r e f l e x  secretion.  demonstrate by  one  reflex  the  may  electrical  of v a g a l  assessed.  The  rhythm  indicating  to afferent  electrical  activity  observed  has  t o be  activity  by  electrical frequency  other non-related factors,  and  was  such  o r d e r as  tive BER  of complete v a g a l observed and  complete  vagotomy.  afferent  The  f o l l o w i n g vagotomy was  sistent,  The  of l i m i t e d value  section.  could not  be  be  t o be  i n any  elec-  caused case  i n assessing considered  t e m p o r a r y and  during e l e c t r i c a l  have d e m o n s t r a t e d t h e  been  vagotomy,  i n t e r p r e t e d as pathognomonic  observations recorded vagal fibres  have  of  any indica-  d i s o r g a n i z a t i o n of both  or  the  of the b a s i c  f o l l o w i n g complete  I t c o u l d t h e r e f o r e not  and  activity  as w e l l by  case.  to  central  been r e c o r d e d ,  found  individual  able  fibres.  was  t o be  gastric  r e f l e x pathway where  statistically,  a low  complete  vagal stimulation  expect  afferent vagal  r e d u c t i o n i n the  though of s i g n i f i c a n c e  activity  fibres,  reasonably  s e c t i o n on t h i s  (BER)  "character-  electrical  e x i s t e n c e of a vago-vagal  s t i m u l a t i o n of the  effects  trical  One  repeated,  r e s p e c t t o i n f l u e n c e on b o t h  might a l t e r g a s t r i c  Gastric  obtained,  responses  have b e e n documented w i t h and  divided,  presumably the p r e v i o u s l y observed  istic"  tone  be  the inconof  s t i m u l a t i o n of  existence of  a  iv v a g o - v a g a l 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 c a n be m o d i f i e d 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 .  These  e f f e c t s a r e presumably conveyed v i a pathways t h r o u g h t h e c e n t r a l nervous system and a l o n g t h e i n t a c t e f f e r e n t  vagal f i b r e s .  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 a r e n e i t h e r nor  reproducible,  The  consistent  whereas t h e 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 t o be c o n s i d e r a b l y more r e l i a b l e .  I n t h e l i g h t o f these  o b s e r v a t i o n s , i t would seem more a p p r o p r i a t e t o s t u d y t h e changes i n the c o n t r a c t i l e force  o f 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 v a g a l s t i m u l a t i o n  i n t h e s e a r c h f o r a method  t o a s s e s s completeness o f vagotomy d u r i n g t h e course o f s u r g e r y . The  development o f such a t e s t w i l l be a major f a c t o r i n p r e -  v e n t i n g t h i s form o f t r e a t m e n t from f a l l i n g i n t o d i s r e p u t e because o f a c o n t i n u e d h i g h r a t e o f r e c u r r e n t  ulceration.  TABLE OF CONTENTS Page  1  C h a p t e r One  1  Introduction Section  I.  Section  II.  Section  III.  1  I n t r a g a s t r i c Pressure Acid  3  Secretion  Gastric Electrical  A.  History  B.  Electrical  C.  The B a s i c  7  Activity  8 9  Recording Electrical  Rhythm: I t s 11  O r i g i n and P r o p a g a t i o n D.  Action Potentials  15  E.  Coordination  16  F.  P a c e m a k e r Dominance  18  G.  Relaxation  19  Section  IV.  Factors  of G a s t r i c P e r i s t a l s i s  Oscillators Which I n f l u e n c e  Electrical  Gastric  Activity  24  A.  Influence  o f Drugs  24  B.  Influence  o f Hormones  29  C.  M e c h a n i c a l and M e t a b o l i c  D.  Neural Influences  S e c t i o n V.  30  Factors  32  V a g a l Pathways and E f f e c t s on Gastric  35  Contractile Activity  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 N e r v e Pathways  38  1.  Vagal A f f e r e n t s  38  2.  Afferent fibres sympathetic  C.  D.  associated  with  efferents  42  E f f e r e n t N e r v e Pathways  43  1.  Introduction  43  2.  Vagal efferents  46  3. S y m p a t h e t i c e f f e r e n t pathways C e n t r a l I n t e g r a t i o n of Autonomic Nerve Pathways  56 57  vi Page Section VI. Section VII. Section VIII. Chapter  The G a s t r o d u o d e n a l The S m a l l  66  Intestine  68  Human BER  Two  Methods  70  of I n v e s t i g a t i o n  1.  The P l a n o f t h e E x p e r i m e n t  70  2.  Group I . R e c o r d i n g o f t h e BER: t h e e f f e c t o f 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 pental anaesthesia  71  Group I I . E f f e c t o f t h e o p e r a t i v e p r o c e d u r e on BER  7^  Group I I I . E f f e c t o f 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 anaesthesia  75  Group I V . Conduction t h e BER  76  3. 4.  5. 6.  Group V. BER  Chapter  60  Junction  Effect before  velocity  of  o f p e n t a g a s t r i n on and a f t e r vagotomy  76  Three  R e s u l t s and D i s c u s s i o n 1. Group I . R e c o r d i n g o f t h e BER: t h e e f f e c t o f 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 pental anaesthesia 2. Group I I . E f f e c t o f t h e o p e r a t i v e p r o c e d u r e on BER 3. Group I I I . E f f e c t o f 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 4. 5.  Group I V . C o n d u c t i o n t h e BER  velocity  78  78 82  82  of  Group V. E f f e c t o f p e n t a g a s t r i n on BER b e f o r e and a f t e r vagotomy  87 87  vii Page Chapter F o u r  90  Summary and C o n c l u s i o n s  90  Tables  94  Figures  98  Bibliography  108  viii  LIST  OF  TABLES Page  Table  I  Basic e l e c t r i c a l and a f t e r  Table  II  The e f f e c t  rhythm  before  95  vagotomy  of laparotomy  and t i m e  96  on t h e BER Table  III  The e f f e c t  o f p e n t a g a s t r i n on t h e  BER b e f o r e  and a f t e r  vagotomy  97  ix L I S T OF FIGURES Page Figure  Figure Figure  Figure Figure Figure  Figure  Figure  Figure  1.  2.  3.  4. 5.  6.  7.  8.  9.  B a s i c e l e c t r i c a l r h y t h m (BER) r e c o r d e d a t antrum. Variations i n configuration 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 . A l t e r a t i o n s i n t h e BER f o l l o w i n g d i s s e c t i o n and d i v i s i o n .  99  vagal 100  The e f f e c t on BER o f a f f e r e n t a n d 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 thiopental anaesthesia).  101  BER f o l l o w i n g c o m p l e t e vagotomy a n d esophageal t r a n s e c t i o n ,  102  The e f f e c t o f d i s s e c t i o n and d i v i s i o n o f t h e c e r v i c a l v a g u s n e r v e s o n t h e BER.  103  The e f f e c t on BER o f 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 anaesthesia).  104  The e f f e c t on BER o f a 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 vagal section (chloralose-urethane anaesthesia, stimulus i s o l a t o r ) .  105  A.  B i p o l a r r e c o r d i n g o f BER, demons 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 b e f o r e and a f t e r vagotomy.  B.  BER r e c o r d e d 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 t i m e c o n s t a n t .  The e f f e c t on BER o f a p e n t a g a s t r i n i n f u s i o n , b e f o r e and a f t e r complete vagal section.  106  107  X  ACKNOWLEDGEMENTS Many p e o p l e have shown i n t e r e s t and concern i n t h e p r e p a r a t i o n and day-to-day work o f 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 b o t h v a l u a b l e and much a p p r e c i a t e d . Dr. R.C, H a r r i s o n ' s enthusiasm for  and p e r s e v e r a n c e  i n the search  a r e l i a b l e i n t r a o p e r a t i v e method t o a s s e s s t h e complete-  ness o f vagotomy has been t h e major s t i m u l u s i n i n i t i a t i n g this investigation.  H i s support and encouragement  throughout  the course o f t h e s t u d y , d e s p i t e c r i t i c i s m from s k e p t i c s , has and w i l l c o n t i n u e t o ensure t h a t even though t h e s e a r c h f o r such a t e s t has n o t c o n c l u d e d , t h e problem w i l l n o t be a l l o w e d to  r e m a i n unanswered.  My a p p r e c i a t i o n i s a l s o extended t o  Mr. J a n Van Den Broek and h i s s t a f f , who have g r e a t l y  facili-  t a t e d t h e e x p e r i m e n t a l work o f t h i s p r o j e c t by o p e r a t i n g a v e r y e f f i c i e n t , c o n g e n i a l animal r e s e a r c h l a b o r a t o r y .  I n any  i n v e s t i g a t i o n o f t h i s t y p e , t h e r e i s perhaps one p e r s o n w i t h out whom t h e p r o j e c t c o u l d n o t f u n c t i o n .  I am t h e r e f o r e p a r -  t i c u l a r l y i n d e b t e d t o Mr. Ken Pope f o r h i s c o n t i n u e d h e l p i n s o l v i n g t h e many t e c h n i c a l problems encountered  throughout  the s t u d y , i n c l u d i n g t h e d e s i g n and maintenance o f t h e s t i m u l a t i n g and r e c o r d i n g equipment so i n d i s p e n s a b l e t o t h i s of i n v e s t i g a t i o n .  type  1 CHAPTER  ONE  INTRODUCTION The  current  e n t h u s i a s m f o r vagotomy w i t h an  d r a i n a g e p r o c e d u r e as b e e n dampened by is  recurrent  incomplete the  treatment  s e v e r a l problems, the  ulceration.  This  i n t e r r u p t i o n of the  stomach.  When one  from p o s t - o p e r a t i v e m e a s u r e d by  for peptic  i s due  assessment  insulin-induced  u l c e r disease  most s e r i o u s  that  of  has  which  i n most i n s t a n c e s  parasympathetic  considers  associated  the  to  innervation  results  to  obtained  o f c o m p l e t e n e s s o f vagotomy  h y p o g l y c e m i a o r maximum  as  stimulated  70 acid  s e c r e t i o n are  limited is  i n value  clear that  often  by  the  equivocal,  course  of  development  surgery  10-15% i n c i d e n c e This  i s an  e s s e n t i a l step  b e e n a p p r o a c h e d by  during  toward r e d u c i n g  studying  include  changes i n i n t r a g a s t r i c p r e s s u r e ,  the  stimulation during  some o f  operation.  acid secretion,  the These and  activity. SECTION I .  electrical  i n which platinum  pressure  INTRAGASTRIC PRESSURE  s t i m u l a t i o n t e s t as  electrodes  stimulation,  gastric  i t  ulceration.  responses to vagal  vagal  are  reproducible  o f vagotomy  gastric  The  these t e s t s  post-operative,  of a r e l i a b l e ,  completeness  of recurrent  p r o b l e m has  electrical  that  v i r t u e of t h e i r being  method f o r d e t e r m i n i n g t h e the  and  depends on  described  a p p l i e d t o the eliciting  upon s t i m u l a t i o n  an  by  Burge, -^' 2  esophagus e f f e c t increase  of i n t a c t e f f e r e n t  in  intra-  vagal  2  motor f i b r e s , and r e d u c t i o n of t h i s p r e s s u r e 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 . T h i s t e s t depends on the premise t h a t s t i m u l a t i o n o f e f f e r e n t v a g a l motor f i b r e s to the stomach causes 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 . N o t w i t h s t a n d i n g the f a c t t h a t 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 w h i c h i t i s based i s a t v a r i a n c e w i t h the o b s e r v a t i o n s o f Harper,  ' who  n o t e d a decrease  in  i n t r a g a s t r i c p r e s s u r e subsequent t o s t i m u l a t i o n of v a g a l efferents.  I n b o t h i n s t a n c e s , the o b s e r v a t i o n s were i n i t i a l l y  r e c o r d e d i n c a t s , u s i n g s i m i l a r but not i d e n t i c a l  electrical  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 o f v o l t a g e , impulse d u r a t i o n , and impulse f r e q u e n c y . be accounted  The  d i s c r e p a n c y i n these o b s e r v a t i o n s  may  f o r i n p a r t by M a r t i n s o n ' s s e r i e s of i n v e s t i g a -  tions^' ^"85  which have demonstrated i n c a t s the e x i s t e n c e  of b o t h e x c i t a t o r y and i n h i b i t o r y v a g a l e f f e r e n t s ,  differen-  t i a t e d by graded v a g a l 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 " h i g h t h r e s h o l d " i n h i b i t o r y  fibres  r e s p o n d i n g t o l o n g e r d u r a t i o n i m p u l s e s , c a u s i n g a decrease  in  i n t r a l u m i n a l p r e s s u r e 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 p r e dominantly  i n the corpus and fundus, but not i n the antrum.  The p o i n t t o be made here i s t h a t the r e s u l t s may  differ,  depending on the s t i m u l u s parameters and a t what l o c a t i o n i n t r a g a s t r i c p r e s s u r e i s measured. to  These f a c t o r s would t e n d  l e n d somewhat l e s s credence t o the v a l i d i t y and  reliability  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 d e s c r i b e d by Burge.  3 The  determination of  stimulation the  may  a l s o he  and  stimulated,  that  the  f a c t have l i t t l e  in  cats  of the  has  1  2-4  of  relatively  o r no  u  the few  at  i n diameter.  myenteric plexuses.  (20-30  plexuses Similar  studies  motor i n  reveal  myelinated  cells  i s an  i n the  are central  a c o m p a r a b l y low  enormous  myenteric  vagal efferent  fibres. percentage  l e v e l which are  efferent  ACID SECRETION  t h i s problem e n t a i l s  g a s t r i c mucosa, and  assessing  demonstrating a l k a l i n i t y  of  mass.  method has  i t can  on  afferent  b o d i e s i n the  vagotomy by This  only  90%  function.  mapping of the  with  may  level,  of f i b r e s  Hence t h e r e  diaphragmatic  A second approach to  complete  are  Investigation  diaphragmatic  3,000  in rabbits-^  SECTION I I .  pH  secretion.  number o f n e r v e the  the  afferent  f i b r e s synapse d i r e c t l y w i t h  m i l l i o n ) and  of v a g a l f i b r e s at  of  smooth m u s c l e t o n u s ,  with t h e i r c e l l  neurones of  most  f i b r e s which  r e m a i n i n g 10%  The  efferent  fact that  diaphragm are  small,  these  d i s c r e p a n c y between the  the  the  nervous system; the  e f f e r e n t motor nerve  efferent  e f f e c t on  v a g a l f i b r e s are  l a r g e r diameter e f f e r e n t s  by  e f f e c t on  demonstrated that  31f000  fibres,  level  t h o u g h h a v i n g an  in  e f f e c t of  influenced  v a g a l f i b r e s a t the  fibres,  the  merit  d e n e r v a t i o n of the one  of the  gastric secretion,  two  i n that  the  parietal cells.  intraoperative completeness  entire parietal accurately  the  vagal  cell  indicate  However, i t d e a l s  m a j o r mechanisms o f v a g a l  specifically  of  influence  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 v a g a l  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  d e l a y e d 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 c o l l e a g u e s  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 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 r e d dye extent  of g a s t r i c s e c r e t i o n . ^ 9  progressively decreasing  overlap  combining  to v i s u a l i z e  They have demonstrated a of i n n e r v a t i o n as one  l a t e s v a g a l 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 plexus  the  t o t h a t of the t e r m i n a l g a s t r i c b r a n c h e s .  stimuesophageal  Griffith  demonstrated t h a t s t i m u l a t i o n of one v a g a l f i b r e cannot  has  influ-  ence the e n t i r e g a s t r i c mucosa v i a c o n n e c t i o n s w i t h i n M e i s s n e r ' s submucosal p l e x u s , but t h a t s t i m u l a t i o n of any v a t e s the antrum can, by way cause a d e l a y e d , mucosa.  f i b r e which i n n e r -  of a n t r a l r e l e a s e of g a s t r i n ,  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  cell  Even though a v a g a l l y d e n e r v a t e d p a r i e t a l c e l l mass  would be l e s s r e s p o n s i v e  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 d e n e r v a t e d .  F a i l u r e to achieve  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 v a g a l i n n e r v a t i o n v i a the u n d i s t u r b e d  reduction be due  h e p a t i c branch of  to  the  a n t e r i o r v a g a l t r u n k , w i t h f i b r e s r e a c h i n g the antrum a l o n g c o u r s e of the r i g h t g a s t r i c a r t e r y . may  the  Alternatively, innervation  o c c u r v i a p a r a s y m p a t h e t i c f i b r e s emerging w i t h t h o r a c i c  dorsal spinal roots. tomy may  Hypersecretion  f o l l o w i n g s e l e c t i v e vago-  be a t t r i b u t e d t o 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 d e l a y e d a n t r a l r e l e a s e of g a s t r i n ; the  5 d e l a y e d 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 be d e t e c t e d by i n t r a o p e r a t i v e There are  pH  mapping.  o t h e r f a c t o r s t o be c o n s i d e r e d i n pH mapping of  the g a s t r i c mucosa.  The  acid-alkaline  j u n c t i o n i s not  a p r e c i s e l y d e f i n e d zone of t r a n s i t i o n , but may a c r o s s a d i s t a n c e of one  centimetre.  The  demarcate the  antrum may  e x t e n t of a n t r a l mucosa.  i n v e r s e r e l a t i o n s h i p between the  s i z e of the  always  i n f a c t extend not  u n i f o r m l y a l k a l i n e , r e n d e r i n g i t d i f f i c u l t f o r the pH accurately  not  be  assay to  There i s an  antrum and  that  of the p a r i e t a l c e l l mass; a s m a l l antrum i s u s u a l l y t o  be  found i n a p a t i e n t  and  w i t h an u n c o m p l i c a t e d duodenal u l c e r  h i g h 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 a r e a 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  c o m p l i c a t e d by p y l o r i c o b s t r u c t i o n . of the  Incomplete d e n e r v a t i o n  antrum ( o r i n c o m p l e t e removal of a n t r a l mucosa d u r i n g  gastrectomy) w i l l therefore r e s u l t i n continued g a s t r i n prod 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 . 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  This  w i t h duodenal u l c e r  t h a n i n those w i t h an u n c o m p l i c a t e d g a s t r i c u l c e r , as l a t t e r have l e s s g a s t r i n p r o d u c t i o n and  factor  generally  a  the small,  a t r o p h i e d 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  a n a t o m i c a l l y i n c o m p l e t e but  may  account f o r  "adequate" v a g o t o m y . ^  A  the  small,  d e l a y e d response t o i n s u l i n h y p o g l y c e m i a , though i n d i c a t i n g a t e c h n i c a l l y i n c o m p l e t e vagotomy, may tact terminal  g a s t r i c b r a n c h t o the  i n f a c t be due  t o an i n -  fundus, w i t h m i n i m a l r i s k  6 of r e c u r r e n t early  ulceration.  response t o i n s u l i n  On t h e o t h e r hand, a p r o n o u n c e d , h y p o g l y c e m i a would i n d i c a t e  c o m p l e t e vagotomy w i t h i n a d e q u a t e p r o t e c t i o n  an i n -  against  recurrent  ulceration. Notwithstanding the c r i t i c i s m mapping t e c h n i q u e this  i n assessing  l e v i e d against  t h e pH  t h e c o m p l e t e n e s s o f vagotomy,  t o o l c a n be o f s i g n i f i c a n t v a l u e i n u p g r a d i n g t h e s u r g i c a l  treatment  of peptic  defence.  Clinical  incomplete  ulcer studies  disease, suggest  antrectomy i n p a t i e n t s  and much c a n be s a i d there  in its  i s a high incidence  who d e v e l o p r e c u r r e n t  of  ulcera-  4. tion  following  This  group o f p a t i e n t s  secretion  gastrectomy with  shows a p e r s i s t e n t  w h i c h may be due e i t h e r  or t o r e s i d u a l Drs.  or without associated  antral tissue  t o an i n c o m p l e t e  with  that  secretion  have r e s u l t e d  from the d e l i b e r a t e  antrectomy a s s o c i a t e d  indicate  that  and  suggest that  performance  of residual  a l t e r s the secretion  demarcation of the proximal extent  the  a method whereby f o l l o w i n g  acid-alkaline  junction  o f an i n -  Their  results  antrum l e f t i n  from such a  i f a n t r e c t o m y i s t o be p e r f o r m e d  t i o n w i t h vagotomy, i t must be c o m p l e t e .  vised  o f Sur-  have e v a l u a t e d t h e  w i t h vagotomy.  even a s m a l l p o r t i o n  significantly  production.  (from H e i d e n h a i n pouches i n dogs)  complete  situ  vagotomy,  i n t h e Department  gery a t the Vancouver General H o s p i t a l , on a c i d  of acid  continued g a s t r i n  R.C. H a r r i s o n and J . L . S t o l l e r ,  effects  elevation  vagotomy.  preparation,  i n associa-  In order t o f a c i l i t a t e  o f t h e a n t r u m , t h e y have de-  mild  histamine  c a n be i d e n t i f i e d - b y  stimulation, means o f a  7 w a n d e r i n g pH stomach. ulcer  sensitive  Best  results  patients  alkaline c a n be  are  area i n g a s t r i c  one  likely  with active  adequately  results,  electrode introduced perorally  ulcer patients  mapped a s w e l l .  "antrum" a r e n o t n e c e s s a r i l y intended to designate  well  parietal  cells.  sumably does n o t that  the  assay  may  the g a s t r i n  into  produce g a s t r i n .  i n o r d e r t o ensure  tissue  (and  thus  the  remove t h e  resection  not  s o l v e t h e p r o b l e m w h i c h may  more d i s t a l  too f a r p r o x i m a l l y .  s i t e s i n the  SECTION I I I .  study  the  test  of the  area  w i t h the  how  arise  may  active pre-  observation the  pH  to  removal of a l l a n t r a l without  from  gastrin  release  i n t e s t i n a l t r a c t , though the as a c a u s e o f  extending  assay  canfrom  signifi-  persistent  undetermined.  GASTRIC E L E C T R I C A L ACTIVITY o f d e v e l o p i n g an  t o a s s e s s c o m p l e t e n e s s o f vagotomy has  electrical  and  stomach,  much s t o m a c h  M o r e o v e r , t h e pH  A t h i r d approach t o the problem operative  these  area"  o c c u p i e d by  of g a s t r i n ) ,  c a n c e o f t h i s s m a l l amount o f g a s t r i n h y p e r s e c r e t i o n i s as y e t  of  uniformly alkaline,  complete  the  area  alkaline  Coupled  precisely  source  secretion  significant gastritis  T h i s newly e s t a b l i s h e d  resect  acid  the  Though "antrum" i s  an a r e a p r e v i o u s l y  always i n d i c a t e  low  terms " a l k a l i n e  producing  with  antrum i s not n e c e s s a r i l y not  with  synonymous.  area i n a patient  have e x t e n d e d  a c t i v i t y , though  In i n t e r p r e t a t i o n the  the  obtained i n duodenal  parietal cell  must r e c o g n i z e t h a t  the a l k a l i n e  t o be  into  a c t i v i t y of the  intrabeen t o  s t o m a c h ; 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  tomy, and  the e f f e c t  vagal stimulation A.  activity  of both a f f e r e n t  on t h i s  electrical  "before and  ( r e f l e x ) and  after  vago-  efferent  activity,  History Several investigations  interest  s e r v e as l a n d m a r k s o f  i n the development of t h i s peristalsis  The  origin  control  of g a s t r i c  niques,  including  gastric  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 o f With  of the  stomach,  o f a s i m i l a r mechanism.  that pacemaker-like  i n neuromuscular  tissue  tissue  intra-  the development of the  o f t h e c a r d i a c p a c e m a k e r , t h e s t o m a c h was  the presence gested  fluoroscopy.  and  b e e n s t u d i e d by v a r i o u s t e c h -  direct visualization  c o n t r a s t m e d i a and concept  has  approach.  historical  Early  examined f o r  investigation  i n the l e s s e r curve  at the g a s t r o e s o p h a g e a l  sug-  ganglia,  junction,  or  i n t h e w e l l - d e v e l o p e d l e s s e r c u r v e m y e n t e r i c p l e x u s may  be  ponsible  1922,  f o r coordinating gastric  Alvarez-^ d e s c r i b e d a slow, in gastric  muscle.  These  rhythmic  i n the g a s t r o i n t e s t i n a l  obvious  contractile  activity.  quency o f the rhythmic s t o m a c h , and  lowest  electrical  In activity  occurring  " a c t i o n c u r r e n t s " were r e c o r d e d  stantly  from v a r i o u s areas of the  peristalsis.  tract,  '  s t o m a c h , he  a c t i v i t y was  i n the d i s t a l  con-  even i n the absence  U s i n g i s o l a t e d muscle  J  res-  demonstrated  h i g h e s t i n the  stomach.  He  that  of strips  the  fre-  proximal  suggested  that  h.  a p a c e m a k e r was these e l e c t r i c a l stomach.  p r e s e n t i n the  r e g i o n of the c a r d i a ,  c u r r e n t s were p r o p a g a t e d  A l v a r e z suggested  that these  aborally  and  that  along the  spreading currents  may  9  coordinate mechanical  and c h e m i c a l 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 o f these o b s e r v a t i o n s , A l v a r e z i n t r o -  duced the " e l e c t r o e n t e r o g r a m "  t o the study o f 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 c o u n t e r p a r t . a b l e t o d i f f e r e n t i a t e between what are now  Though he was  not  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 n e v e r t h e l e s s  intro-  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.  Electrical The  Recording  concepts  o f m o t i l i t y s h o u l d be based on the measure14  ment o f v a r i a b l e s which c o n t r i b u t e t o c o n t r a c t i l i t y .  Activa-  t i o n o f muscle f i b r e s i s accompanied by e l e c t r i c a l charges a c r o s s the s u r f a c e o f t h e i r membranes and i n the extracellular fluid.  surrounding  These i n v i v o b i o e l e c t r i c a l phenomena,  as p o r t r a y e d i n the enterogram, can supplement d a t a  obtained  from manometry, r a d i o l o g y , and o t h e r s t a n d a r d methods o f e v a l u a t i o n of m o t i l i t y . There a r e t h r e e t y p e s o f b i o e l e c t r i c phenomena which i n the GI t r a c t .  They may  occur  be c l a s s i f i e d a c c o r d i n g 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 v o l t a g e changes a c r o s s a s i n g l e c e l l membrane of an i s o l a t e d  tissue;  t h i s type o f p o t e n t i a l would be d e t e c t a b l e , f o r example, by i n s e r t i n g a m i c r o e l e c t r o d e 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 r e c o r d e d i n t h i s f a s h i o n ;  10 (ii)  transmucosal  p o t e n t i a l s , i n d i c a t i n g voltage  change  a c r o s s a mucosal s u r f a c e ; ( i i i ) surface o r 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 v o l t a g e changes a c r o s s t i s s u e s u r f a c e s o r e x t r a c e l l u l a r f l u i d as r e c o r d e d 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 ; s u r f a c e e l e c t r o d e s r e g i s t e r t h e mean of p o t e n t i a l s g e n e r a t e d by many c e l l s exposed t o t h e recording t i p . The e l e c t r o e n t e r o g r a m  d e s c r i b e d by A l v a r e z i s an example o f  s u r f a c e p o t e n t i a l r e c o r d i n g , as a r e t h e 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 t h e use o f e x t e r n a l e l e c t r o d e s w h i c h serve as c o n n e c t o r s  between a d e s i g n a t e d  region 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 d e v i c e .  To  r e c o r d i n a monopolar f a s h i o n , one e l e c t r o d e i s p l a c e d i n cont a c t w i t h t h e t i s s u e under i n v e s t i g a t i o n , and a r e f e r e n c e e l e c t r o d e i s p l a c e d i n an a r e a o f low e l e c t r i c a l a c t i v i t y . other b i o l o g i c a l generators  Though  may l i e i n t h e p a t h o f t h e v o l t a g e  b e i n g measured, and may t h u s c o n t r i b u t e t o t h e p o t e n t i a l d i f f e r ' ence r e c o r d e d , these unwanted p o t e n t i a l s a r e u s u a l l y randomly o r i e n t a t e d , and t e n d t o c a n c e l each o t h e r o u t . t i o n of the p o t e n t i a l recorded 14 factors;  The c o n f i g u r a -  i s i n f l u e n c e d by many p h y s i c a l  20 '  i n c l u d e d among t h e f a c t o r s t o be c o n s i d e r e d a r e  the amount o f p r e s s u r e  e x e r t e d by t h e e l e c t r o d e , t h e degree o f  p e n e t r a t i o n of the electrode i n t o the t i s s u e , the s i z e of the r e c o r d i n g t i p , t h e amount o f e l e c t r o l y t e between t h e e l e c t r o d e and t h e a c t i v e t i s s u e , t h e development o f c o n n e c t i v e t i s s u e  11 beneath t h e e l e c t r o d e d u r i n g t h e course the p r o p a g a t i o n  of long-term  recording,  o f t h e p o t e n t i a l s , and t h e s i n k r e l a t i o n s v i a  l o w - r e s i s t a n c e pathways t o d i s t a n t  sources.  1 0 0  S u r f a c e r e c o r d i n g s o f e l e c t r i c a l p o t e n t i a l from t h e g a s t r o intestinal tages, ' 1 2  t r a c t o f i n t a c t animals ^  1  0  have s e v e r a l d i s t i n c t  advan-  0  (i)  the preparation i s p h y s i o l o g i c a l ;  (ii)  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 t h e same a n i m a l under v a r i a b l e c o n d i t i o n s , o r over a p r o longed  period;  ( i i i ) many a r e a s o f t h e GI t r a c t can be e x p l o r e d s i m u l t a n e o u s l y i n t h e same p r e p a r a t i o n ; (iv)  a c t i v i t y can be r e c o r d e d  from a l o c a l i z e d  area;  (v)  t h e r e c o r d i n g u n i t does n o t o b s t r u c t t h e bowel lumen, and does n o t a c t as an abnormal s t i m u l u s t o mucosal r e f l e x e s ;  (vi)  t h e 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  activity. 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 P r o p a g a t i o n R e s e a r c h o v e r t h e y e a r s has more a c c u r a t e l y d e f i n e d t h e  e l e c t r i c a l a c t i v i t y o f t h e stomach as c o m p r i s i n g two t y p e s o f 4T  potential variation.  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 -  c o r d e d by A l v a r e z a r e now d e s c r i b e d as a r h y t h m i c , e l e c t r i c a l depolarization with a characteristic  omnipresent  triphasic  12 ( p o s i t i v e , negative, p o s i t i v e ) configuration, designated b a s i c e l e c t r i c a l rhythm, o r BER.  " B a s i c " i n d i c a t e s the  s i s t e n t o r fundamental p r o p e r t y of the e v e n t ;  the per-  "electrical" l  describes The  BER  the type of phenomenon; "rhythm" denotes p e r i o d i c i t y .  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 ,  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 .  and  It is 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 r e n d e r s 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 absolutely r e f r a c t o r y . ^  Synonymous terms f o r the BER  i n i t i a l p o t e n t i a l , slow wave, p a c e s e t t e r electrical control activity. The  BER  c a t e d a t the greater  and  include  p o t e n t i a l (PP),  and  J  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 j u n c t i o n of the p r o x i m a l and  middle t h i r d s of  c u r v a t u r e of the s t o m a c h , a n d i s p r o p a g a t e d  the  caudally  a l o n g the l o n g i t u d i n a l muscle f i b r e s t o the antrum and  to  l e s s e r c u r v e 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 p r o p a g a t e d as a c o n t i n u o u s s h e a t h a l o n g  muscle w a l l , such t h a t i t i s a t the same phase i n any ferential cross-section time. ^ 1  of the stomach a t any  one  the  the  circum-  point  in  ^  A n a t o m i c a l s t u d i e s of the g a s t r i c m u s c u l a t u r e " ^  0  reveal  c o n f l u e n c e of l o n g i t u d i n a l muscle b u n d l e s on b o t h a n t e r i o r p o s t e r i o r a s p e c t s of the upper t h i r d of the g r e a t e r  a  and  curve.  From t h i s r e g i o n , the muscle b u n d l e s r a d i a t e i n m u l t i p l e  arcs  a l o n g the g r e a t e r  lesser  curve.  c u r v e t o the antrum, and  a c r o s s t o the  I n the d i s t a l antrum, l o n g i t u d i n a l muscle b u n d l e s from  k  13 the g r e a t e r curve s i m i l a r bundles fourths curve  continue  from  over t h e l e s s e r c u r v e , and j o i n  the opposite side.  o f t h e stomach, t h e r a d i a t i n g  fibres  An a s s e s s m e n t o f p a r t i a l  muscle bundles  at various levels  bridge  entrainment  transection,  that  i n gastric  of these  that  a narrow  (Z0%> o f t h e c i r c u m -  o f t h e stomach d i s t a l  the g r e a t e r curve  continuity t o the  i s considerably  conduction than are other areas of  stomach, i n c l u d i n g t h e l e s s e r c u r v e .  t u d i n a l muscle  in  transection  t o m a i n t a i n normal e l e c t r i c a l  i n t h e segment  indicating  more i m p o r t a n t  curve  the g r e a t e r  has demonstrated  o f muscle a l o n g the g r e a t e r curve  ference) i s s u f f i c i e n t  the  from  three-  terminate before r e a c h i n g the s u p e r i o r margin o f the  lesser curve.  and  I n the proximal  on t h e p r o x i m a l  e x p l a i n s the absence  The p a u c i t y o f l o n g i -  three-fourths of the l e s s e r  o f s l o w wave a c t i v i t y  and c o n d u c t i o n  this region. Each i n i t i a l  stomach w a l l , length.  extends  The segment o f s t o m a c h  segment, a n d c o n t r o l s  pagation rates  segment o f  ( o r bowel) beneath  each  cycle  r e p r e s e n t s a p h y s i o l o g i c a l m o t o r segment.-^' ^  BER o r p a c e s e t t e r p o t e n t i a l  this  over a s p e c i f i c  a n d may be d e s c r i b e d a s h a v i n g a wave o r c y c l e  of t h i s p o t e n t i a l The  potential  determines  the dimensions  i t s motor a c t i v i t y .  Rate o f p r o -  o f t h e BER i n c r e a s e s a s t h e a n t r u m i s a p p r o a c h e d ,  r a n g i n g from  p e r second  0.1  cm. p e r s e c o n d  i n the corpus  i n the terminal a n t r u m , ^  the cycle  t o 2-4  with cm.  Cycle length 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 t h e v e l o c i t y increases,  of  of propagation  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 o f t h e u n d e r l y i n g m o t o r segment i s a l s o i n c r e a s e d .  This rapid  spread  responsible rate  of d e p o l a r i z a t i o n  f o r i t s behaviour  or frequency  over the  entire  as a m o t o r u n i t .  w h i c h i s c o n s t a n t and  The  complex o c c u p i e s  1.5-2,5  BER  has  species specific  c y c l e s p e r minute i n dogs, 3 c y c l e s p e r minute triphasic  antrum i s  seconds,  (4-5  i n man).  and  a  The  i s followed ko  by  a r e f r a c t o r y p e r i o d of just  less  than three  seconds.  J  4 Propagation which are areas  is facilitated of f u s i o n  provides a direct without  of adjacent  electrical  integrity. sources  and  Contiguous  space,  cells  current sinks,  one  cells  cell  membrane t o a n o t h e r .  behave e l e c t r i c a l l y and  much as  current i s propagated  at  sites  electrotonic  spread  of n e x a l connections  provide  '  The  the  inability  (ii)  a theoretical genic  The  con-  cell  cells  membranes  are exposed t o h i g h potassium  the  concept  thus  provide  origin  o f t h e BER.  a neurogenic  Most origin.^  include:  of n e u r o t r o p i c drugs t o a l t e r inability  a potential  and  flow.  of the  the  BER;  s m a l l mass o f n e u r o -  elements of the g a s t r o i n t e s t i n a l  generate  spread  o f c u r r e n t o c c u r s between  f a v o u r s a myogenic r a t h e r t h a n  (i)  interiors  i n t e r i o r s were  a l o n g an a x o n .  surrounded  this  nexus  smooth m u s c l e  r e s i s t a n c e pathways f o r c u r r e n t  F a c t o r s which support  The  '  J  21  low  evidence  '  simultaneous  c a l c i u m c o n c e n t r a t i o n s , a r e d e p o l a r i z e d , and  has  ^o  maintaining  low  Controversy  *  membranes.  while  as t h o u g h t h e i r  nected,  J  allowing electrotonic  20 from  cell  c o n n e c t i o n between c e l l  intervening extracellular  cellular current  by n e x a l c o n n e c t i o n s ,  46  tract  o f the magnitude o f the  to BER;  15 (iii)  the  absence of the  the  GI  BER  i n hypomuscular areas  t r a c t , f o r example, t h e  of  gastroduodenal  junction; (iv)  cyclical  e l e c t r i c a l phenomena a r e  l o n g i t u d i n a l but the D.  Action The  vity"  BER  as  polarization  43 "spikes",  has  been d e s i g n a t e d  This  the  the  the  by  "electrical  appearance of the  i s represented  following  initial  be  (4-8  This  one  activity  ( u s u a l l y by  burst  cycle  of  of  coordinates  its  p r o p a g a t i o n and  of the  "second"  contraction,  and  frequency BER.  0.5  potential  s e c o n d s ) as  the  and  or  (PP),  faster  fibres.  the  of c o n t r a c t i o n D u r i n g the  percentage  observed  or with  strain  associated  The  BER  f i x e s the  i t s caudal migration  contraction,  precedes  with  " a c t i o n p o t e n t i a l s " , and  d e t e r m i n i n g the  width  of the  contracting  can  therefore  not  synchronizes  velocity band.  exceed the  i s markedly i n c r e a s e d  25%  during  thus  maximum  o f BER  of  The frequency  fasting state, action potentials  occur i n a s s o c i a t i o n with approximately This  de-  seconds) negative  o r m o t o r segment has  band of c o n t r a c t i n g  frequency  a second  "second p o t e n t i a l " immediately  E a c h BER  only  acti-  4"5  gauges.  one  of  activity",  superimposed a s e r i e s of  o r measured e i t h e r k y m o g r a p h i c a l l y  only  control  as  or p a c e s e t t e r  visually  it  layers  "response  electrically  a more p r o l o n g e d  upon w h i c h may  J %  contractile  c i r c u l a r muscle  the  Potentials  i s characterized  deflection,  the  in  tract.  i t controls  contraction.  and  GI  not  generated  (AP's)  cycles. ^'  feeding,  1  and  ^  1  during  16 3*5 the  administration  or "spike"  of v a r i o u s  potential, unlike  drugs. the  BER,  J %  J (  37 '  J  43 '  i s not  91 The  7  action  p r o p a g a t e d more  43 t h a n a few  millimetres  in either direction.  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 tractile  activity  pressure. records and  a change due  increase  t o the  By  simultaneously  t u d i n a l and  the  layers,  contractile acti-  s t r a i n gauges o r i e n t a t e d contractile activity  c i r c u l a r m u s c l e , i t has  a c t i o n p o t e n t i a l s are  pressure  mean e f f e c t o f a l l m u s c l e  means o f  associated  con-  in intraluminal  i n d i c a t e w i t h i n which l a y e r the  originates.  to record  c o r r e l a t e d with  However, a measurement o f i n t r a l u m i n a l  does n o t  vity  as m e a s u r e d by  J  so  as  of both l o n g i -  been demonstrated t h a t  w i t h c i r c u l a r muscle  the  contrac-  14 tion.  The  portional the  number and  to e i t h e r the  contractile force  would t e n d t o c o n f i r m origin.  amplitude  Further  are  directly  pro-  change i n i n t r a l u m i n a l p r e s s u r e  as m e a s u r e d w i t h s t r a i n g a u g e s ; that  evidence  a c t i o n p o t e n t i a l s are i n support  these p o t e n t i a l s i s found i n the occurs i n muscle c e l l s  o f AP's  of the  of the  rhythmic  chick  or this  myogenic  myogenic  in  origin  contraction  of  which  amnion, w h i c h i s d e v o i d  of  88 nerve  fibres.  This  observation  would i n d i c a t e t h a t  taneous c o n t r a c t i o n need not  be  E.  Peristalsis  Coordination  of G a s t r i c  neurogenic  Coordinated g a s t r i c p e r i s t a l s i s  sweeping i n a rhythmic p a t t e r n  pylorus.  I t synchronizes  a  suitable electrical  origin,  depends on  potential  the  in  spon-  the  pacesetter  from i t s o r i g i n t o  g a s t r i c m u s c u l a t u r e by  the  providing  framework t h r o u g h w h i c h g a s t r i c s t i m u l i  17 may  71  a c t t o 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 a r e p r o p a g a t e d 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 c o n d u c t i n g u n i t s con-  s i s t o f b u n d l e s 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 o f d e p o l a r i z a t i o n t h a t spreads t o the c i r c u l a r l a y e r t h e n 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 p l e x u s e s and perhaps o t h e r e x c i t a t o r y t r a n s mitters 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  contraction  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 s i m p l y p a r a l l e l cont 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 a c t 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 ( A c h ) , o r i t may s e n s i t i z e the g a s t r i c m u s c u l a t u r e t o the e f f e c t s o f Ach. r e l e a s e d Ach may  The  i n i t i a t e the second d e p o l a r i z a t i o n o r 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 c a l c i u m r e l e a s e and subsequent c o n t r a c t i o n .  y  Whether o r n o t 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 i m p u l s e s mediated v i a b o t h i n t r i n s i c and e x t r i n s i c n e t w o r k s . 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 contract  layers  s i m u l t a n e o u s l y , and a r e a b l e t o do so i n the absence  of M e i s s n e r ' s p l e x u s , s u g g e s t s t h a t 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 control  18 i s not  a prerequisite for peristalsis,  rather  t h a n commanding i n i t s r o l e .  and  i s more  Peristalsis  modulating  can  also  occur  k<a  in  the  presence  activity.  of t e t r o d o t o x i n ,  It is likely  response to  that neural  activity  s l o w wave d e p o l a r i z a t i o n by  the  p r o b a b i l i t y of  BER  complex.  F.  ^ which e l i m i n a t e s  spiking during  the  at various  of the  l e v e l s has  transects  the  n o r m a l PP  i s not  order  depolarized  decreasing  phase o f  new,  distal  will  b o t h c a u d a d and larity pulse  due  separating  to interposed  the  l e s s e r curve gastric  the  ^'  1 0  location  concept  ^»  1  1  of i f  0  dominant pacemaker, the  site  of  slower rate  greater  pacemaker.  from the  i n the  may  occasional  no  l e s s e r curvature  longer  driven  foci  distal The  show irreguof  by  causes  the  im-  f r e q u e n c y and  an  irregularity ectopic  foci  the  dominant  T h i s procedure a l s o r e s u l t s i n the  appearance of m u l t i p l e  in of  developthe pace-  73 making a c t i v i t y .  ne  the  assume p a c e m a k i n g a c t i v i t y .  p r o p a g a t i o n and  0  transection,  p o t e n t i a l s from e c t o p i c  segment t o be  t o the  t o the  1 0  planes  Similarly, longitudinal gastric bisection  ment o f a r e d u c e d BER due  the  have a s l o w e r f r e q u e n c y , and  retrograde  generation.  only  supported the  inherently  stomach w i l l  BER  has  propagated across  a p a c e m a k e r w i t h an  stomach i n v a r i o u s  pacemakers."^'  stomach d i s t a l  segment o f t h e  BER  the  i n c r e a s i n g or  demonstrated not  g a s t r i c pacemaker, but  dominance o f h i g h e r  and  modulates  P a c e m a k e r Dominance E x p e r i m e n t a l t r a n s e c t i o n of the  and  a l l neural  J  This  u n c o u p l i n g of e l e c t r i c a l  activity  19  between the two segments i s o n l y temporary, w i t h r e c o v e r y o c c u r r i n g by two weeks.  The r e - e s t a b l i s h m e n t o f 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  but the models i n each i n s t a n c e 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 s t u d y . "permanently"  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  l o w e r BER  f r e q u e n c y i s i n k e e p i n g w i t h the con-  c e p t of a g r a d i e n t i n the r a t e o f g e n e r a t i o n o f 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 73  gastrointestinal  tract.'  J  The normal pacemaker on the p r o x i m a l t h i r d o f the g r e a t e r c u r v e , h a v i n g the f a s t e s t i n t r i n s i c f r e q u e n c y , e n t r a i n s the 73  110  l e s s e r c u r v e and d i s t a l stomach.'-"  The more d i s t a l stomach  has a l o w e r i n t r i n s i c PP f r e q u e n c y , but can a c c e p t 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 p r o p a g a t i o n of  the PP i s determined by the s i t e o f the group of c e l l s  having  the f a s t e s t f r e q u e n c y ; p r o p a g a t i o n o c c u r s from t h i s r e g i o n t o those w i t h s l o w e r i n h e r e n t f r e q u e n c i e s . The smooth muscle c e l l s of the fundus and p r o x i m a l corpus p o s s e s s 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 o f the r e mainder of the stomach, as they n e i t h e r a c c e p t n o r  propagate  73  the c o r p o r a l P P . '  V  Lack o f measurable  rhythmic  electrical  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 . G. Relaxation Oscillators I n o r d e r t o e l a b o r a t e on the mechanism o f e n t r a i n m e n t , i t 1 1 0  1 0  ^  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  oscillators  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 o f g a s t r o i n t e s t i n a l motility.  D %  GI 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 c o u p l e d r e l a x a t i o n o s c i l l a t o r s i n which  potential  pacemaking f o c i o s c i l l a t e w i t h f r e q u e n c i e s i n h e r e n t t o 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  longitudinal  muscle c e l l s are capable o f spontaneous slow wave g e n e r a t i o n . 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 more l i k e l y , comprise phase.  be as s m a l l as one c e l l ,  or,  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  Coupling occurs v i a n e x a l contact or c u r r e n t flow i n  the s u r r o u n d i n g e x t r a c e l l u l a r f l u i d .  Thus each c e l l o r c e l l  group can s i m u l t a n e o u s l y c o n t a i n b o t h a source and s i n k of current. An o s c i l l a t o r w i t h a h i g h e r n a t u r a l f r e q u e n c y can dominate, " p u l l i n " , o r e n t r a i n l o w e r f r e q u e n c y o s c i l l a t o r s such t h a t the l a t t e r t e n d t o a c c e p t the f r e q u e n c y o f the f a s t e r The r e l a x a t i o n p r o p e r t i e s of the l o w e r f r e q u e n c y  oscillator. oscillators  102  allow t h i s modulation to occur. T h i s concept may be b e s t iti l l u s t r a t e d by r e f e r e n c e t o the c o n d u c t i n g system o f the h e a r t . The SA and AV nodes behave as c o u p l e d r e l a x a t i o n  oscillators,  w i t h the SA node dominant, and the AV node t e n d i n g t o " p u l l i n " towards the r a t e of the dominant node.  The l e s s  stable,  l o w e r f r e q u e n c y o s c i l l a t o r adopts a r a t e e q u a l t o o r some h a r monic o f the r a t e of the dominant o s c i l l a t o r . t h i s concept may  One  can see  how  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 a r e a has i t s own  i n h e r e n t 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 s t o m a c h , and  from p r o x i m a l t o d i s t a l  pacemakers i n each or  The in  segments by  t r a n s e c t i o n and 1 0  ^*  anastomotic  segments, w i t h e v i d e n c e  secondary  t o the  under the  control  "pull in" serial  are  experiments  a s l o w e r BER  i n both  frequency  of abnormal  described  i n the  of the  faster,  dominant p r o x i m a l  following  local  pacemaker.  trauma, l o c a l  anaesthesia applied to a cross-sectional  stomach o r bowel.  longer  an u n c o u p l i n g o f t h e p a c e m a k e r s .  observed  These e f f e c t s  are temporary,  post-  propagation  emergence o f e c t o p i c p a c e m a k e r s no  i s , i n effect,  local  tract  have d e m o n s t r a t e d  small intestine  or  Proximal  coupling of  re-anastomosis  s t o m a c h and  effects  distal  pacemakers.  the p r e v i o u s s e c t i o n  This  s m a l l bowel.  o f t h e s e r e g i o n s o f t h e GI  e n t r a i n t h e more d i s t a l  oscillating  d e c r e a s i n g from p r o x i m a l t o  Similar  cooling, zone  of  remaining f o r  71 p e r i o d s up  t o two  weeks.  I t has  been suggested  of  the pacemakers o c c u r s such  is  r e s t o r e d i n the post-anastomotic  situation  i s observed  an AV  o f i t s own  electrical  but  An  BER  analogous  and  may  be  i n the  a l s o be  gener-  event  muscle.  of  o r perma-  b l o c k w i l l allow r e c o u p l i n g of  of the c a r d i a c  is  interpreted  temporary  the dominant a t r i a l pacemaker w i l l  control  frequency  the v e n t r i c l e  frequency  T h i s s i t u a t i o n may  C o r r e c t i o n o f t h e AV and  segment.  i n t r i n s i c rhythmic  conduction block.  oscillators,  original  of a c t i v i t y ,  as an u n c o u p l i n g o f o s c i l l a t o r s , nent.  the  i n t h e h e a r t ; an a t r i a l p a c e m a k e r  ates the h i g h e s t frequency capable  that  that coupling  assume  the  22 T h i s concept i s i m p o r t a n t i n c o n s i d e r a t i o n o f d i s o r g a n i z e d m o t i l i t y and d e l a y e d g a s t r i c emptying which so o f t e n f o l l o w s vagotomy o r g a s t r i c r e s e c t i o n .  The p r o x i m a l g a s t r i c pacemaker  has t h e h i g h e s t i n t r i n s i c f r e q u e n c y o f o s c i l l a t i o n ; u n c o u p l i n g of t h e d i s t a l stomach from t h e e l e c t r i c a l dominance o f t h i s p r o x i m a l 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 t h e m o t i l i t y d i s t u r b a n c e s 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 p r e m i s e , i t  may be p o s s i b l e t o u t i l i z e t h i s model and a p p l y e x t e r n a l  oscil-  l a t o r s t o t h e stomach t o o v e r r i d e t h e 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 d i s t u r b a n c e s which o c c u r f o l l o w i n g u l c e r s u r g e r y , much i n t h e same manner i n which c a r d i a c p a c i n g o v e r r i d e s t h e u n d e s i r a b l e a r r y t h m i a s and c o n d u c t i o n d i s o r d e r s f o l l o w i n g m y o c a r d i a l 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 t o  p a c i n g t h e c a n i n e stomach e l e c t r i c a l l y .  U s i n g c u r r e n t s o f 1-8  ma, and i m p u l s e s o f 0.1-2.0 seconds' d u r a t i o n a p p l i e d a t 2-12 i m p u l s e s p e r minute, he has demonstrated  c o u p l i n g between t h e  s t i m u l u s and t h e e x c i t a b l e t i s s u e s i n t h e g a s t r i c w a l l  such  t h a t t h e f r e q u e n c y o f t h e PP c o r r e s p o n d e d e x a c t l y t o t h e f r e quency o f a p p l i e d s t i m u l a t i o n , w i t h subsequent the n a t u r a l g a s t r i c PP.  suppression of  The a r t i f i c i a l l y g e n e r a t e d PP was  p r o p a g a t e d b i d i r e c t i o n a l l y , b u t was n o t observed i n t h e fundus. The v e l o c i t y o f p r o p a g a t i o n was i d e n t i c a l i n b o t h d i r e c t i o n s , and was o f t h e same magnitude as t h a t o f t h e n a t u r a l PP.  The  n a t u r a l PP i n t h i s s t u d y had a mean f r e q u e n c y o f 5.0 c y c l e s p e r  23 minute; t h i s  could  decreased to 4.2 of a p p l i e d  be  increased  cycles per  stimulation.  t o 8.0  m i n u t e by  cycles per  minute,  or  varying  the  frequency  Beyond t h e s e l i m i t s ,  the  natural  PP  reappeared. Previous trol  a t t e m p t s t o g e n e r a t e PP's  gastrointestinal activity  s u c c e s s and results.  Varied  contractile applied resulted  have c o n t r i b u t e d studies  activity  electrical i n any  and  have g e n e r a l l y  little  i n the  associated  AP's  s t i m u l a t i o n t o the  way  a t a f r e q u e n c y and  '  y  '  n a t u r a l p a c e m a k e r and stomach.  on n e u r o n e s i n t h e  intramural  externally have  unlike  been a b l e  external  plexuses  not  post-operative  assume c o n t r o l o f t h e Whether t h e  little  gastric  delivering  w i t h a rhythm not  con-  concrete  following  By  the  i n the  with  of  p a r t i c u l a r success i n a l t e r i n g  n a t u r a l g a s t r i c p a c e m a k e r , K e l l y has  acted  met  stomach, but  the  activity  consequently  have d e m o n s t r a t e d i n c r e a s e d  gastrointestinal motility. stimuli  and  electrical that  to  of  override  pacemaking s t i m u l i have  or d i r e c t l y  on  the the  smooth m u s c l e i t s e l f  i s unknown.  F r e q u e n c y p u l l i n g between  site  stimulus  the  of the  external  maker o c c u r r e d able,  within  and  i n s u c h a manner t h a t  certain defined  limits,  site the  of the  external  natural  pace-  stimulus  was  t o c o n t r o l the  natural oh.  pacemaker.  This  i n v e s t i g a t i o n supports Nelsen's  t h a t g a s t r o i n t e s t i n a l smooth m u s c l e a c t s loosely  coupled r e l a x a t i o n o s c i l l a t o r s  s i t e s which o s c i l l a t e other cies  at the  areas of e l e c t r i c a l are  lower.  highest  activity  like  hypothesis'  a matrix  of  i n which pacemaking  frequency  where t h e  e n t r a i n or  intrinsic  couple  frequen-  24  SECTION IV.  FACTORS WHICH INFLUENCE  GASTRIC ELECTRICAL ACTIVITY We  may  now  consider  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 .  c l a s s i f i e d as c h e m i c a l , A.  Influence 1.  the f a c t o r s which are known t o These may  broadly  m e c h a n i c a l , and n e u r a l f a c t o r s .  of Drugs  Acetylcholine  (Ach)  S e v e r a l s u g g e s t i o n s as t o how  the BER  e x e r t s 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 a l r e a d y been o u t l i n e d . t r i g g e r the r e l e a s e of Ach, l a t u r e to i t s e f f e c t s .  r e l e a s e may  or may  Ach may,  t e n t i a l s , promote c a l c i u m Ach  be  The  PP  may  s e n s i t i z e the g a s t r i c muscu-  i n turn, i n i t i a t e action  r e l e a s e , and  po-  thus l e a d t o c o n t r a c t i o n ,  a l s o be brought about by d i s t e n s i o n of the  t r a c t , which a c t i v a t e s mechanoreceptors t o s e t up  GI  nervous  44 l m p u l s e s 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 n e r v e s . A c e t y l c h o l i n e i s thought t o be the s o l e t r a n s m i t t e r a t b o t h 93 p r e - 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 e n d i n g s . Ach may o c c a s i o n a l l y cause a s l i g h t i n c r e a s e i n the a m p l i 14 43 J  tude o f the BER,  *  on i t s r a t e .  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  Ach  J  but o t h e r w i s e has no c o n s i s t e n t  ( 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 ) d u r i n g the period"  "susceptible  ( 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  w i l l produce o r enhance a c t i o n p o t e n t i a l s . ^ an i n a p p r o p r i a t e  potential)  I f i n j e c t e d at  time (e.g. i m m e d i a t e l y a f t e r the  r e f r a c t o r y p e r i o d of 2.8  effect  absolute  seconds, but w i t h i n 5 seconds of  the  25 onset of t h e i n i t i a l initial  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  p o t e n t i a l . ^  T h i s premature PP w i l l he p r o p a g a t e d  b o t h c a u d a l l y and i n a r e t r o g r a d e f a s h i o n .  The r e t r o g r a d e  p r o p a g a t i o n r e s u l t s i n t h e l o s s o f the n e x t e x p e c t e d n o r m a l l y p r o p a g a t e d PP; t h e premature p o t e n t i a l c o l l i d e s w i t h the n o r m a l l y e x p e c t e d PP, and the l a t t e r i s unable t o pass a l o n g t h e muscle w h i c h i s r e f r a c t o r y as a r e s u l t of the premature tial.  poten-  The r e s u l t i s an i r r e g u l a r i t y o f the BER t h a t i s a n a l o -  gous i n i t s o r i g i n t o the compensatory  pause w h i c h 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 r e c o r d e d i n the 2.  ECG.  Atropine  A t r o p i n e i n h i b i t s o r 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 cont r a c t i l e a c t i v i t y by p r e v e n t i n g a c e t y l c h o l i n e from e x e r t i n g 43  h/O  i t s action.  •  r a t e o f t h e BER,  '  J  98  *  G e n e r a l l y , i t has no e f f e c t on t h e  though i t has on o c c a s i o n been r e p o r t e d t o  decrease the a m p l i t u d e o f the i n i t i a l  p o t e n t i a l s . - ^ * ^9  Atro-  p i n e does n o t a f f e c t the p r o p a g a t i o n of the BER, s u g g e s t i n g i n d i r e c t l y t h a t Ach i s n o t e s s e n t i a l f o r the p r o d u c t i o n o f initial  potentials.  H i g h doses of a t r o p i n e may,  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  potentials,  however, i n i The p a t t e r n so  d e s c r i b e d on the g a s t r o g r a m has been l a b e l e d the " s y m p a t h e t i c 44  dominance p a t t e r n " ;  t h i s phenomenon i s observed whenever  t h e r e i s a dominance o f s y m p a t h e t i c over p a r a s y m p a t h e t i c activity. 3.  Catecholamines  C a t e c h o l a m i n e s i n t h r e s h o l d doses i n j e c t e d  intra-arterially  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  contractile  26  37 activity.  42 '  43 '  T h i s e f f e c t has been demonstrated w i t h  both e p i n e p h r i n e and i s o p r o t e r e n o l , s u g g e s t i n g t h a t t h e r e  are  two k i n d s o f i n h i b i t o r y a d r e n e r g i c r e c e p t o r s i n the stomach: a l p h a r e c e p t o r s i n the m y e n t e r i c p l e x u s e s s t i m u l a t e d by n o r e p i n e p h r i n e , p r e v e n t 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 , and b e t a r e c e p t o r s i n the smooth muscle c e l l s s t i m u l a t e d by  iso-  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 o f Ach on the g a s t r i c muscu44 lature. C a t e c h o l a m i n e s 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 d e c r e a s i n g the a m p l i t u d e of the p o t e n t i a l . ' • Large dosage, however, r e s u l t s i n a s e r i e s o f r e p e t i t i v e t r i 39 Jf  p h a s i c p o t e n t i a l s w i t h o u t c o n t r a c t i o n , ' and thus local control activity.  suppresses  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 t o the s i t e o f l o c a l i n j e c t i o n , e l e c t r i c a l a c t i v i t y which may  be g e n e r a t e d  J  below the  s i t e i s p r o p a g a t e d i n b o t h caudad and r e t r o g r a d e I n o t h e r words, the muscle may  J  and injection  directions.  be a b l e t o propagate p a c e s e t t e r  p o t e n t i a l s a t a time when i t does not i n i t i a t e them. the c a p a b i l i t y o f g a s t r i c musculature  Moreover,  t o propagate p o t e n t i a l s  i n b o t h d i r e c t i o n s s u p p o r t s the concept o f the  electrotonic  spread o f c u r r e n t ; the a b i l i t y t o 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 i n c o m p a t i b l e 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 a t synapses. The phenomenon d e s c r i b e d as the sympathetic p a t t e r n i s due  dominance  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  a t the l e v e l of the smooth muscle c e l l s .  This pattern r a d i c a l l y  27 disorganizes the  the  rapid rate  BER.  I t i s of i n t e r e s t to note t h a t  of the  p o t e n t i a l s , the  between e a c h p o t e n t i a l i s 2.8  minimum t i m e  seconds; t h i s  despite  interval  is identical  to  43 the  duration  patterns  of the  4.  m o r p h i n e , and  l4 BER.  injection  blocking  a g e n t s have no  specific  However, b o t h c o n t r a c t i l e and  J l  s t i m u l a t i o n are  preganglionic  vagal  of adrenergic  neurones.  5.  activity  amplitude  abolished  by  these be  f i b r e s which synapse w i t h  and  a corresponding 14  of a c t i o n p o t e n t i a l s .  increase  i t s effect The  the  on  res98  drugs.  mediated v i a ganglion  cells  Morphine  tractile  to the  effects  relaxant  Morphine causes a s p a s t i c , non-propulsive  but  high  histamine.  h e x a m e t h o n i u m - s e n s i t i v e r e l a x a t i o n may  slight  of  37 *  ponses to v a g a l  and  Similar  J  Hexamethonium  Ganglionic  This  refractory period.  have b e e n o b s e r v e d f o l l o w i n g l o c a l  doses of a t r o p i n e ,  the  absolute  i n the on BER  effect  amplitude  o f m o r p h i n e on  o f AP's  c a u s e d by  m a i n t a i n e d between t h e 6.  increase 42 '  i n the  I t may  of the  i n con-  frequency  cause  a  i n i t i a l potentials,  rate i s variable.  c i r c u l a r muscle l a y e r .  frequency  increase  H i s t a m i n e and  BER  and  contractile activity Despite  the  marked i n c r e a s e  m o r p h i n e , a 1:1 the  is limited  ratio  i s always  AP's.  5-hydroxytryptamine  (5-HT)  Histamine excites c h o l i n e r g i c ganglionic  cells  presynap-  98 tically,  r e s u l t i n g i n an  increase  in  i n AP's  and c o n t r a c t i l e  28 activity.  I t a l s o has  smooth m u s c l e . on  intrinsic  5-HT  a direct  may  be  excitatory effect  either  on  e x c i t a t o r y or  c h o l i n e r g i c n e u r o n e s , d e p e n d i n g on  antral  inhibitory the  prior  kk  degree o f tonus m  the  smooth m u s c l e c e l l s .  5-HT  may  also  77 play  a role  i n vagal  Neither the  inhibition  histamine  nor  5-HT  of  contractility.  have c o n s i s t e n t e f f e c t s  on  BER. 7.  Serotonin  Serotonin but  a slowing  c a u s e s an o f t h e BER  i n c r e a s e i n the frequency,  and  amplitude  of  PP's,  some d i s o r g a n i z a t i o n  37 in  i t s rhythm. 8.  Local  Procaine  anaesthetics  or cocaine  n e u r a l e l e m e n t s does n o t that  the  initial  9t  appreciable  potential  with  effect  gastrointestinal  on  to a decrease  negligible,  influence.  sympathetic  effect one  i n the  decreased  stimulation.  Though t h e be  neural  t h e BER,  confirming  in origin.-^'  a c t i o n p o t e n t i a l s o r on  atony r e s u l t s . ^ '  a significantly  to vagal  i s not  affect  s o d i u m t h i o p e n t a l i n low  With deeper a n a e s t h e s i a ,  and  apparently  to paralyse a l l  ^  Barbiturates  Anaesthesia  limited  i n dosage s u f f i c i e n t  the  ^*  response  ^  The  effects  are  of a c t i o n p o t e n t i a l s , of i n t r a g a s t r i c  o f b a r b i t u r a t e s on 29 has  BER.  and  pressure  H a l o g e n a n a e s t h e t i c s have s i m i l a r  7  no  resting  tone predominates  incidence  investigation  Recordings  d o s a g e has  the  BER  reported a  from u n a n a e s t h e t i z e d  dogs  effects.  i s thought significant demonstrated  to  29 a mean c y c l e with  o f 12.2  sodium t h i o p e n t a l  seconds. slowing the  duration  fall  B.  i n body  Influence 1.  s e c o n d s ; dogs  recorded cycle  The p r o l o n g a t i o n o f t h e BER  t 0.55  o f t h e BER  r a t e may  durations  anaesthetized  o f 15.5  -  3*5  c y c l e , and hence t h e  have b e e n due  i n part  temperature which accompanies  at least to  anaesthesia.  o f Hormones  Insulin  I n s u l i n r e s u l t s i n a marked pagation  o f t h e BER,  increase  and i n c r e a s e s  i n v e l o c i t y of pro-  the incidence  of a c t i o n  71 potentials.  However, i t does n o t s i g n i f i c a n t l y  alter  the 107  BER  rate.  The  2.  has b e e n  Gastrin  e f f e c t described  i s v a g a l l y mediated.  Gastrin  Gastrin It  excitatory  has a n e x c i t a t o r y shown t o i n c r e a s e  c a u s e s a marked  e f f e c t on g a s t r i c m u s c u l a t u r e . t h e BER  increase  25-35%."^'  f r e q u e n c y by  i n antral contractile  ^  acti-  44 vity can  v i a direct action  on smooth m u s c l e r e c e p t o r s .  cause p o w e r f u l c o n t r a c t i o n  in a totally  It  denervated g a s t r i c  107 pouch; local  ' t h i s e f f e c t i s n o t b l o c k e d by a n t i c h o l i n e r g i c s , anaesthetics,  potentiated  or g a n g l i o n i c  blocking  by a n t i c h o l i n e s t e r a s e s .  The  agents; nor i s i t  e f f e c t s of  increased  c o n t r a c t i l e a c t i v i t y and t h e a s s o c i a t e d i n c r e a s e i n AP's o c c u r w i t h a d o s a g e c o m p a r a b l e t o t h a t w h i c h w i l l p r o d u c e a maximal 107 secretory gation-^  response.  Of i n t e r e s t however  w h i c h has d e m o n s t r a t e d t h a t , force  despite  investi-  the i n c r e a s e  contractile  activity  with  gauges), g a s t r i c emptying time i s a c t u a l l y  strain  and a c t u a l  i s a recent  of c o n t r a c t i o n  in  (measured delayed  30  d u r i n g the i n f u s i o n of p e n t a g a s t r i n a t r a t e s v a r y i n g from 1-4  ugm/kg./hr. 3.  8.2  A l k a l i n i z a t i o n of the duodenum t o a pH g r e a t e r t h a n  r e s u l t s i n i n c r e a s e d m o t i l i t y of a t o t a l l y d e n e r v a t e d o r  a u t o t r a n s p l a n t e d g a s t r i c pouch, w i t h c o r r e s p o n d i n g 107 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 . suppression  increase i n  Whether t h i s i s due  of an i n h i b i t o r y hormone such as  to  enterogastrone,  o r t o the p r o d u c t i o n 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 e t al.^ ""^* ') may 7  7  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 n e r v e , r e s u l t i n g i n a r e f l e x i n c r e a s e in gastric contractility.  T h i s m a t t e r w i l l be d i s c u s s e d  fur-  t h e r i n a subsequent s e c t i o n . C.  Mechanical 1.  and M e t a b o l i c  Factors  Body temperature  A f a l l of 10° C. i n body temperature d e c r e a s e s the quency of the BER  by 50%',^*  3 7  t h e i r v e l o c i t y of p r o p a g a t i o n  the amplitude  fre-  of the PP's  are a l s o r e d u c e d .  and  Conversely,  these parameters are p r o p o r t i o n a t e l y i n c r e a s e d f o l l o w i n g an i n c r e a s e i n body t e m p e r a t u r e .  The  s l o w e r BER  provides  an  e l e c t r i c a l environment c o n d u c i v e t o 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 rhythm i r r e g u l a r .  generation, thus rendering  the  T h i s i s analogous t o 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 d u r i n g p e r i o d s of b r a d y c a r d i a .  be  31 2.  Anoxia  Anoxia r e s u l t s i n a progressive quency, w i t h d e c r e a s e d v o l t a g e fractory period. contractile  local  However, d u r i n g  activity  Selective  and  is  reduction  i n the  a prolongation the  initial  BER  fre-  of the  stages of  reanoxia,  increased.^  destruction  of the  i n t r i n s i c nerve plexus  h y p o x i a r e s u l t s i n a l o w e r e d BER  rate  distal  to  by  the  Ik damaged segment.  It i s postulated  t h a t when t h e  nerve  is  damaged, t h e  smooth m u s c l e g e n e r a t e s an  initial  at  i t s inherent  myogenic r a t e , a r a t e  i s lower than  of the  i n t a c t bowel w a l l .  One  that  might conclude t h a t  potential  a  that  functional  myenteric p l e x u s r a i s e s the  excitability  so  at a f a s t e r frequency than i t s  that  natural  i t g e n e r a t e s the inherent  3. the  Trauma, i n t h e  t o the  the  distal  the  BER  period, tials  site  form  of clamping  and  o f the  distal  insult.  slowing  r e s u l t s from the  a c c o m p a n i e d by p r o b a b l y has  own  to vagal  a reduction no  BER  of the  frequency  stimulation.  e f f e c t on  the  p r o p a g a t i o n of  of  variable poten-  pylorus.  I t may  incidence BER.  in  Disorganization  reduces both p a r i e t a l  i n the  of  V e l o c i t y of propagation  retrograde  region  Hyperventilation  muscular response  of the  segment i s u s u a l l y o b s e r v e d f o r a  o r i g i n a t i n g i n the k.  system  or t r a n s e c t i o n  segment i s p e r m a n e n t l y r e d u c e d .  of the  myogenic  rate.  antrum, r e s u l t s i n a temporary  distal  It  PP  of the  plexus  cell  and  therefore  be  of a c t i o n p o t e n t i a l s .  32  Whether o r n o t 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 o c c u r w i l l t h e r e f o r e depend not o n l y on the a r r i v a l of a p r o 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 c h e m i c a l  and  p h y s i c a l environment o f 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 t o 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 d e t e r m i n i n g the quant i t i e s o f t r a n s m i t t e r s and hormones t o be r e l e a s e d , and r e g u l a t e the b a l a n c e between e x c i t a t i o n and D.  Neural  thereby  inhibition.  Influences  The v a g i may  e x e r t 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 s l o w i n g of the BER f r e q u e n c y , a d i s o r g a n 93 96 i z a t i o n of the r e g u l a r rhythm, and a permanent s l o w i n g 71 7  of the caudad p r o p a g a t i o n  o f 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 days.  One  5-10  i n t e r p r e t a t i o n of these o b s e r v a t i o n s i s t h a t 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 t o assume i t s n a t u r a l s l o w e r r a t e .  Since  higher  o r d e r pacemakers dominate, the l o w e r i n t r i n s i c r a t e p r o v i d e s as a l r e a d y d e s c r i b e d 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 o f e c t o p i c f o c i of impulse g e n e r a t i o n ; hence the o r g a n i z e d BER  w i t h m u l t i p l e c o n d u c t i o n pathways and b o t h caudad  and r e t r o g r a d e ( a n t i p e r i s t a l t i c ) p r o p a g a t i o n .  The p a t t e r n on  the e l e c t r o g a s t r o g r a m i s somewhat analogous t o the ECG of slow a t r i a l  dis-  pattern  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 p r e -  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 i m p a i r e d g a s t r i c t o n e , 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 peristalsis,  and d e l a y e d  emptying of s o l i d s .  '  '  U n s y n c h r o n i z e d p e r i s t a l t i c waves, not c o o r d i n a t e d d i r e c t i o n of p r o p a g a t i o n ,  would not p r o v i d e  y:>  i n time or  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 i n c r e a s e i n tone c o u l d  achieve  normal o r 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 c o n t e n t  of  the stomach and t h u s 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 t i m e " 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 s m a l l bowel can 93 a t t i m e s be so r a p i d as t o be c o n s i d e r e d The  a form of dumping.  J  major postvagotomy motor d i s t u r b a n c e , 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 p r o d u c t i o n  of the a c t i o n p o t e n t i a l and  t r a c t i o n , and t h u s c o o r d i n a t e l a r , d i s o r g a n i z e d BER  subsequent con-  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 -  w i t h the a s s o c i a t e d e q u a l l y  a c t i o n p o t e n t i a l s so produced by vagotomy may  disorganized  w e l l account f o r  the u n s y n c h r o n i z e d 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 d e l a y e d The  emptying which so o f t e n f o l l o w s vagotomy.  random d i s o r g a n i z a t i o n of the BER  persists  approximately  one week; t h i s p e r i o d i s comparable t o the d u r a t i o n of ficantly  signi-  i m p a i r e d 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  s e r v e d f o l l o w i n g vagotomy i n humans.  The  ob-  e n t i r e concept i s  analogous t o the sequence of e v e n t s observed f o l l o w i n g a c u t e s p i n a l c o r d t r a n s e c t i o n , f o l l o w i n g which l o w e r o r d e r . . . 10? a c t i v i t y temporarily p r e v a i l s . '  reflex  3 F u r t h e r e v i d e n c e of v a g a l c o n t r o l over g a s t r i c  '  k  electrical 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 h y p o g l y c e m i a . P r i o r t o vagotomy, i n s u l i n has been shown t o cause an v e l o c i t y of p r o p a g a t i o n i n the i n c i d e n c e of AP's  of the BER  increased  i n dogs, and a marked i n c r e a s e  and c o n t r a c t i l e a c t i v i t y .  a b o l i s h e s t h i s e f f e c t of i n s u l i n i n d u c e d  Vagotomy  hypoglycemia.  In  p r e v a g o t o m i z e d 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 p r o p a g a t i o n of the PP, and markedly d i m i n i s h e s the i n c i d e n c e of  AP's;  once a g a i n , vagotomy s u b s t a n t i a l l y d i m i n i s h e s 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 The  o i l no l o n g e r reduces the i n c i d e n c e of AP's 71  activity.  Both i n v e s t i g a t i o n s support  activity.  or c o n t r a c t i l e  the concept t h a t  v a g a l l y mediated s t i m u l i e x e r t 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 t h a t 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 . 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 J  107  l i k e l y t h a t b o t h humoral and n e u r a l f a c t o r s are i n v o l v e d . F a t i n the upper s m a l l i n t e s t i n e , i n the presence of b i l e and p a n c r e a t i c j u i c e , d e l a y s g a s t r i c emptying by gastric motility.  ' salts  inhibiting  T h i s i n h i b i t i o n can o c c u r i n b o t h i n n e r v a t e d  and d e n e r v a t e d stomach and i n an a u t o t r a n s p l a n t e d g a s t r i c pouch, s u g g e s t i n g t h a t humoral f a c t o r s ( e n t e r o g a s t r o n e )  are i n v o l v e d .  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 a b o l i s h e s 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  1 0 7  the  attenuates  the i n h i b i t o r y r e s p o n s e , 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  implicated  that vagally  d e p e n d e n t n e u r a l mechanisms a r e  i n t h i s phenomenon.  the  inhibition  lar  to the  by  fat is initiated  initiation  perpetuated  I t has  of the  v i a the a c t i o n  i n the  release of enterogastrone;  of c o n t r o l  implies a local  i n a fashion simiand  enterogastrone.  this  r e f l e x may  be  A similar  e x i s t s with respect to g a s t r i n .  effects  The  The  o f vagotomy on t h e  facilitated mechanism  participation  h o r m o n a l p a t h w a y s p r o v i d e s a more  e x p l a n a t i o n f o r the  i s then  r e f l e x mechanism i n v o l v e d  m o d i f i e d by v a g a l i m p u l s e s .  o f b o t h n e u r a l and  tion  reflexly  of c i r c u l a t i n g  of procaine  or otherwise  been p o s t u l a t e d t h a t  enterogastric reflex,  action  also  complete  gastric  inhibi-  by f a t . SECTION V.  VAGAL PATHWAYS AND  EFFECTS  ON  GASTRIC CONTRACTILE ACTIVITY Much o f t h e work i n t r a c i n g v a g a l a f f e r e n t pathways t h r o u g h by  the  studying gastric  vagal  and  c e n t r a l n e r v o u s s y s t e m has tone  and  s t i m u l a t i o n on g a s t r i c  been  motility.  Though t h e  electrical  activity  specifically  studied, i t i s probably  justified  the  formulated  of m o t i l i t y  concepts  tion study  of g a s t r i c are  by  electrical  closely  the  study  activity,  as t h e two  efferent accomplished  effects  have n o t  of been  t o a p p l y many o f to the  examina-  parameters  of  related.  I n o r d e r t h a t c o n t r a c t i o n s may t h e y must be  c o o r d i n a t e d and  needs of the  organism,  and  brought  serve into  a useful  purpose,  harmony w i t h  the  must c o n f o r m t o a p a t t e r n w h i c h  will  36 serve t h e purposes o f d i g e s t i o n .  Regulation, of t h i s  activity,  whether i n t h e form o f augmentation o r i n h i b i t i o n , i s accomp 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 t h e e f f e c t s o f c i r c u l a t i n g hormones.  The o n l y known d i r e c t i n n e r -  v a t i o n o f g a s t r i c smooth muscle c e l l s (except f o r a few p o s t g a n g l i o n i c sympathetics) i n t r i n s i c plexuses.  i s v i a e f f e r e n t neurones i n t h e l o c a l  These motor neurones c o n s t i t u t e t h e f i n a l  common p a t h i n a r e f l e x a r c i n which t h e a f f e r e n t neurones a r e 107  a l s o l o c a t e d i n t h e same i n t r i n s i c p l e x u s e s . f l e x a r c s through  The l o n g r e -  t h e c e n t r a l nervous system a r e comprised o f  b o t h v a g a l and sympathetic  v i s c e r a l afferents plus t h e i r corres-  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 t h e same n e r v e s .  The ex-  t r i n s i c n e r v e s do n o t i n f a c t i n n e r v a t e t h e g a s t r i c smooth muscle d i r e c t l y , b u t serve as c o n n e c t i n g l i n k s between r e f l e x c e n t r e s i n t h e CNS which a r e 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 t h e l o c a l r e f l e x c e n t r e s i n t h e m y e n t e r i c  plexuses,  through which t h e a c t i v i t y o f t h e muscle i s c o o r d i n a t e d .  The  v i s c e r a l e f f e r e n t nerve f i b r e s a r e i n r e a l i t y a f f e r e n t s t o t h e 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 a t e i t h e r f a c i l i t a t i n g o r i n h i b i t i n g t h e l o c a l axon r e f l e x e s mediated through A.  the i n t r i n s i c myenteric  Gastrointestinal  network.  Receptors  B e f o r e d i s c u s s i n g t h e autonomic nerve pathways, i t i s relevant at t h i s point t o b r i e f l y o u t l i n e the various gastroi n t e s t i n a l r e c e p t o r s and i n d i c a t e t h e r o l e o f t h e e x t r i n s i c nerves i n modifying t h e i r  responses.  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 t o osmotic f o r c e s .  S o l u t i o n s having  g r e a t e r or l e s s e r a c t i v i t y t h a n the osmolar c o n c e n t r a t i o n of b l o o d plasma s t i m u l a t e these r e c e p t o r s w i t h r e s u l t a n t s l o w i n g 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 n e t -  work i n t h i s phenomenon i s u n c e r t a i n . 2.  Hydrogen I o n R e c e p t o r s  These r e c e p t o r s 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.  Acid 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 d e l a y s gast r i c emptying.  Recording  from s i n g l e v a g a l f i b r e s , I g g o ^ ^ 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 i n c r e a s e d when s o l u t i o n s w i t h a pH of l e s s t h a n 3*0 of 8.0  are a p p l i e d t o the g a s t r i c mucosa.  or g r e a t e r t h a n a pH The  f u n c t i o n of  these  g a s t r i c pH r e c e p t o r s i s unknown. 3.  Other Chemoreceptors  Amino a c i d s , p r o d u c t s  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, p r o b a b l y v i a s p e c i f i c r e c e p t o r s .  F a t s and  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 m o t i l i t y ; both enterogastrone  products gastric  and v a g a l pathways are i n v o l v e d  i n t h i s phenomenon. 4.  Mechanoreceptors  Contact each p r e s e n t  ( p r e s s u r e ) r e c e p t o r s and  s t r e t c h receptors  are  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 local the  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 .  gastric  able  i n afferent vagal  motility has  w a l l , when s t i m u l a t e d ,  v i a long  described  fibres.  reflex  result  a r c s t h r o u g h t h e CNS.  distension  o f a segment o f i n t e s t i n e  intestinal  inhibition,  on g a s t r i c  The s i t u a t i o n  vides the  various  effects  mediated i n p a r t  activity.  over-  i n generalized  i s not clear,  effect however,  between t h e r e f l e x  effects  f o r the role  by  axon  a r c s t h r o u g h t h e CNS p r o b a b l y  and s p e c i a l  pro-  assumed by  sense r e c e p t o r s  at least  by t h e i r  Afferent  function.  Their  i n f l u e n c e on  such as e x c e s s i v e injury  effects  electrical  muscular  result  direct  contrac-  i n non-specific  Body t e m p e r a t u r e h a s a l r e a d y  i n s o f a r as i t a f f e c t s  Vagal  a l l have  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 .  of v i s c e r a l  A f f e r e n t Nerve 1.  i n which  111  Receptors  Noxious s t i m u l i  been d i s c u s s e d B.  Youmans  Integration of local  m e c h a n i c a l trauma o r c h e m i c a l  inhibition  97  mechanoreceptors.  thermal,  or i n d i r e c t  tion,  nerves.  long r e f l e x  Miscellaneous  Pain,  *  and t h e responses o b t a i n e d  t h e most s u i t a b l e e x p l a n a t i o n  5.  are  receptors  of e x t r i n s i c  reflexes with  64  T h i s i n t u r n has an i n h i b i t o r y  when one a t t e m p t s t o draw p a r a l l e l s  stimulation  influence  reflex  results  detect-  p r e s u m a b l y due t o s t i m u l a t i o n o f s t r e t c h  peristalsis.  of s t i m u l a t i n g these  i n impulses  These i m p u l s e s  an " i n t e s t i n o - i n t e s t i n a l "  or t e n s i o n r e c e p t o r s .  Stretch receptors i n  electrical  activity.^  7  Pathways  Afferents  vagal  fibres  are concerned with  the autonomic  39  regulation of g a s t r o i n t e s t i n a l function.  Pavlov, i n h i s  account o f t h e nervous r e g u l a t i o n o f d i g e s t i o n , ' emphasized the importance o f a d i s c h a r g e down e f f e r e n t v a g a l f i b r e s t o the abdominal v i s c e r a .  T h i s d i s c h a r g e 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 " s e 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 o f c e p h a l i c nerve endings which i n t u 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 a l o n g t h e course o f t h e abdominal v a g i (and s y m p a t h e t i c s as w e l l ) . 88 E x i s t e n c e o f t h i s r e f l e x was q u e r i e d when McSwiney and 7  Alvarez  .  .  .  demonstrated t h a t 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  c o u l d be a l t e r e d i n t h e absence o f an e x t r i n s i c nerve s u p p l y . Nevertheless,  s e v e r a l i n v e s t i g a t o r s have d e s c r i b e d  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 o f v a g a l a f f e r e n t f i b r e s , measured as a change i n t h e tonus o r c o n t r a c t i l e a c t i v i t y o f t h e g a s t r i c musculature. o  B a b k i n and K i t e  7  have demonstrated i n h i b i t i o n o f 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 following c e n t r a l ( r e f l e x ) stimulation of one  d i v i d e d c e r v i c a l vagus, t h e o t h e r nerve r e m a i n i n g i n t a c t .  However, a s i m i l a r degree o f a n t r a l i n h i b i t i o n was u s u a l l y observed 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, splanchnic  nerves.  The a u t h o r s p o s t u l a t e d  s c i a t i c , or  s e v e r a l mechanisms  t o 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, o r r e t i c u l a r s u b s t a n c e ; (ii) s t i m u l a t i o n o f v a g a l 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 o f t h e 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 , m e d u l l a , and hypothalamus. I n these experiments, m i x t u r e was  used.  a chloralose-urethane anaesthetic  T h i s p a r t i c u l a r c o m b i n a t i o n has been shown 9  t o s t i m u l a t e v a g a l s e c r e t o r y c e n t r e s i n the CNS,  54 J  and  may  l i k e w i s e s t i m u l a t e v a g a l motor c e n t r e s i n the r e g i o n of the d o r s a l v a g a l n u c l e u s and r e t i c u l a r s u b s t a n c e . are a b o l i s h e d by vagotomy. agent may  The  These e f f e c t s  i n f l u e n c e of the a n a e s t h e t i c  be o f 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 o f the observa- .  t i o n s as r e c o r d e d by these  investigators. co 9 7 TQ7  H a r p e r and h i s c o l l e a g u e s ^ '  ' have s t u d i e d the  7  e f f e c t s of b o t h 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 i n cats.  U s i n g square wave i m p u l s e s 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.,  p e r i o d s of 10-30  a p p l i e d a t 30-50 i m p u l s e s p e r second f o r seconds, as w e l l as c u r a r e o r h i g h ( 0 3 )  cord s e c t i o n to eliminate r e t c h i n g m o v e m e n t s , t h e y  spinal have  demonstrated an i n c r e a s e i n a c i d and p e p s i n 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 w h i l e the o t h e r 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 musculature was  evidence  i n tone of the  i n the m a j o r i t y (80%) of e x p e r i m e n t s ,  gastric  though t h e r e  o f 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  o n e - h a l f o f these c a s e s .  The  o v e r a l l decrease  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 t o 15-20 the r e m a i n i n g 20% o f e x p e r i m e n t s ,  i n tone  out-  minutes.  In  t h e r e was no background de-  c r e a s e i n t o n e , but o n l y s l i g h t i n c r e a s e i n c o n t r a c t i l e  activity  41 as measured by w a t e r manometry. response was 5-10 Efferent  The l a t e n t p e r i o d  of t h i s  seconds.  s t i m u l a t i o n o f t h e s e same n e r v e s u s i n g 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 p e p s i n s e c r e t i o n , but p r i m a r i l y a s t r o n g c o n t r a c t i l e response of the g a s t r i c m u s c u l a t u r e .  I n a p p r o x i m a t e l y 50% of t h i s  group, t h e r e was no l o s s of g a s t r i c t o n e ; i n the remainder, the o v e r a l l l o s s o f tone upon which the c o n t r a c t i o n s superimposed was o n l y s l i g h t and v a r i a b l e . latent period  of t h i s response was 5-7  were  Once a g a i n , the  seconds.  The e f f e c t of a f f e r e n t o r 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 d e s c r i b e d 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 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 By way of c o n t r a s t ,  excitatory.  b o t h a f f e r e n t and e f f e r e n t v a g a l  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 .  activity.  w i t h an i n c r e a s e  stimula-  Following  vagotomy, Harper demonstrated a p r o g r e s s i v e i n c r e a s e tone a s s o c i a t e d  inhi-  complete  i n gastric  i n spontaneous c o n t r a c t i l e  T h i s c o u l d be i n t e r p r e t e d as a removal o f 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 o f v a g a l i n h i -  b i t o r y f i b r e s w i l l be d i s c u s s e d i n more d e t a i l i n a subsequent section.  Harper has t h e r e f o r e  demonstrated t h a t v a g o - v a g a l  r e f l e x e f f e c t s can be o b t a i n e d 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 v a g a l f i b r e s , and t h a t the s e c r e t o r y c r i b e d are abolished Jefferson^""^  and motor changes as des-  by complete vagotomy. has demonstrated t h a t e l e c t r i c a l  stimula-  t i o n o f 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 v a g a l 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  localized primarily  42 t o the a r e a of the c a r d i a and  fundus.  f a c t o r s l i b e r a t e d from the CNS t r a c t i l e response.  may  He  s u g g e s t s t h a t humoral  be i m p l i c a t e d i n t h i s con-  H i s i n v e s t i g a t i o n has  ence t o suggest t h a t t h e r e are e x t r a v a g a l  a l s o put f o r t h e v i d e f f e r e n t parasympa-  t h e t i c f i b r e s w h i c h l e a v e the s p i n a l c o r d 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 ; t h e y t r a v e l t o the stomach v i a the s p l a n c h n i c s  and  o t h e r as y e t undetermined pathways, 68  r e s u l t i n a c o n t r a c t i l e response. b l o c k e d by a t r o p i n e Jefferson's  and  That t h e i r e f f e c t i s  s u g g e s t s t h a t t h e y are p r o b a b l y c h o l i n e r g i c .  i n v e s t i g a t i o n suggests t h a t 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 i m p u l s e s t o the stomach cannot be a c h i e v e d i n the dog by vagotomy. At the p r e s e n t t i m e , one  can o n l y conclude t h a t i t i s  d i f f i c u l t t o a s s e s s 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 v a g a l  fibres,  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 unr e l a t e d organs, and  account f o r a t l e a s t 90%  of a l l v a g a l  fibres. 2.  Afferent Fibres Associated with 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 s y m p a t h e t i c ~  nerves.  A f f e r e n t s e n t e r the s p i n a l c o r d v i a the d o r s a l  of the l o w e r t h o r a c i c n e r v e s , u s u a l l y Tg_j2» though t h e y be found w i t h i n the range of T - L . ^ ' k  existence  2  1 0 7  roots may  Support f o r the  of t h e s e a f f e r e n t pathways i s found i n D r a g s t e d t ' s  work i n the 1940*s.  He has  demonstrated t h a t 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 o f a vagotomized s u b j e c t c a n s t i l l e l i c i t  pain, 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.  Introduction  The autonomic nervous system r e g u l a t e s two t y p e s o f g a s t r i c response: (i)  pure tonus changes i n t h e form o f c o n t r a c t i o n or r e l a x a t i o n ;  (ii)  augmentation o r i n h i b i t i o n o f r h y t h m i c movements .  The tonus o f smooth muscle may be d e f i n e d as " t h e r e s i s t a n c e of i t s s u b s t a n c e t o e x t e n s i o n " .  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 n o t a p p l y t o p l a i n muscle. A s t a t e o f tonus may be c o n s i d e r e d as a c o n t i n u e d c o n t r a c t i o n , o r as an i n h i b i t i o n o r 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 o f f u r t h e r c o n t r a c t i o n o r f u r t h e r r e l a x a t i o n c a n be o b t a i n e d . I t i s a g r o s s o v e r s i m p l i f i c a t i o n t o d e s i g n a t e t h e vagus the motor n e r v e and t h e s y m p a t h e t i c t h e i n h i b i t o r nerve o f t h e stomach.  S y m p a t h e t i c and p a r a s y m p a t h e t i c 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 t h e purpose  of t h e subsequent s e c t i o n s t o o u t l i n e some o f t h e e a r l y i n v e s t i g a t i o n w h i c h has l e n t s u p p o r t t o t h i s c o n c e p t , and t o r e v i e w more s p e c i f i c a l l y t h e r o l e o f t h e e f f e r e n t pathways i n the r e g u l a t i o n o f g a s t r o i n t e s t i n a l m o t i l i t y .  kk  Vagal e f f e r e n t f i b r e s reaching  the stomach t e r m i n a t e i n 88  a r b o r i z a t i o n s around the neurones i n Auerbach's C e l l s of t h i s p l e x u s i n t u r n i n n e r v a t e cells.  W i t h the e x c e p t i o n  plexus.  the smooth muscle  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 n e r v e s do not d i r e c t l y i n n e r v a t e  the  g a s t r i c muscle f i b r e s , but s e r v e r a t h e r as l i n k s between centres  and  the m y e n t e r i c p l e x u s e s ;  CNS  t h e i r influence i s primarily 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  y e a r s a l m o s t every c o n c e i v a b l e  demonstrated over the  c o m b i n a t i o n of c o n t r a c t i o n 98  and  r e l a x a t i o n i n response t o e x t r i n s i c nerve s t i m u l a t i o n . consensus, put s i m p l y ,  The  has been t h a t g a s t r i c muscle, when  s t i m u l a t e d , i s more l i k e l y t o c o n t r a c t i f f u l l y r e l a x e d , to relax i f f u l l y contracted.  and  G e n e r a l l y , weak s t i m u l i have  f a v o u r e d c o n t r a c t i o n , and s t r o n g s t i m u l a t i o n has f a v o u r e d 28 relaxation. 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 v a g a l s t i m u l a t i o n t h a n i s the antrum.  '  It  has  a l s o been observed t h a t the response t o s y m p a t h e t i c 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 t o v a g a l s t i m u l a t i o n .  To e l a b o r a t e  on  this  c o n c e p t , i t can be s t a t e d t h a t tonus i s dependent upon passage, of p r o p a g a t e d d i s t u r b a n c e s  over the p e r i p h e r a l p a r t of  the  n e u r o m u s c u l a r mechanism, and t h a t the degree of tonus i s dependent upon the f r e q u e n c y of t h e s e p r o p a g a t e d  disturbances.  When tonus i s h i g h , v a g a l s t i m u l a t i o n i s thought t o decrease the f r e q u e n c y of the p r o p a g a t e d d i s t u r b a n c e  t o an i n h i b i t o r y  45 v a l u e ; when tonus i s l o w , t h e f r e q u e n c y o f t h e p r o p a g a t i o n i s a l s o l o w , and v a g a l s t i m u l a t i o n w i l l r a i s e t h i s f r e q u e n c y t o excitatory  values.^' op  McSwiney, i n h i s r e v i e w o f g a s t r i c i n n e r v a t i o n ,  comments  t h a t t h e immediate r e s u l t s o f nerve s e c t i o n may n o t he o f great p h y s i o l o g i c a l and  i m p o r t a n c e , as t h e y a r e o f b r i e f d u r a t i o n  are often i n d i s t i n g u i s h a b l e  anaesthesia.  from t h e e f f e c t s o f shock and  He c i t e s t h e i n h i b i t i o n o f m o t i l i t y and l o s s o f  g a s t r i c tone f o l l o w i n g laparotomy as an example o f t h i s conc e p t , and s u g g e s t s t h a t t h e more remote e f f e c t s o f nerve s e c 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 .  H i s review of the subject t o  1931 concludes t h e f o l l o w i n g : (i)  s e c t i o n o f one vagus o r o f one s p l a n c h n i c has no a p p r e c i a b l e e f f e c t on g a s t r i c tone o r motility;  (ii)  complete v a g a l s e c t i o n r e s u l t s i n g a s t r i c  dila-  t a t i o n , d e c r e a s e d t o n u s , slow and weakened p e r i s t a l s i s , and d e l a y e d g a s t r i c emptying; ( i i i ) complete s p l a n c h n i c 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 function to those of v a g a l (iv)  and e f f e c t s  opposite  section;  complete v a g a l p l u s s p l a n c h n i c s e c t i o n  results  i n a sequence o f e v e n t s s i m i l a r t o , b u t l e s s pronounced t h a n t h a t which f o l l o w s vagotomy.  complete  46 There a r e two s t a g e s i n t h e response which f o l l o w s vagotomy.  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 f o l l o w e d by a g r a d u a l  return of function.  A f t e r a v a r i a b l e period, the p e r i p h e r a l  i n t r i n s i c n e r v o u s network assumes c o n t r o l o f t h e e x t r i n s i c a l l y d e n e r v a t e d stomach, s u p p o r t i n g the s p l a n c h n i c s )  t h e premise t h a t t h e v a g i ( o r  are not e s s e n t i a l t o g a s t r i c f u n c t i o n , but  are i n s t e a d m o d u l a t i n g 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 t o the c e l l s i n Auerbach's m y e n t e r i c p l e x u s ,  and a r e i n f l u e n t i a l i n m o d i f y i n g  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 t h e g a n g l i o n  cells  of t h e p l e x u s t o d i s c h a r g e i m p u l s e s over t h e i r axons, o r 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 reflexes. the t e m p o r a r i l y  As an example,  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 s u g g e s t s t h a t t h e v a g i do have some r e g u l a t o r y  influence  on l o c a l r e f l e x mechanisms. I t has been shown t h a t v a g a l  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 o r augmentation o f g a s t r i c c o n t r a c t i l e activity.  As e a r l y as 1889» Openchowski d e s c r i b e d  a "dilator  nerve o f t h e c a r d i a " , presumably a v a g a l f i b r e w h i c h , when rig  stimulated, 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 d e s c r i b e d  110  OO  '  b o t h c o n t r a c t i o n and r e l a x a t i o n o f t h e c a r d i a  following vagal  s t i m u l a t i o n ; t h e response depended upon t h e  s t r e n g t h and f r e q u e n c y o f t h e 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 t h e c e n t r a l end o f t h e s c i a t i c nerve o r o f one  47 vagus n e r v e ; 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 vagotomy.  complete  Wertheimer made r e f e r e n c e t o e a r l i e r work by Morat,  i n France ( 1 8 8 2 ) , who a p p a r e n t l y observed c e s s a t i o n o f 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 o f t h e c e n t r a l end o f t h e vagus, and a t t r i b u t e d t h i s phenomenon t o t h e i n f l u e n c e o f v a g a l i n h i b i t o r y fibres.  L a n g l e y , i n 1898, d e s c r i b e d a r e l a x a t i o n o f t h e upper  p o r t i o n o f t h e body o f t h e stomach and t h e esophageal  orifice  79  on p e r i p h e r a l s t i m u l a t i o n o f t h e c e r v i c a l vagus.  The g r e a t e r  the tone o f t h e s p h i n c t e r , t h e g r e a t e r t h e e f f e c t o f v a g a l stimulation.  L a n g l e y suggested t h a t t h e 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 p r e s s u r e s was due t o a c t i v e  relaxation  of t h e c a r d i a c o r i f i c e , r a t h e r t h a n an opening o f t h e s p h i n c t e r by c o n t r a c t i o n o f t h e l o n g i t u d i n a l muscle o f t h e esophagus.  At  the same t i m e , v a g a l s t i m u l a t i o n was observed t o i n c r e a s e cont 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 .  I n t h e presence o f  atropine s u f f i c i e n t t o b l o c k the e x c i t a t o r y response, Langley n o t e d a much g r e a t e r degree o f r e l a x a t i o n f o l l o w i n g v a g a l s t i m u l a t i o n t h a n when a t r o p i n e was n o t used.  L a n g l e y ' s work has  t h e r e f o r e demonstrated b o t h motor and i n h i b i t o r y v a g a l e f f e r e n t fibres. Subsequent i n v e s t i g a t i o n i n 1911 by Gannon and L i e b c o n f i r m e d L a n g l e y * s o b s e r v a t i o n s by d e m o n s t r a t i n g r e l a x a t i o n o f the l o w e r 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 s t i m u l a t i o n o f t h e d i s t a l end o f a d i v i d e d c e r v i c a l vagus n e r v e . They n o t e d f u r t h e r t h a t s w a l l o w i n g 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 o f what t h e y termed t h e c a r d i a c s p h i n c t e r .  The fundus  k  was  observed to  relax  j u s t p r i o r to the  esophageal p e r i s t a l t i c swallowing. of the  Maximal r e l a x a t i o n c o i n c i d e d  gastric  capacity  gastric  pressure. the  without  with continued  of a n t a g o n i s t i c reciprocal  ated  by  this  Cannon and  received  designed  i n t o the was  stomach  termed  associated  fundus.  This  of r e c i p r o c a l i n n e r v a t i o n  i n which opposing muscles act  in  relaxation, i n d i c a t i n g that efferent fibres.  i t i s medi-  Hexamethonium  also  phenomenon. Lieb  stimulation.  a l s o n o t e d motor e f f e c t s f o l l o w i n g Low  l a t i o n were a s s o c i a t e d  frequencies  and  intensities  w i t h e x c i t a t o r y e f f e c t s on  m u s c u l a t u r e , whereas i n h i b i t i o n intensity  intra-  a mechanism  c a r d i a and  concept  increased  Vagotomy r e s u l t e d i n a b o l i t i o n o f  i n h i b i t o r y vagal  abolishes  vagal  the  cooperation.  r e f l e x receptive  t o be  of  arrival  in  R e p e a t e d s w a l l o w i n g was  muscles,  this  increase  i n e s o p h a g e a l work, and  r e l a x a t i o n of the  phenomenon i l l u s t r a t e d  onset  w i t h the  i n t e r p r e t e d as  swallowed m a t e r i a l  relaxation".  the  wave, r e s u l t i n g i n an  a concomitant  T h i s was  with a minimal increase "receptive  of  wave; i . e . , j u s t a f t e r t h e  esophageal p e r i s t a l s i c  to allow  arrival  8  followed  high  of  the  efferent stimu-  gastric  frequency,  high  stimulation.  Other i n v e s t i g a t o r s s t u d i e d  the  inhibitory effects  of  109 V e a c h , i n 1925,  efferent  vagal  that  i n h i b i t o r y e f f e c t s were due  the  transmission bition.  stimulation.  t o an  postulated exhaustion of  mechanism, s i m i l a r i n p r i n c i p l e t o Wedensky  McSwiney and  Wadge^  7  r e i t e r a t e d the  concept that  the inhithe  49 response to e f f e r e n t vagal basal  tone  of the  stomach a t the  i n 1936,  and  McSwiney,  due  to adrenergic  s t i m u l a t i o n was time  of s t i m u l a t i o n .  suggested that  fibres  i n the  d e p e n d e n t upon  inhibitory  v a g i , as  the  Harrison  e f f e c t s were  i n h i b i t i o n was  not  98 abolished this  by  atropine.  view, c l a i m i n g  gastric  motility  atropine,  and  P a t o n and  that  they could  on v a g a l  t h a t the  Vane'  were p r o p o n e n t s  achieve  s t i m u l a t i o n only  inhibitory  effect  inhibition i n the  was  of  of  presence  abolished  of  by  sym-  54 patholytic bition brain  E l i a s s o n , i n 1952,  drugs.  f o l l o w i n g the  s t i m u l a t i o n of the  stem o f c a t s , and  conveyed v i a v a g a l  are  confusing.  these  say,  has  66 l e a g u e s i n Sweden. smooth m u s c l e low  This  of the  response no  inhi-  in  the  was  longer  atropine. contradictory results  M a r t i n s o n and  of  his c o l -  5  81—8 ~  region  quantitative evaluation  b e e n o f f e r e d by  i s exerted  frequency,  of  these c o n f l i c t i n g ,  '  this  gastric  r e s p o n s e was  administration  More d e f i n i t i v e  observations  orbital  established that  efferents.  o b s e r v e d f o l l o w i n g the Needless to  elicited  Autonomic nervous c o n t r o l  D  by  order  a fibre o f 1-4  discharge  of  impulses per  of  relatively second at  rest,  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 . V e a c h has d e m o n s t r a t e d 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 direct  vagal  s t i m u l a t i o n with  impulse  frequencies  o f up  to  frequency,  or  12  109 per  second.  increase  With f u r t h e r i n c r e a s e  J  i n the  strength  inhibition  r e s u l t e d , and  hibition.  As  already  i n the  of s t i m u l a t i o n at higher Veach a t t r i b u t e d t h i s  described,  McSwiney and  frequencies,  t o Wedensky i n 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 d e t e r m i n i n g whether v a g a l s t i m u l a t i o n would cause i n c r e a s e d o r d e c r e a s e d m o t i l i t y ; t h e y observed i n h i b i t i o n i f the b a s a l tone were h i g 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 v a g a l 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  in a  82 c o n t r o l l e d manner, M a r t i n s o n  has d e s c r i b e d f r e q u e n c y - r e s p o n s e  c u r v e s 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 v a g a l f i b r e s : t o r y f i b r e s responding impulses,  "low t h r e s h o l d " e x c i t a -  t o s h o r t d u r a t i o n ( l e s s t h a n 0.2  c a u s i n g i n c r e a s e d tone and c o n t r a c t i l i t y , and  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 impulses  (1 msc.  predominantly The  msc.) "high  to longer duration  o r 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  i n the corpus i n fundus, but not i n the antrum.  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 i n this region.  The  most pronounced e x c i t a t o r y r e s p o n s e s  o c c u r r e d w i t h s t i m u l i of 0.1-0.2 msc. a t impulse  effect  f r e q u e n c i e s of 8-10  d u r a t i o n , 4-5  i m p u l s e s p e r second.  V, a p p l i e d The  s t r e n g t h of the response i n c r e a s e d w i t h an i n c r e a s e i n the r a t e of s t i m u l a t i o n up t o 8-10  p e r second, and t h e n l e v e l e d out;  f u r t h e r i n c r e a s e i n o n l y the f r e q u e n c y  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 r e s p o n s e .  This  observation  c o n f l i c t s w i t h t h a t of Veach which s u g g e s t s t h a t an i n c r e a s e i n the f r e q u e n c y  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 t o 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 c o u l d 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 M a r t i n s o n * s work t h a t i n h i b i t i o n appears o n l y 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 t h e n o c c u r s whether t h e f r e q u e n c y o f s t i m u l a t i o n i s h i g h o r 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 d e p r e s s i o n  o f n e u r o g e n i c i n f l u e n c e due t o f a t i g u e i n some  l i n k i n the neuroeffector u n i t , provided  that the rate of stimu-  l a t i o n exceeds t h e c a p a c i t y o f t h e system; t h i s , however, i s a 82 n o n - s p e c i f i c suppression Atropine  of the e f f e c t o r response.  a b o l i s h e s t h e e x c i t a t o r y r e s p o n s e , b u t does n o t  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 that 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 a d r e n e r g i c ,  i s n o t a b o l i s h e d by s y m p a t h o l y t i c i n h i b i t i o n i s i d e n t i c a l before t o r y response by a t r o p i n e . response ( a p p r o x i m a t e l y  drugs.  as i t  The t h r e s h o l d f o r  and a f t e r a b o l i t i o n o f t h e e x c i t a -  The s h o r t l a t e n c y o f t h e i n h i b i t o r y  f i v e seconds) i n d i c a t e s t h a t i t must  be n e u r a l i n o r i g i n , and t h a t humoral f a c t o r s a r e n o t i n v o l v e d . The  i n h i b i t i o n caused by v a g a l s t i m u l a t i o n has been a t t r i -  buted by some t o a d r e n e r g i c some a d r e n e r g i c  mechanism.^  f i b r e s i n the v a g i , or a t l e a s t to 1  However, t h e f a c t o r s as o u t l i n e d 8 3  below s e r v e t o d i f f e r e n t i a t e v a g a l from s y m p a t h e t i c (i)  inhibition:  v a g a l l y i n d u c e d i n h i b i t i o n i s more p o t e n t , l o p s more r a p i d l y , and has a s h o r t e r  deve-  latency  (5 seconds v . 30 seconds) t h a n i n h i b i t i o n i n duced by s y m p a t h e t i c s t i m u l a t i o n u s i n g compara b l e s t i m u l a t i o n p a r a m e t e r s ; t h e response t o  infused catecholamines i s of even lesser degree than i s the response to stimulation of sympathetic f i b r e s ; (ii)  7 7 ,  8  1  the extremely short latency of the gastric inhibitory 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 i s achieved with lower impulse frequencies than those required to obtain a maximum response to sympathetic stimulation; (iv)  vagal relaxation i s 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 i s 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 i n i t s response to antagonistic drugs; sympathetic and catecholamine induced responses are abolished by guanethidine, whereas vagal relaxation i s not affected by  53 e i t h e r a l p h a or "beta a d r e n e r g i c  blocking  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 t h a n d e c r e a s e d by a t r o p i n e , but i s 81 a b o l i s h e d by hexamethonium. 66 ' 77 The  a b o l i t i o n of v a g a l r e l a x a t i o n by hexamethonium s u g g e s t s  t h a t 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  step.^  That a t r o p i n e enhances the r e l a x a t i o n s u g g e s t s t h a t i t may here a t a g a n g l i o n i c l e v e l , r a t h e r t h a n o n l y a t the  act  periphery.  I t appears t h a t v a g a l l y i n d u c e d g a s t r i c i n h i b i t i o n i s not media t e d by an a d r e n e r g i c adrenergic  mechanism, though t h e r e are i n f a c t  f i b r e s which e n t e r the vagus w i t h i n the t h o r a x  abdomen; t h e i r e f f e c t i s c o n s i d e r e d  negligible.^  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  and  Sympathetic  results in inhibi-  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 o v e r f l o w  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 t h a n anything  e l s e , accounting  f o r the l o n g e r l a t e n c y and  shorter  8 2  d u r a t i o n of the r e s p o n s e .  The  long-lasting specific relaxa-  t i o n of the stomach on e x c i t a t i o n of h i g h 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 v a g a l f i b r e s which are n e i t h e r adrenergic mechanism may  nor s t r i c t l y c h o l i n e r g i c .  The  peripheral  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 p o t e n t t h a n the  c a t e c h o l a m i n e s , and i s e l i m i n a t e d a t a s l o w e r rate.. t h i s type have not been d e s c r i b e d w i t h h i s t a m i n e ,  E f f e c t s of  bradykinin,  s e r o t o n i n , o r g a s t r i n , but i t has been suggested t h a t perhaps 5 - h y d r o x y t r y p t a m i n e 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 -  m i s s i o n s t e p of t h i s v a g a l i n h i b i t o r y p a t h w a y *  ^  5 The  k  c e p h a l i c phase o f g a s t r i c s e c r e t i o n , m e d i a t e d v i a t h e  v a g i , r e s u l t s i n i n c r e a s e d s e c r e t i o n o f h y d r o c h l o r i c a c i d and pepsin.  T h i s i s an energy consuming p r o c e s s , r e q u i r i n g i n -  c r e a s e d "blood f l o w .  The s e c r e t o r y response i s a c h i e v e d v i a  s t i m u l a t i o n o f h i g h 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 w h i c h would p r o v i d e t h e i n c r e a s e d b l o o d f l o w f o r the s e c r e t o r y response.  necessary  M a r t i n s o n has p r o p o s e d t h a t s t i m u -  l a t i o n o f these h i g h t h r e s h o l d v a g a l 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 o f the s e c r e t i o n o f h y d r o c h l o r i c a c i d and p e p s i n o g e n , 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 o f t h e corpus and fundus ( r e c e p t i v e r e l a x a 84  t i o n ) i n a s s o c i a t i o n with swallowing.  85  '  The i n d i v i d u a l com-  ponents o f t h i s response p a t t e r n cannot be s e p a r a t e d by means of t h e 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 o f t h e f i b r e s i n v o l v e d . At t h e same t i m e , a n t r a l a c t i v i t y i s enhanced, w i t h e f f e c t i v e m i x i n g and p r o p u l s i o n o f t h e stomach c o n t e n t s . fewness o f e f f e r e n t v a g a l f i b r e s suggests i n i t i a t e the p a t t e r n of response,  The r e l a t i v e  t h a t though they  t h e f i n a l response i s governed  by t h e f a r g r e a t e r number o f neurones i n t h e m y e n t e r i c  plexuses,  and p r o b a b l y 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 o f nervous t i s s u e a t h i g h f r e q u e n c i e s can r e s u l t i n i n c r e a s e d r e s 19  ponsiveness  t o subsequent s t i m u l a t i o n .  7 1  103 J  Rapid,  repetitive  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 o f t h e t e r m i n a t i o n s o f t h e p r e s y n a p t i c o r motor f i b r e s i n v o l v e d a t t h e l e v e l o f Auerbach's p l e x u s , w i t h a consequent i n c r e a s e  55 i n t h e amount o f t r a n s m i t t e r substance r e l e a s e d i n response t o 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 contraction  i n response t o e f f e r e n t v a g a l s t i m u l a t i o n has been a c h i e v e d bypreceding a regular t e s t stimulus  ( a t f o r example 5-10  impulses  p e r second) by a t h i r t y second p e r i o d o f s t i m u l a t i o n u s i n g t h e same v o l t a g e higher  and i m p u l s e d u r a t i o n , b u t a p p l i e d a t a  considerably  i m p u l s e f r e q u e n c y , o f t h e o r d e r o f 20-50 i m p u l s e s p e r  second.  S i m i l a r p o t e n t i a t i o n o f 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  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 o b s e r v e d .  Potentiation  of a f f e r e n t o r r e f l e x v a g 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 i n c r e a s ing 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 regular t e s t  stimulus;  however, slow s t i m u l a t i o n o f a f f e r e n t v a g a l 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 b e f o r e o r a f t e r the a p p l i c a t i o n o f a p o t e n t i a t i n g s t i m u l u s .  The  increased  response o f i n t e s t i n a l (but n o t g a s t r i c ) muscle t o slow a f f e r ent v a g a l 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 s t i m u l u s  i s an ex-  ample o f p o t e n t i a t i o n mediated v i a an autonomic r e f l e x a r c t h r o u g h t h e CNS. P o t e n t i a t i o n i s increased vagal connections are severed.  i n degree and d u r a t i o n when a l l T h i s has been i n t e r p r e t e d as  b e i n g due t o t h e removal o f t h e 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 acid  o r p e p s i n s e c r e t i o n has n o t been demonstrated, b u t perhaps t h i s c o u l d y e t be a c h i e v e d u s i n g d i f f e r e n t s t i m u l u s The  parameters.  p o t e n t i a t i o n i s produced by i m p u l s e f r e q u e n c i e s  (20-  50 p e r second) a t which t h e v a g a l f i b r e s may be expected t o  56 conduct.  Iggo  64  has  of 30  recorded impulse frequencies  second i n n o n - m y e l i n a t e d v a g a l a f f e r e n t s i n c a t s .  per  I t has a l -  ready been n o t e d t h a t i n c a t s , a p p r o x i m a t e l y 3»00° e f f e r e n t v a g a l f i b r e s are g i v e n the t a s k of c o o r d i n a t i n g  or a t l e a s t  m o d i f y i n g 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 . cept of p o t e n t i a t i o n and may  This  con-  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  account f o r the economic achievement of a t 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 s m a l l 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 s i m p l e 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  vagal  s u p p l y t o the abdomen. 3.  S y m p a t h e t i c E f f e r e n t Pathways  S y m p a t h e t i c 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 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 synapse a t the m y e n t e r i c p l e x u s l e v e l , and  sympathetic g a n g l i a .  probably  high threshold  b i t o r y f i b r e s which are p r o b a b l y a d r e n e r g i c , 107  and  low  inhi-  synapse i n the  Kure has d e s c r i b e d m y e l i n a t e d 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 r o o t s from l e v e l s T - L , k  passing  t h r o u g h the p r e v e r t e b r a l g a n g l i a w i t h o u t synapse,  2  and  7R  88  r e a c h i n g the stomach v i a the g r e a t e r s p l a n c h n i c n e r v e s . * These e x c i t a t o r y s y m p a t h e t i c f i b r e s have been shown t o be c h o l i n e r g i c , as response t o t h e i r s t i m u l a t i o n i s b l o c k e d by 107 atropine. and may  They have been termed " s p i n a l p a r a s y m p a t h e t i c s " ,  be the same e x t r a v a g a l p a r a s y m p a t h e t i c o u t f l o w  to i n Jefferson's w o r k . ^ " ^ 7  Splanchnic s t i m u l a t i o n  alluded generally  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 t h e a p p l i c a t i o n o f n i c o t i n e t o the s y m p a t h e t i c ganglia, 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 t h e f i b r e s j u s t D.  described.  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 studies of the b r a i n  have demonstrated l o c i i n many c e r e b r a l a r e a s which have b o t h 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 a r e conveyed by s y m p a t h e t i c and p a r a s y m p a t h e t i c v i s c e r a l e f f e r e n t f i b r e s , each o f which c o n t a i n b o t h e x c i t a t o r y and  inhibitory fibres.  They f u n c t i o n r e c i p r o c a l l y t o r e g u l a t e  m o t i l i t y by i m p o s i n g a h i g h e r c o n t r o l .  The e f f e c t s a r e g u i d e d  by i m p u l s e s w h i c h o r i g i n a t e i n v i s c e r a l and somatic  receptors  which respond t o o s m o t i c a l l y a c t i v e s u b s t a n c e s , pH, p r e s s u r e 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 . ceral pain receptors,  s p e c i a l sense r e c e p t o r s ,  Somatic and v i s and r e c e p t o r s  i n v o l v e d w i t h emotional responses c o n t r i b u t e t o 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 l i m b o f each r e f l e x i s i n c o r -  p o r a t e d i n t o v a g a l and s y m p a t h e t i c 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 w h i c h w i l l b e s t p r e p a r e t h e stomach f o r i t s f u n c t i o n s , and m o d i f y i t s ongoing a c t i v i t y i n accordance w i t h the needs o f t h e organism as a whole.  C o r t i c a l influence i s  f u n n e l l e d t h r o u g h t h e s u b c o r t e x and b r a i n s t e m .  There a r e f e e d -  back mechanisms a t each l e v e l o f c o n t r o l t o p r o v i d e  f o ra hier-  a r c h y p e r m i t t i n g any g i v e n r e g i o n t o e x h i b i t a d u a l r o l e i n i n f l u e n c i n g r e g i o n s more c e n t r a l o r more d i s t a l t o i t ,  thus  58 s e c u r i n g homeostasis  i n the r e g u l a t i o n of g a s t r i c  motility.  I n i n t e r p r e t a t i o n o f t h e s e c o n c e p t s , one must c o n s i d e r t h a t the response t o s t i m u l a t i o n o f any g i v e n a r e a i s r e l a t e d t o the s p e c i e s o f a n i m a l s t u d i e d , t h e degree o f tonus o f t h e organ a t t h e time o f s t i m u l a t i o n , t h e s t i m u l u s parameters, t h e e f f e c t of a n a e s t h e s i a , and many o t h e r f a c t o r s o f t h i s n a t u r e .  It is  v a l i d t o compare t h e r e s u l t s o f d i f f e r e n t s t u d i e s o n l y i f these c i r c u m s t a n c e s a r e t a k e n i n t o c o n s i d e r a t i o n . Eliasson  '  has c o n c i s e l y d e s c r i b e d many o f t h e i n t r a -  c e r e b r a l pathways i n v o l v e d i n t h e r e g u l a t i o n o f g a s t r i c  motility.  He has t r a c e d f i b r e s from each o f t h e c o r t i c a l a r e a s 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 t o t h e t h a l a m i c n u c l e i and  hypothalamus.  F i b r e s pass from b e h i n d t h e d i e n c e p h a l o n t o t h e c o r p o r a q u a d r i gemina and r e t i c u l a r s u b s t a n c e .  Here t h e f i b r e s s e p a r a t e 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  inhibitory  v e n t r a l bundle; both are then t r a c e d t o the v a g a l n u c l e i .  The  m e d u l l a , which i s comprised i n p a r t from t h e d o r s a l motor n u c l e u s o f t h e vagus and t h e b u l b a r a c c e s s o r y n e r v e s , r e c e i v e s f i b r e s from t h e nodose g a n g l i o n , which i s i n t u r n t h e s i t e o f c e l l b o d i e s o f some o f t h e v i s c e r a l a f f e r e n t f i b r e s from t h e abdominal  cavity.  S t i m u l a t i o n o f t h e s e v a r i e d r e g i o n s has c o n f i r m e d t h e conc e p t t h a t t h e v a g i and s y m p a t h e t i c s each c o n t a i n b o t h 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 M a r t i n s o n ' 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 t h e c o n f l i c t i n g r e s u l t s o b t a i n e d by o t h e r  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 t h e s e pathways have been due  t o a mixed p e r i p h e r a l e f f e c t of s i m u l t a n e o u s a c t i v a t i o n o f  b o t h t y p e s of f i b r e s . The  f o l l o w i n g examples s e r v e t o i l l u s t r a t e some of t h e s e 107  principles.  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 s t i m u -  l a t i o n of the thalamus are a b o l i s h e d by a t r o p i n e , but not by s p l a n c h n i c  by b i l a t e r a l vagotomy or  section.  Thus, the g a s t r i c  motor i m p u l s e s e l i c i t e d by t h a l a m i c 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 .  Stimulation  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 r e s p o n s e , 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 . i s abolished  by b i l a t e r a l s p l a n c h n i c o t o m y , and  This e f f e c t  suggests t h a t  motor pathways i n the d o r s a l r o o t s connect the s p l a n c h n i c s the m e d u l l a . has  Jefferson's  work, d e s c r i b e d  to  i n a previous section,  demonstrated an e x c i t a t o r y response t o s t i m u l a t i o n of e i t h e r  d o r s a l o r v e n t r a l s p i n a l r o o t s i n the r e g i o n from T^-L^; he suggested t h a t b o t h r o o t s convey motor f i b r e s t o the T h i s p a r t i c u l a r phenomenon i s not a b o l i s h e d the s t e l l a t e o r c e l i a c g a n g l i a .  has  stomach.  by removal of e i t h e r  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 t h o r a x ( s e c t i o n e d b o t h i n the neck and 107 phragm);  ' from t h i s o b s e r v a t i o n  efferent, extravagal  above the  he c o n c l u d e s t h a t t h e r e  are  motor f i b r e s t o 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 l e a v e the c o r d between T^ and r e a c h the stomach v i a the s p l a n c h n i c s as y e t u n c h a r t e d .  dia-  Following  L^,  and  and perhaps o t h e r pathways  s e c t i o n of the v a g i and  the  spinal  60 cord, supra-spinal  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  motility.'  Generally,  i n h i b i t o r y i m p u l s e s , 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 t i o n a l disturbances,  w i t h emo-  a r e conveyed v i a t h e s y m p a t h e t i c n e r v e s .  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  relaxation.  Thus a l l l e v e l s o f t h e 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 t o 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 levels of control  a b l a t i o n from h i g h e r t o l o w e r  i s g e n e r a l l y accompanied by i n c r e a s e d  motility. ''' 1 0  I t i s evident that 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 t h e a s s o c i a t e d  e l e c t r i c a l phenomena a r e complex.  Once a g a i n , i t i s p r u d e n t t o c o n s i d e r  t h a t t h e response t o  s t i m u l a t i o n may be m o d i f i e d by t h e numerous f a c t o r s at the beginning of t h i s s e c t i o n ; i t i s therefore not i m p o s s i b l e  outlined  difficult i f  t o draw any sweeping o r dogmatic c o n c l u s i o n s i n  t h i s f i e l d of study. SECTION V I . THE GASTRODUODENAL JUNCTION Though t h e major f o c u s o f t h i s r e v i e w i s concerned w i 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 , t h e 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 relevant  to this  discussion. The d e t a i l s o f a n a t o m i c a l c o n t i n u i t y o f t h e p y l o r u s and duodenal cap a r e e s s e n t i a l t o u n d e r s t a n d i n g t h e 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 a r e b a s i c a l l y  t h r e e f u n c t i o n a l u n i t s t o be c o n s i d e r e d :  t h e p y l o r u s and  antrum o p e r a t i n g as one u n i t ; t h e duodenal b u l b above t h e ent r a n c e o f t h e common b i l e d u c t ; and t h e duodenum p r o p e r below that l e v e l .  C i r c u l a r muscle on e i t h e r s i d e o f t h e p y l o r i c  r i n g i s d i s c o n t i n u o u s ; however, a p p r o x i m a t e l y 20% o f t h e l o n g i t u d i n a l muscle f i b r e s from t h e antrum c o n t i n u e i n t o t h e duodenum, p r i m a r i l y a l o n g t h e l e s s e r curve." " 1  0  The m y e n t e r i c  p l e x u s , which remains l a r g e l y i n a s s o c i a t i o n w i t h t h e 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 c o n t i n u e d i n t o t h e duodenum. The  J  o u t e r subserous p l e x u s c o n t a i n i n g v a g a l and s y m p a t h e t i c  f i b r e s i s a l s o c o n t i n u o u s a c r o s s t h e p y l o r u s , b u t t h e degree of  c o n t i n u i t y o f t h e submucous p l e x u s 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 s e p a r a t e  pacemakers.  The duodenal  b u l b has an e r r a t i c , i r r e g u l a r , low  v o l t a g e BER; a p p r o x i m a t e l y 70% o f BER c y c l e s a r e a s s o c i a t e d w i t h 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 . centage  1 0  This per-  i s s u b s t a n t i a l l y h i g h e r t h a n t h a t which i s observed i n  a s s o c i a t i o n w i t h t h e g a s t r i c o r main duodenal p a c e s e t t e r potentials. of  The main duodenal pacemaker i s s i t u a t e d a t t h e l e v e l 14  t h e common b i l e d u c t ,  b u t a s p e c i f i c , l o c a l i z e d pacemaker  node has n o t as y e t been i d e n t i f i e d . inherent frequency propagated  T h i s pacemaker has an  ( i n dogs) o f 17-19 p e r m i n u t e , a n d i s  i n i t i a l l y a t 20 cm. p e r second, w i t h a p r o g r e s s i v e l y  d e c r e a s i n g r a t e o f p r o p a g a t i o n i n t h e more d i s t a l s m a l l bowel such t h a t i l e a l  slow waves become independent  o f t h i s pacemaker  62 and  originate  itself.  instead  within  the  distal  bowel  wall  3 6  The  duodenal pacemaker i s a f f e c t e d  t h o s e w h i c h have b e e n d i s c u s s e d to  i k  pacemaker.  •  J J  by  factors  with reference  to  similar the  to  gastric  RQ  *  Vagotomy has  the  d u o d e n a l BER.  Localized  BER  f r e q u e n c y , and  may  or clamping  of  maker d e c r e a s e t h e  no  appreciable  precipitate ectopic  the  BER  effect  on  duodenal h e a t i n g increases  grade c o n d u c t i o n o f p o t e n t i a l s . tion,  small  foci  Localized  retro-  cooling,  duodenum b e l o w t h e  f r e q u e n c y by  with  site  transec-  of  interrupting  the  the  pace-  conduction  14 pathways. Duodenal pacemaker a c t i v i t y with thyroid increased  function;  BER  hyperactivity  frequency;  observed i n a s s o c i a t i o n The  influence  of the  gland  supports the  involved  of  correlated with  the  an  BER  is 30-32  function. view  J  that  i n governing  the  frequency.  Daniel the  a slowing  with decreased t h y r o i d  thyroid  been  i s associated  conversely,  c e l l u l a r m e t a b o l i c p r o c e s s e s are s l o w wave  i n humans has  J  BER  of  the  following  has  recently  compared t h e  stomach w i t h t h a t  (i)  of the  control activity  duodenum, and  observed  similarities: both a r i s e  i n l o n g i t u d i n a l m u s c l e , and  pagated e l e c t r o t o n i c a l l y i n t o the  (ii)  has  or  circular  muscle;  both are  inherent  and  are  not  and  r e l a t e d to  are  pro-  underlying  spontaneous i n o r i g i n , contractile activity;  a  63 h i g h e r i n t r i n s i c f r e q u e n c y i s found i n t h e p r o x i m a l r e g i o n s o f each organ; ( i i i ) b o t h 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 t h e l o w e r d i s t a l f r e q u e n c i e s a r e " p u l l e d i n " or coupled t o the higher proximal frequencies; (iv)  b o t h a r e s e n s i t i v e t o i n h i b i t o r s o f ATP^^-, i n d i c a t i n g a p o s s i b l e common mode o f o r i g i n . - '  There were, however, a p p r e c i a b l e d i f f e r e n c e s between t h e two PP's.  Though t h e duodenal p o t e n t i a l i s c a p a b l e o f b o t h  caudad  and r e t r o g r a d e p r o p a g a t i o n , i t does n o t demonstrate t h e 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 a r e observed w i t h t h e g a s t r i c PP: (i)  t h e r e 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 t h e duodenal slow wave;  (ii)  premature PP's cannot be i n d u c e d by a c e t y l choline ;  ( i i i ) c a t e c h o l a m i n e s do n o t a b o l i s h t h e PP a t e i t h e r local or distant  sites.  These o b s e r v a t i o n s suggest t h a t perhaps t h e mechanisms underl y i n g t h e i n i t i a t i o n o f slow waves i n t h e stomach and duodenum are n o t i n f a c t  identical.  O p i n i o n v a r i e s as t o t h e degree o f 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 o u l d seem r e a s o n a b l e W  t o suggest t h a t mechanisms e x i s t t o f o r m u l a t e a c o o r d i n a t e d motor u n i t which would promote g a s t r i c m i x i n g and emptying, and a t t h e same time p r e v e n t 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 t h e p r o x i m a l g r e a t e r c u r v e , sweeps down t h e g a s t r i c musculature with 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 rate of 3 -  k  cm. p e r second i n t h e antrum due t o t h e g r e a t l y i n c r e a s e d  conductivity i n t h i s region.  The r a p i d p r o g r e s s  of t h i s  initial  d e p o l a r i z a t i o n p e r m i t s t h e e n t i r e antrum t o 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 m i x i n g o f the 29 53  g a s t r i c chyme.  J  The f r e q u e n c y  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 t h e f r e q u e n c y  o f t h e BER,  The  p y l o r i c r i n g m u s c u l a t u r e p e r se does n o t 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 o f a pumping mechanism which regu53 l a t e s g a s t r i c e j e c t i o n o f chyme i n t o t h e duodenum. A c c o r d i n g t o many i n v e s t i g a t o r s , t h e g a s t r i c  J  pacesetter  p o t e n t i a l c o n t i n u e s as f a r as t h e c o n n e c t i v e t i s s u e septum between t h e antrum and duodenum, and t h e r e c e a s e s .  I t has been  suggested t h a t t h i s "hypomuscular zone" a c t s 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 t h a t t h e r e can be no e l e c t r o t o n i c spread of c u r r e n t t h r o u g h t h i s segment. recorded  However, some s t u d i e s have  o c c a s i o n a l e v i d e n c e o f duodenal e l e c t r i c a l  activity  i n t h e 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 t h e 43 duodenum.  y  These s t u d i e s have suggested t h a t t h e e l e c t r o t o n i c  spread o f c u r r e n t a c r o s s t h i s j u n c t i o n o c c u r s by way o f t h e contiguous support  l o n g i t u d i n a l muscle f i b r e s .  This observation  t o t h e myogenic t h e o r y o f o r i g i n and c o n d u c t i o n  lends of the  65 s l o w wave p o t e n t i a l . n e c t i o n s a c r o s s the it  is difficult  silent  to  In view of  gastroduodenal conceive  of  Allen  '  J  has  J  provided  Most work has  there  tionship  shown t h a t  between the  antral  duodenal c o n t r a c t i o n s ,  (dogs).  In  fasted  activity)  and  the  i s no  and  an  conabove,  electrically  BER,  traction  i n which the  of  an  antral  a n t r a l BER  i s associated cycle  interlocking into play  of  cycle  antral  following  the  occur v i a e l e c t r i c a l  onset and  4:1  harmonic  the  gastric as  of and  fed  BER  into  gastric  antral  relationship contractile  dogs, a  and  of  the  rela-  duodenal  duodenal  second or  the  concontrac-  antral  third BER  the  contrac-  duodenal  cycle.  The  d u o d e n a l a c t i v i t y i s somehow b r o u g h t of food.  the  v i a the  duodenum.  d u o d e n a l BER BER,  Integration  J  be  of  also  i s usually  two  oscillators.  the  stimulus I t has  t h e r e may  duodenal rhythms; the  coupled r e l a x a t i o n  rela-  animals  suppresses a duodenal  the  ingestion  because the the  or  impulses transmitted within  chyme e j e c t e d  suggested that  temporal  associated  Instead,  p l e x u s , v i a hormonal pathways, or gastric  (and  interlocked.  begins synchronously with  cycle.  the  fasted  antral  BER  with either  following  possible  or between  However, i n f e d  does e x i s t b e t w e e n t h e  t i o n when a d u o d e n a l BER  consistent  i s s i m i l a r l y no  potentials  antral  suggest a  d u o d e n a l BER,  in either  tionship  tion  outlined  duodenal a c t i v i t y are  animals, there  between duodenal a c t i o n  BER  as  t h i s r e g i o n as  evidence to  and  tion  junction  neural  53  mechanism whereby a n t r a l  onset  m u s c u l a r and  insulator. 2  and  the  may  myenteric the been  a 3si  or  a coupling  of  p a c e m a k e r s may  func-  66 With r e s p e c t junction, plain  to surgical  an i n t e r e s t i n g  the e f f i c a c y  alteration  BER t h a n w o u l d  occur  of gastric k-3 J  f o l l o w i n g vagotomy. *  briefly  peristalsis  disorganization of  and improved g a s t r i c  less emptying  io4  THE SMALL INTESTINE  o f view o f comparison, the f o l l o w i n g s e c t i o n o f s m a l l b o w e l m o t o r and  activity.  There i s a g r a d i e n t distally  propagated  p y l o r o p l a s t y , and hence  o u t l i n e s some o f t h e f e a t u r e s  electrical  randomly  w o u l d be l e s s  without  SECTION V I I . From t h e p o i n t  foci  o f e c t o p i c pacemakers i n t h e r e g i o n  w h i c h may have i n i t i a t e d  The n e t e f f e c t  disturbance  a d i s o r g a n i z e d BER d u r i n g t h e  I t has been s u g g e s t e d t h a t p y l o r o p l a s t y  may r e d u c e t h e e x c i t a b i l i t y  the  vagotomy.  week, due t o t h e emergence o f e c t o p i c  of impulse g e n e r a t i o n .  potentials.  t o ex-  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  postoperative  of the p y l o r u s  gastroduodenal  c o n c e p t has been p u t f o r w a r d  Vagotomy h a s b e e n a s s o c i a t e d w i t h first  of the  along  of e l e c t r i c a l  the course  rhythmicity  o f the s m a l l bowel, w i t h  progressing t h e dominant  l4 pacemaker l o c a t e d i n t h e second p a r t BER f r e q u e n c y  o f t h e duodenum.  62 '  d e c r e a s e s p r o g r e s s i v e l y towards the ileum, a t  w h i c h p o i n t t h e d u o d e n a l p a c e m a k e r no l o n g e r  assumes c o n t r o l o f  36 the  electrical  collectively provides out  activity.  forming  J  The c o n c e p t  a s e r i e s of coupled  t h e most p l a u s i b l e e x p l a n a t i o n  o f segmental pacemakers relaxation oscillators f o r entrainment  t h e s m a l l bowel, and a c c o u n t s f o r normal caudad  stalsis.  6 2  '  through-  peri-  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 b o t h e x t r i n s i c and i n t r i n s i c nerve pathways.  The more p r o l o n g e d l a t e n t p e r i o d  of r e s p o n s e , t h e r e l a t i v e p a u c i t y o f nerve endings i n i n t e s t i n a l v e r s u s g a s t r i c muscle, and t h e d i s p r o p o r t i o n a t e l y h i g h number o f i m p u l s e s 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 o r i n h i b i t i o n o f i n t e s t i n a l smooth muscle  results  from a g e n e r a l i z e d d i f f u s i o n o f t r a n s m i t t e r s u b s t a n c e , r a t h e r t h a n l i b e r a t i o n o f t h e t r a n s m i t t e r a t d i s c r e t e nerve i n t h e muscle  endings  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 s m a l l i n t e s t i n e t h a n i n t h e stomach. '  The m y e n t e r i c  r e f l e x has been r e f e r r e d t o as t h e "law o f t h e i n t e s t i n e " as l o n g ago as 1899 by B a y l i s s and S t a r l i n g . * D  Local stimu-  l a t i o n o f t h e 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 o f 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 r e c e p t o r s r a t h e r than i n c r e a s e i n transmural pressure i s the e f f e c t i v e stimulus. is  T r a n s m i s s i o n i n t h i s phenomenon  cholinergic. The e x t r i n s i c i n n e r v a t i o n o f t h e s m a l l 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 v a g a l  and s y m p a t h e t i c f i b r e s may a c t i n e i t h e r an e x c i t a t o r y o r 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 t o those d i s cussed w i t h r e f e r e n c e t o g a s t r i c  motility.  The s y m p a t h e t i c system i s e s s e n t i a l l y i n h i b i t o r y .  Inhi-  b i t o r y adrenergic alpha receptors are l o c a t e d i n the g a n g l i o n c e l l s i n n e r v a t i n g t h e smooth muscle, w h i l e i n h i b i t o r y b e t a  68 ik  r e c e p t o r s r e s i d e i n the smooth muscle f i b r e s t h e m s e l v e s . S t i m u l a t i o n o f sympathetic  77  '  efferents generally results i n i n h i -  b i t i o n o f 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 i l e u m . V a g a l f i b r e s may be e i t h e r e x c i t a t o r y o r i n h i b i t o r y i n their influence.  The e x c i t a t o r y e f f e c t s are more p r e v a l e n t i n  the upper s m a l l i n t e s t i n e , as t h e s p l a n c h n i c s 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 i l e u m .  Post-activation  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  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 has a l r e a d y been d i s c u s s e d . * 7  77 1 1  To summarize, t h e 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 o f i n t e s t i n a l m o t i l i t y t h a n i n regulation of gastric m o t i l i t y .  The e x t r i n s i c n e r v e s a r e  p r i m a r i l y geared t o f a c i l i t a t e o r o t h e r w i s e modify t h e i n t r i n s i c reflexes. SECTION V I I I .  HUMAN BER  The BER o f t h e human stomach has been examined and r e c o r d e d by means o f 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 c o n t a c t w i t h t h e 90  g a s t r i c mucosa.  I t c o n s i s t s o f 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 p r o p a g a t e d a t a v e l o c i t y o f a p p r o x i m a t e l y 2 cm. p e r second i n the antrum, and has an i n h e r e n t n a t u r a l frequency  o f t h r e e c y c l e s p e r minute.  approximately  D u r i n g the f a s t i n g s t a t e ,  25-30% o f the BER c y c l e s a r e a s s o c i a t e d w i t h a c -  t i o n p o t e n t i a l s , which are r e p r e s e n t e d of r a p i d s p i k e s o f u n e q u a l a m p l i t u d e ,  e l e c t r i c a l l y by a b u r s t b e g i n n i n g 3-4  seconds  69 after  the onset  o f t h e BER complex, and l a s t i n g  The  AP's a r e a s s o c i a t e d w i t h g a s t r i c  The  electromyographic  r e l a t e d both  i n time  discharge  3-6  contractile  seconds.  activity.  o f the a c t i o n p o t e n t i a l i s  and a m p l i t u d e  to the pressure  wave 35  r e c o r d e d b y e i t h e r a s t r a i n gauge o r i n t r a l u m i n a l b a l l o o n . D u o d e n a l BER h a s b e e n r e c o r d e d  i n humans a t a  J  1  o 7  frequency  30-32  o f 11.7 c y c l e s p e r m i n u t e . ent  o f BER f r e q u e n c y  with  J  along the length of the small  r a t e s r e c o r d e d a t 9.5  ileal  There i s a descending  Human BER i s s e n s i t i v e  with the a c t i v i t y  t o temperature  is  observed  The BER f r e q u e n c y  of the t h y r o i d  intestine,  c y c l e s p e r minute.  s i m i l a r to that described f o r animals. a f f e c t e d by f a s t i n g .  gradi-  gland;  i n hyperthyroid states,  change i n a manner I t i s apparently not  h a s b e e n shown t o v a r y i n c r e a s e d BER  and d e c r e a s e d  frequency  rates are  30  associated with impaired thyroid hypoglycemia frequency  function.  h a s b e e n shown t o i n d e p e n d e n t l y  o f t h e BER.  Insulin  induced  decrease the  70 CHAPTER TWO METHODS OF INVESTIGATION 1.  The P l a n o f t h e Experiment The p l a n o f t h e experiment  aimed a t 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 a s s e s s t h e completeness o f 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 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 connect i o n s had been s e v e r e d ; ( i i ) t o d i v i d e one vagus a t t h e l e v e l o f t h e esophageal h i a t u s , a s s e s s t h e e f f e c t on t h e e l e c t r i c a l  activity  of s t i m u l a t i o n o f i t s d i s t a l o r p e r i p h e r a l end, then s t i m u l a t e t h e c e n t r a l end w i t h 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 path-  ways t h r o u g h t h e b r a i n stem and v a g a l n u c l e i , and hence down t h e r e m a i n i n g 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 ; the r e m a i n i n g f i b r e s would t h e n 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 o f e i t h e r v a g a l t r u n k r e p e a t e d , and p r e sumably t h e p r e v i o u s l y observed response  "characteristic"  o f t h 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 would no  l o n g e r be o b t a i n e d , i n d i c a t i n g complete d i v i s i o n o f a l l vagal f i b r e s . The  r e f l e x pathway o f v a g a l i m p u l s e 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  to afferent  v a g a l s t i m u l a t i o n have b e e n  documented i n t h e i n t r o d u c t o r y c h a p t e r o f t h i s may  reasonably expect  electrical reflex.  activity  To  that  review.  a corresponding effect  c o u l d a l s o be  investigate  adequately-  on  obtained v i a t h i s  these questions, f i v e  One  gastric vago-vagal  groups of  animals  were s t u d i e d . 2,  Group I .  R e c o r d i n g o f t h e BER; t h e e f f e c t o f 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 anaesthesia  Twenty-six studied  15-25  m o n g r e l dogs w e i g h i n g  i n acute  experiments  kilograms  were  f o l l o w i n g an o v e r n i g h t f a s t .  The  a n i m a l s were a n a e s t h e t i z e d w i t h s o d i u m t h i o p e n t a l ( P e n t o t h a l , Abbott),  and  r e s p i r a t i o n was  Mark V I I r e s p i r a t o r .  controlled  Anticholinergic  by  t h e use  drugs  of a  were n o t  Bird  adminis-  tered pre-operatively. Gastric In  the  electrical  initial  s i l v e r wire,  trials,  activity  was  r e c o r d e d by  e l e c t r o d e s of both  0.006-0.010  several  stainless  inches i n diameter,  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  were  methods.  steel  and  implanted  of the  stomach.  However, r e c o r d i n g s o b t a i n e d i n t h i s manner were o f u n s u i t a b l e quality, trical of The  and  t h i s method was  recordings evaluated i n both t h i s  abandoned. and  A l l elec-  subsequent  groups  s t u d y were o b t a i n e d u s i n g m o n o p o l a r s i l v e r w i r e e l e c t r o d e s . e l e c t r o d e t i p p r o j e c t e d 2 mm.  double-layered Teflon the  consequently  disc.  e x c e p t i o n o f i t s t i p , was  The  from  one  surface of a  s i l v e r wire  insulated  by  flat,  electrode, with  a Teflon  sheath,  and  72 was  connected between the d i s c s t o an i n s u l a t e d copper w i r e  lead.  The  e n t i r e e l e c t r o d e assembly, a g a i n w i t h the  of the e l e c t r o d e t i p , was The  stomach was  incision.  The  exception  s e a l e d w i t h epoxy r e s i n .  exposed t h r o u g h a m i d - l i n e laparotomy  e l e c t r o d e d i s c s were s u t u r e d v i a d r i l l h o l e s i n  each of the f o u r c o r n e r s t o the s e r o s a l s u r f a c e of the  greater  curve o f the stomach i n a s e r i a l f a s h i o n from the fundus t o the t e r m i n a l antrum.  I n s u l a t e d w i r e l e a d s 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 t o an a l t e r n a t i n g c u r r e n t a m p l i f i e r , which i n t u r n was  l i n k e d t o one c h a n n e l  system ( P h y s i o g r a p h of 0.3 was  S i x - E & M Instruments).  mm.  A time  s e l e c t e d on the AG a m p l i f i e r .  a d j u s t e d such t h a t a one m i l l i v o l t impulse  by a 15 was  seconds was  of a r e c t i l i n e a r r e c o r d i n g  pen d e f l e c t i o n .  constant  Calibration  was  represented  A r e l a t i v e l y l o n g time  constant  chosen t o a l l o w a c c u r a t e r e c o r d i n g of the BER  and  evalua-  t i o n of the t e m p o r a l 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 . S h o r t e r time c o n s t a n t s were found t o deform o r even e l i m i n a t e the BER One  disadvantage  complex ( F i g . 8 B ) .  of the l o n g e r time c o n s t a n t r e l a t e d t o the  need t o reduce the a m p l i f i e r g a i n i n o r d e r t o a v o i d d r i f t i n g of the b a s e l i n e .  excessive  S h o r t e r time c o n s t a n t s and  higher  a m p l i f i c a t i o n a l l o w e d 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 , 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  but  most  s a t i s f a c t o r y r e c o r d i n g s were o b t a i n e d when the e l e c t r o d e s were i n f i r m c o n t a c t w i t h s e r o s a , but not p e n e t r a t i n g i t .  Electrode  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  r e c o r d i n g s w h i c h were u n r e a d a b l e trical  because  dissected  at the l e v e l  l a t e d by r e t r a c t i o n c a v i t y was a 3- k  afferent  cm.  and e f f e r e n t  steel bipolar Electrical  of the Physiograph of impulse  impulse  frequencies volts).  impulses  as d e l i v e r e d  seconds. concept  (2-200  In the i n i t i a l  Impulse  0.5,  trial  little  d u r a t i o n s were v a r i e d  V) p r o d u c e d  "  o f 10  minimal  a n d 2.0  by means o f of a  i n the form of g e n e r a t o r com-  milliseconds), and v o l t a g e s  experiments,  single  d u r a t i o n s were  Thereafter,  f o r p e r i o d s of  on t h e b a s i s and i n h i b i t o r y  D  60-120  of the fibres  Most o f t h e i n t e r p r e t a b l e d u r a t i o n s o f 0,1  o r 0.5  impulses p e r second.  effect;  therefore,  u n p h y s i o l o g i c , were r e q u i r e d  responses.  t o both  Q j;  ponses o c c u r r e d w i t h impulse at a frequency  isolation  The s t i m u l a t o r p r o v i d e d  response.  of the existence of e x c i t a t o r y  V, t h o u g h  applied  g r a d a t i o n s were a p p l i e d  by M a r t i n s o n .  iso-  thoracic  Stimuli  o f v a r i o u s v o l t a g e s and i m p u l s e  of v a r i e d  as o u t l i n e d  cant  The  impulses p e r second),  Q "I  applied  a n d were  by t h e i m p u l s e  S i x system.  a p p l i e d , but these produced stimuli  were  e l e c t r o d e f a s h i o n e d i n the form  d u r a t i o n s (0.1,  a range  trunk.  s t i m u l a t i o n was  ponent  volley  hiatus,  v a g a l t r u n k s were d e l i v e r e d  wave i m p u l s e s  120  elec-  the vagus nerves  of adjacent structures.  segment o f e a c h n e r v e  hook.  (0.1-130  BER,  of the esophageal  square  (5-20  of extraneous  e n t e r e d on a l l o c c a s i o n s t o f a c i l i t a t e  a stainless nerve  produced  noise.  A f t e r r e c o r d i n g the baseline  of  lumen  res-  rase,  Low v o l t a g e s  stimuli  o f up t o  to detect  signifi-  74 The of  one  BER  was  vagal  following  recorded  trunk  i n a l l animals f o l l o w i n g  section.  vagotomy, t h e  BER  the  circumstances»  in five  a f t e r esophageal  (ii)  following  rapid sacrifice  using in  was  the  6 0  same v o l t a g e  The  '  before  but 1 Q  and  complete  further  truncal  studied  of the  a n i m a l by  of p o t a s s i u m  under  a thirty impulse  at  the  second p e r i o d duration  frequencies  of  intra-  chloride.  several procedures,  and  applied  as  regular  of  test  stimulation  the  test  stimulus  50-100 impulses  per  3  c e r v i c a l vagi  centrally  of  p r e c e d e d by  question,  second.  course  then  transection;  venous a d m i n i s t r a t i o n  stimulus  Following  a n i m a l s was  (i)  D u r i n g the  division  ( e i t h e r a n t e r i o r o r p o s t e r i o r ) , and  complete v a g a l  following  the  and  were d i s s e c t e d ,  p e r i p h e r a l l y i n two  during  stimulation,  and  divided,  dogs.  The  and  BER  stimulated  was  examined  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 procedure  on  operative BER  A c o n t r o l g r o u p o f s i x a n i m a l s was the BER.  e f f e c t of Five  o v e r a two  the  operative  studied  procedure per  m i n u t e t r a c i n g s were r e c o r d e d hour p e r i o d  under o p e r a t i v e  t h o s e w h i c h p r e v a i l e d . i n Group  I.  se  on  to  determine  the  rate  each f i f t e e n  conditions  of  the  minutes  s i m i l a r to  75 k  .  Group I I I .  Effect  of v a g a l  s t i m u l a t i o n on  using chloralose-urethane A third account thesia  the  series  o f e x p e r i m e n t s was  reported inhibitory  on t h e  response  effect  of i n t r a g a s t r i c  BER,  anaesthesia  undertaken to take  into  of b a r b i t u r a t e anaespressure  to vagal  stimu-  Q  lation,  as  i t was  considered  as w e l l t o t h e v a g a l A mixture  that this  i n h i b i t i o n might  i n f l u e n c e on g a s t r i c  o f c h l o r a l o s e and  urethane  was  electrical  apply  activity.  t h e r e f o r e u s e d as  a  kg substitute was by  f o r sodium t h i o p e n t a l .  boiling,  mg./kg.  and  of the  only a n t r a l  Because  upon c e n t r a l initial Dow)  less  steel  recorded  as  3*5  d e s c r i b e d i n the but  in this  to both the  afferent  and  efferent  stimulus generator  series,  o f d i s t u r b i n g r e t c h i n g movements  encountered  20-30  procedures  this was  mgm.  effect.  was  i n the  administered  S t i m u l a t i o n i n the  a p p l i e d w i t h the b i p o l a r  e l e c t r o d e employed i n Group I , u s i n g t h e  stimulus parameters  0.01-30.0  des-  studied, s u c c i n y l c h o l i n e c h l o r i d e (Anectine,  to counteract  t h i r t e e n animals  vagal  already  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  twelve  introduced. of  was  i n i n t e r m i t t e n t dosage o f  intravenously  ing  stimuli  f o u r animals  following  cc of water, d i s s o l v e d  group of experiments,  were d e l i v e r e d by  cribed.  G.)  e l e c t r o d e s were a p p l i e d .  Electrical trunks  (2  i n t r a v e n o u s l y i n a dosage of  activity  first  i n 100  G.)  administered  Electrical  discussion  of  (10  mixed w i t h urethane  Alpha-chloralose  outlined i n that section.  studied i n this  A stimulus i s o l a t o r milliamperes  was  g r o u p , two  (Tektronix  added t o t h e  stain-  same r a n g e  I n the  remain-  i n n o v a t i o n s were  2620)  with  a  range  s t i m u l a t o r component  76 with 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 t h e r e s i s t a n c e o f t h e e x p e r i m e n t a l 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 b r o a d , f l a t t e n e d c o n t a c t s u r f a c e s was i n t r o d u c e d f o r t h e purpose o f m i n i m i z i n g damage t o t h e nerve d u r i n g s t i m u l a t i o n . f a c e s o f t h e e l e c t r o d e t i p s were d e s i g n e d  heat  The f l a t t e n e d s u r t o permit the current  t o be d i s t r i b u t e d over a c o n s i d e r a b l y l o n g e r segment o f t h e nerve f i b r e . 5.  Group I V . C o n d u c t i o n v e l o c i t y o f t h e BER C o n d u c t i o n v e l o c i t y o f t h e BER was s t u d i e d i n f o u r  E l e c t r i c a l a c t i v i t y was r e c o r d e d  animals.  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 t h e p y l o r u s .  C o n d u c t i o n v e l o c i t y was examined 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 .  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 v a g a l t r u n k so d i s t o r t e d t h e BER t h a t  conduction  v e l o c i t y d u r i n g s t i m u l a t i o n c o u l d n o t be measured. 6•  Group V.  E f f e c t o f p e n t a g a s t r i n on BER b e f o r e and a f t e r vagotomy  The e f f e c t o f p e n t a g a s t r i n ( P e p t a v l o n , A y e r s t ) 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 bef o 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 r e c o r d e d as  o u t l i n e d f o r the i n i t i a l experimental recorded,  groups.  B a s e l i n e BER was  and p e n t a g a s t r i n was t h e n i n f u s e d c o n t i n u o u s l y by  means o f a H a r v a r d pump a t a r a t e o f  k  ugm/kg./hr.  Twenty  77  minutes a f t e r commencement o f t h e i n f u s i o n , one vagus n e r v e (either anterior or posterior) esophageal h i a t u s .  was d i v i d e d  a t the l e v e l of the  The r e m a i n i n g v a g a l t r u n k was d i v i d e d  after  a f u r t h e r f i f t e e n m i n u t e s , and t h e i n f u s i o n was d i s c o n t i n u e d f i f t e e n minutes a f t e r complete v a g a l s e c t i o n .  Random f i v e  minute r e c o r d i n g s a t each stage o f t h e p r o c e d u r e were examined t o d e t e r m i n e t h e e f f e c t on t h e 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 v a g a l t r u n k s , u t i l i z i n g t h e new phosphorbronze e l e c t r o d e and s t i m u l u s i s o l a t o r , was c a r r i e d out i n t h r e e a n i mals d u r i n g t h e c o u r s e o f 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 . R e c o r d i n g o f t h e BER; t h e 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 anaesthesia R e c o r d i n g s from t h e fundus and p r o x i m a l o n e - t h i r d o f t h e  corpus d i d n o t r e v e a l any e v i d e n c e o f r h y t h m i c a l activity.  electrical  I n i t i a l p o t e n t i a l s w i t h the g r e a t e s t amplitude  observed i n t r a c i n g s r e c o r d e d  over t h e antrum ( F i g . 1 ) .  were This  o b s e r v a t i o n i s i n agreement w i t h p r e v i o u s work which has l o c a l i z e d the o r i g i n of the p a 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 t h e p r o x i m a l and m i d d l e t h i r d s o f t h e stomach." " 1  10  Action  p o t e n t i a l s were r e c o r d e d most o f t e n a t t h e antrum ( F i g . 1 ) , and were f o l l o w e d i m m e d i a t e l y activity.  by v i s u a l l y observed c o n t r a c t i l e  S i m u l t a n e o u s r e c o r d i n g o f i n t r a g a s t r i c p r e s s u r e was  not p e r f o r m e d i n t h i s s e r i e s o f e x p e r i m e n t s .  As many as 50%  of t h e 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 o f t h e animals  studied, p a r t i c u l a r l y a f t e r manipulation  o f t h e stomach.  Electrodes 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 a s p e c t s o f t h e g r e a t e r curve demonstrated i d e n t i c a l BER r a t e s t h r o u g h o u t t h e l e n g t h o f t h e d i s t a l t w o - t h i r d s o f t h e organ. The mean f r e q u e n c y i n twenty a n i m a l s  o f t h e BER was c a l c u l a t e d from r e c o r d i n g s  t o be 4 . 4 l t 0.40 c y c l e s p e r minute (Table I ) .  F o l l o w i n g d i v i s i o n o f one v a g a l t r u n k ( e i t h e r a n t e r i o r o r post e r i o r ) , t h e mean f r e q u e n c y  was 4.27  t 0.55 c y c l e s p e r minute.  Complete vagotomy r e s u l t e d i n a mean f r e q u e n c y  o f 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 "before and a f t e r complete vagotomy (p < 0.002). i n the BER  The  frequency difference  f r e q u e n c y w i t h one vagus d i v i d e d as compared w i t h  t h a t 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 four animals,  the BER  became d i 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 ) .  T h i s 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 i n s t a n c e s 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  s e r v e d on s e v e r a l o c c a s i o n s vagal trunk  perhaps due  also  f o l l o w i n g d i v i s i o n of o n l y  ( F i g . 2 ) ; t h i s phenomenon was  Sequences of d e s y n c h r o n i z e d  was  BER  ob-  one  a g a i n o n l y temporary.  a l s o occurred  spontaneously,  t o a n o x i a , change i n body t e m p e r a t u r e ,  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 o r 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 r r e g u l a r , d i s o r g a n i z e d BER  I t t h e r e f o r e appears t h a t  an  i s by no means pathognomonic of  complete v a g a l s e c t i o n . Previous  r e f e r e n c e was  made t o D a n i e l ' s o b s e r v a t i o n s  which  r e p o r t m i n o r v a r i a t i o n s i n the a m p l i t u d e of the BER 37 ko-hh  complex  secondary t o the e f f e c t of v a r i o u s d r u g s .  The  J <  *  present  study has demonstrated t h a t spontaneous changes i n the a m p l i t u d e 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 s h o r t t r a c i n g s from the same e l e c t r o d e ( F i g . 1 ) .  These v a r i a -  t i o n s were not a p p a r e n t l y p r e c i p i t a t e d by any m a n i p u l a t i o n the experimental  model.  I t i s d i f f i c u l t t o draw any f i r m  of  80 conclusions  w i t h r e s p e c t t o f a c t o r s which may i n f l u e n c e  a m p l i t u d e of the PP's,  o t h e r t h a n perhaps the f i r m n e s s o f  c o n t a c t o r depth of p e n e t r a t i o n 14, 20 the s e r o s a . '  of the e l e c t r o d e  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 vagal trunk, using a p p l i e d a t 5-1°  the  s t i m u l i of 100-120 V,  t i p into  of e i t h e r  0.1-0.5 msc.  divided  duration,  i m p u l s e s p e r second f o r p e r i o d s 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 a s e r i e s of AP's,  and  i n most i n s t a n c e s  i z a t i o n of the BER f o r the d u r a t i o n  of one  disorgan-  of the s t i m u l a t i o n and up  t o 20-30 seconds t h e r e a f t e r ( F i g . 3K c e n t r a l end  an a s s o c i a t e d  antrum,  Stimulation  of  d i v i d e d vagus ( e i t h e r a n t e r i o r or  the posterior)  w i t h the o t h e r t r u n k r e m a i n i n g i n t a c t had no demonstrable e f f e c t on the BER o r 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 ments d e s p i t e t i o n , and  s y s t e m a t i c v a r i a t i o n of v o l t a g e ,  experi-  impulse dura-  i m p u l s e f r e q u e n c y a c r o s s 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 desc r i b e d i n t h i s s e r i e s has not  demonstrated the e x i s t e n c e  of a  v a g o - v a g a l 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 o r 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. Following  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 a n i m a l s so studied  (Fig, 4).  R a p i d s a c r i f i c e of t h e s e a n i m a l s by the  intravenous administration  of p o t a s s i u m 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  alter  81  the BER i n t h e i n i t i a l  few minutes post-mortem.  Following  t h i s v a r i a b l e p e r i o d , the amplitude o f 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 o f rhythm was o b s e r v e d .  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 r a t e i d e n t i c a l t o t h e p r e vagotomy r a t e f o r a f u l l t w e l v e minutes a f t e r c a r d i a c  stand-  still. Attempts t o o b t a i n an enhanced response o f t h e BER t o e i t h e r a f f e r e n t o r e f f e r e n t v a g a l s t i m u l a t i o n by p r e c e d i n g t h e r e g u l a r t e s t s t i m u l u s w i t h a t h i r t y second p e r i o d o f h i g h quency s t i m u l a t i o n were u n s u c c e s s f u l . t h i s model t o c o n f i r m  fre-  I t was n o t p o s s i b l e i n  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 t o g a s t r i c e l e c t r i c a l  activity.  I n two a n i m a l s , t h e 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  stimulated.  S t i m u l a t i o n o f t h e 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 i m p u l s e s p e r second x 60-90 seconds) produced no e f f e c t on t h e BER.  C e n t r a l s t i m u l a t i o n o f one  c e r v i c a l vagus w h i l e t h e o t h e r t r u n k remained i n t a c t r e s u l t e d o n l y i n t h e c h a r a c t e r i s t i c r e t c h i n g movements, b u t no e f f e c t on t h e BER.  Following  complete c e r v i c a l v a g a l s e c t i o n i n one  of t h e a n i m a l s , a f i f t e e n minute p e r i o d o f g r o s s 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 d u r i n g d i s s e c t i o n b u t b e f o r e d i v i s i o n o f t h e nerve t r u n k s r e s u l t e d i n t h i s same a n i m a l i n a p r o l o n g e d 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 o f t h e sympat 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 p r o c e d u r e on  operative BER  A c o n t r o l group of s i x a n i m a l s was the e f f e c t of the o p e r a t i v e of the BER was  (Table I I ) .  examined t o determine  procedure per  se on the  frequency  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  d e s i g n e d t o e v a l u a t e the combined e f f e c t s of t i m e , anaes-  t h e s i a , and  change i n body temperature on the BER  rate.  Se-  q u e n t i a l f i v e minute t r a c i n g s o b t a i n e d a t f i f t e e n minute i n t e r v a l s o v e r a two  hour c o n t r o l p r o c e d u r e were examined.  t i c a l evaluation regression  u s i n g a n a l y s i s of c o v a r i a n c e and  Statis-  linear  i n d i c a t e d a s i g n i f i c a n t s l o w i n g of the BER  c o u r s e of the two  hour t e s t p e r i o d  (p < 0 . 0 5 ) .  over the  Slopes f i t t e d  f o r d a t a o b t a i n e d from each a n i m a l i n d i c a t e d t h a t the r a t e reduction studied 3.  o f the BER  (p =  f r e q u e n c y was  of  s i m i l a r i n each a n i m a l  0.01).  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,  using 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  t a k e n i n t o con-  s i d e r a t i o n 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 g a s t r i c c o n t r a c t i l e response t o v a g a l  stimulation.  As i t was  apply  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 o r y e f f e c t may  w e l l t o 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 of acute e x p e r i m e n t s was  u n d e r t a k e n , i n which a  as  series  chloralose-  u r e t h a n e a n a e s t h e t i c m i x t u r e was s u b s t i t u t e d f o r sodium t h i o 48 8 pental. C h l o r a l o s e , though d e p r e s s i n g c o r t i c a l a c t i v i t y , i s thought t o 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 t u r e s , and  may,  v i a i t s a c t i o n on l o w e r c e r e b r a l  struc-  centres,  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  secretion.'  A t o t a l o f t w e n t y - n i n e p r o c e d u r e s was a s s e s s e d i n t h i s series.  The s p e c i f i c e f f e c t o f vagotomy on the f r e q u e n c y o f  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 t h 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 potential.  e f f e c t on the f r e q u e n c y o f t h i s  Succinylcholine abolished  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 w i t h o u t 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 v a g a l In twenty-five  stimulation.  a n i m a l s , b o t h a f f e r e n t and e f f e r e n t  t r u n k s were s t i m u l a t e d  electrically.  I n the i n i t i a l  vagal  twelve  p r o c e d u r e s (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 u s i n g the s t a i n l e s s s t e e l e l e c t r o d e The  as d e s c r i b e d  f o r Group I .  r e m a i n i n g t h i r t e e n p r o c e d u r e s (Group I I I B ) d i f f e r e d from  the i n i t i a l t w e l v e i n t h a t the s t i m u l u s  i s o l a t o r and  bronze s t i m u l a t i n g e l e c t r o d e were i n t r o d u c e d  phosphor-  i n t o the  experi-  mental model. I n Group I I I A , d i s t a l s t i m u l a t i o n o f e i t h e r v a g a l  trunk  ( w h i c h e v e r 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 s t r o n g a n t r a l c o n t r a c t i o n s and o c 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 o f the BER complex f o r the d u r a t i o n o f 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 (Fig.  6 ) . The l a t e n c y o f t h i s response was l e s s t h a n f i v e  seconds.  The most pronounced e f f e c t s were a c h i e v e d w i t h  s t i m u l i o f 100-120 V, 0.5-2.0 msc. i m p u l s e s p e r second f o r p e r i o d s  d u r a t i o n , a p p l i e d a t 10  o f 60 seconds.  84 I n n i n e o f t w e l v e t r i a l s of p r o x i m a l o r 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 r e m a i n i n g vagus i n t a c t , an  effect  c o n s i s t i n g o f s l i g h t t o moderate a n t r a l and upper s m a l l "bowel c o n t r a c t i l e a c t i v i t y was  observed  p e r i o d o f 30-40 seconds. from s t i m u l i of 120 V, 0.5  after a variable latent  The most pronounced e f f e c t s r e s u l t e d msc.  d u r a t i o n , a p p l i e d a t 10  p e r second f o r more p r o l o n g e d p e r i o d s , up t o t h r e e  impulses  minutes.  I n f i v e o f the n i n e a n i m a l s 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 d u r i n g the p e r i o d o f  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 ) . the d i s t o r t i o n of the BER  However,  was n o t observed w i t h e v e r y p e r i o d o f  p r o x i m a l s t i m u l a t i o n i n t h e same a n i m a l . c r e a s e i n s m a l l bowel a c t i v i t y was  G e n e r a l l y , the i n -  more predominant t h a n  a c t i v i t y o f the antrum f o l l o w i n g p r o x i m a l s t i m u l a t i o n .  the However,  the o b s e r v a t i o n s o f c o n t r a c t i l e a c t i v i t y were o n l y s u b j e c t i v e i m p r e s s i o n s , and must be c o n f i r m e d by measuring e i t h e r  intra-  l u m i n a l p r e s s u r e change o r c o n t r a c t i l e f o r c e b e f o r e assuming significance. I n seven o f the n i n e a n i m a l s i n w h i c h 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 o c c u r r e d on p r o x i m a l  stimu-  l a t i o n o f one d i v i d e d vagus, p r o x i m a l s t i m u l a t i o n o f e i t h e r v a g a l t r u n k a f t e r s e c t i o n of the r e m a i n i n g vagus no l o n g e r p r o duced t h e s e e f f e c t s ( F i g . 6 ) , s u g g e s t i n g t h a t the r e f l e x s t i m u 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 t h r o u g h the c e n t r a l nervous system and a l o n g v a g a l e f f e r e n t s t o the stomach and s m a l l i n t e s t i n e .  intact T h i s would  85 seem t o c o n f i r m t h e e x i s t e n c e o f a v a g o - v a g a l  reflex.  I n the  r e m a i n i n g two a n i m a l s , however, p r o x i m a l s t i m u l a t i o n o f e i t h e r v a g a l t r u n k f o l l o w i n g complete vagotomy r e s u l t e d i n i n c r e a s e d s m a l l bowel motor a c t i v i t y , r a t h e r t h a n a b o l i s h i n g t h e r e s p o n s e . T h i s may be i n t e r p r e t e d as due t o e i t h e r a removal o f v a g a l i n h i b i t o r y f i b r e s , o r perhaps t o s t i m u l a t i o n o f s y m p a t h e t i c cholinergic excitatory  efferents.  7 8  I n one a n i m a l , p r o x i m a l s t i m u l a t i o n o f t h e d i v i d e d  anterior  vagus nerve w i t h t h e p o s t e r i o r t r u n k s t i l l i n t a c t produced no change i n t h e 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, p r o x i m a l s t i m u l a t i o n o f e i t h e r v a g a l t r u n k 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 o f t h e upper s m a l l bowel, b u t no o b s e r v a b l e change i n t h e a n t r a l BER.  Distal  s t i m u l a t i o n o f e i t h e r t r u n k i n t h i s a n i m a l produced t h e c h a r a c t e r i s t i c s t r o n g 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 o f t h e BER.  I n t h e r e m a i n i n g two a n i m a l s o f t h i s s e r i e s  (Group I I I A ) , p r o x i m a l s t i m u l a t i o n o f one d i v i d e d vagus produced no change i n t h e 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 a n i m a l s 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 o r 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 included 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 t h e same degree o f 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 o c c u r r e d i n Group IIIA.  I n t e n of t h i r t e e n animals, afferent or r e f l e x s t i m u l a t i o n  86 o f one d i v i d e d vagus ( w h i l e the o t h e r 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 s m a l l bowel c o n t r a c t i l e a c t i v i t y . t h r e e of t h e s e a n i m a l s was change i n t h e BER  However, i n o n l y  there a d e f i n i t e ,  pattern ( F i g . 7).  simultaneous  The most pronounced  e f f e c t s were o b t a i n e d u s i n g low i n t e n s i t y , low s t i m u l i i n accordance w i t h M a r t i n s o n ' s hold e x c i t a t o r y vagal f i b r e s . of the o r d e r o f 3-7  ma,  0.1  frequency  concept o f low t h r e s -  The most e f f e c t i v e s t i m u l i were  msc.  duration, applied at 5  p u l s e s p e r second f o r p e r i o d s o f 60-120 seconds.  im-  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 contractile activity.  P r e c e d i n g the t e s t s t i m u l u s w i t h t h i r t y  second p e r i o d s o f h i g h f r e q u e n c y  s t i m u l a t i o n was  not  effective  i n p o t e n t i a t i n g the response t o e i t h e r a f f e r e n t o r e f f e r e n t stimulation.  P r o x i m a l s t i m u l a t i o n o f one a f f e r e n t t r u n k  not a s s o c i a t e d w i t h any o b s e r v a b l e change i n BER a c t i v i t y i n the r e m a i n i n g t h r e e a n i m a l s  was  or c o n t r a c t i l e  o f t h i s group.  F o l l o w i n g complete v a g a l s e c t i o n , p r o x i m 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 t r u n k u s i n g the same s t i m u l u s parameters no produced the e f f e c t s r e c o r d e d above i n n i n e of the t e n ( F i g . 7).  The  one e x c e p t i o n t o t h i s p a t t e r n was  longer animals  an i n c r e a s e  i n s m a l l 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 v a g a l s t i m u l a t i o n , even though a l l v a g a l f i b r e s had been  severed.  Once a g a i n , the r e s u l t s t e n d t o 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 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  fibres.  87 4.  Group I V .  Conduction v e l o c i t y  Conduction v e l o c i t y four  o f t h e BER  o f t h e BER c o m p l e x was s t u d i e d i n  a n i m a l s by r e c o r d i n g i n a b i p o l a r  adjacent  antral  electrodes  fashion  ( F i g . 8A).  f r o m two  The a v e r a g e  conduction  v e l o c i t y was 2 cm. p e r s e c o n d a s m e a s u r e d o v e r t h e a n t r u m . The  c o n d u c t i o n v e l o c i t y was n o t a l t e r e d  vision  of either  lation  of the d i s t a l  that  vagal  conduction v e l o c i t y  lation not  one o r b o t h v a g i  o f one d i v i d e d  trunks  s i g n i f i c a n t l y by d i -  ( F i g . 8A).  E l e c t r i c a l stimu-  so d i s t o r t e d  the  c o u l d n o t be m e a s u r e d .  tracings  Central  stimu-  vagus, w i t h the o t h e r trunk i n t a c t , d i d  a l t e r the conduction v e l o c i t y  o f t h e BER i n t h e a n i m a l s  studied. 5.  Group V.  A final the  effect  Effect  o f p e n t a g a s t r i n on BER  before  and a f t e r  group o f e i g h t  a n i m a l s was e x a m i n e d t o  of a continuous pentagastrin i n f u s i o n  q u e n c y a n d on g a s t r i c tained  vagotomy  contractile  activity.  f r o m s i x a n i m a l s were s u i t a b l e  resting  BER f r e q u e n c y was c a l c u l a t e d  W i t h i n 15-30 infusion,  s e c o n d s o f t h e commencement  antral  contractile  on t h e BER f r e -  The r e c o r d i n g s ob-  f o r analysis. a t 4.06  ascertain  cycles  The mean p e r minute.  of the pentagastrin  a c t i v i t y i n c r e a s e d m a r k e d l y , and  continued a t t h i s heightened l e v e l f o r the duration of the i n fusion  and u s u a l l y  ponding increase onset  f o r 15-20  minutes t h e r e a f t e r .  latent  corres-  i n t h e BER f r e q u e n c y was o b s e r v e d a f t e r t h e  of pentagastrin infusion  a variable  A  period  i n a l l cases studied,  o f 15-30  seconds  ( F i g . 9).  following The i n c r e a s e d  88  BER f r e q u e n c y  o u t l a s t e d t h e d u r a t i o n o f t h e i n f u s i o n "by up t o  40-45 m i n u t e s i n two a n i m a l s o b s e r v e d f o r t h a t l e n g t h o f t i m e . The  mean BER f r e q u e n c y  infusion,  minute, an i n c r e a s e  5.51  division  of  Jkfo  gastrin  Jkfo  increase  this  effect  and Monges.  one o r b o t h v a g a l  trunks  ma,  91  consistently  msc,  However, i t seems c l e a r t h a t appreciable  was o b s e r v e d f o l l o w i n g s e c t i o n o f ( F i g . 9).  5-10  animals during  infusion.  the course  of the (5-10  Peripheral stimulation  i m p u l s e s p e r s e c o n d f o r 60-120 s e c o n d s )  as observed i n the p r e v i o u s  s t i m u l a t i o n , however, p r o d u c e d  effects  on BER r h y t h m a n d a n t r a l c o n t r a c t i l i t y .  suggest t h a t p e n t a g a s t r i n  k g . / h r . ) does n o t s i g n i f i c a n t l y response t o r e f l e x vagal  at this  a c t i v i t y and  experimental  or reflex  tile  penta-  the s i m i l a r increases des-  Central  tions  during  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  BER d i s t o r t i o n ,  was  s t i m u l a t i o n o f b o t h a f f e r e n t and e f f e r e n t v a g a l  pentagastrin  0.1-0.5  recorded  c o n t r o l , a s no  trunks  was s t u d i e d i n t h r e e  continuous  with  i s not under v a g a l  Electrical  (Table I I I ) .  (Table I I I ) .  i n BER f r e q u e n c y  change i n t h e BER f r e q u e n c y either  cycles per  c o m p l e t e vagotomy, t h e mean r a t e  i n f u s i o n i s i n accord  35 c r i b e d by C o o k e ^  of the  o f one v a g u s n e r v e , t h e mean f r e q u e n c y  c y c l e s p e r minute  The  stage  over the r e s t i n g r a t e  c y c l e s p e r minute; a f t e r  was 5«^5  the i n i t i a l  t h e v a g i were d i v i d e d , was 5.45  before  Following  during  only  inconstant  Gross  observa-  r a t e o f i n f u s i o n (4  potentiate  the g a s t r i c  s t i m u l a t i o n , though f i n e  e n c e s c o u l d p e r h a p s be d e t e c t e d  groups.  ugm/  contracdiffer-  by m e a s u r i n g c o n t r a c t i l e  force  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 t h a t the  use  of p e n t a g a s t r i n as an a d j u n c t t o p o t e n t i a t e v a g o - v a g a l 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 v a l u e i n the s e a r c h f o r a r e l i a b l e t e s t t o a s s e s s the completeness of vagotomy.  90 CHAPTER FOUR SUMMARY AND CONCLUSIONS Electrical both  electrical  vagotomy. noted  slower  rhythm  the slowing  0.002),  Also of significance  o f t h e BER a s a r e s u l t itself  (effect  o f a two h o u r p e r i o d  o f t h e reduced  p l e t e vagotomy. rate if  Certainly  i s indicative  purely t o vagal  o f complete v a g a l  of the  recorded  Therefore, i t  conclusions concerning the w h i c h f o l l o w s com-  section.  statistically,  reduced  Moreover,  could i n fact  limited value  even  be a t t r i b u t e d i nthis  investi  i s o f such  i n t h e assessment  a low  o f any  case.  On s e v e r a l o c c a s i o n s , following  when  0.05).  s e c t i o n , the r e d u c t i o n observed  o r d e r a s t o be o f v e r y  How-  a n a e s t h e s i a , de-  one c a n n o t c l a i m t h a t t h i s  though o f s i g n i f i c a n c e  individual  (p <  BER f r e q u e n c y  t h e r e d u c t i o n i n BER f r e q u e n c y  gation,  0.01).  of the effects  o f time,  i s n o t p o s s i b l e t o draw a n y d e f i n i t e significance  was a  f o l l o w i n g c o m p l e t e vagotomy a s compared  i n body t e m p e r a t u r e ) was a l s o s i g n i f i c a n t  the course  and a f t e r  but not a f t e r the  o n l y one v a g u s d i v i d e d (p <  operative procedure crease  (p <  o f o n l y one v a g a l t r u n k .  BER f r e q u e n c y  before  antrum,  r e d u c t i o n o f t h e BER f r e q u e n c y was  c o m p l e t e vagotomy  the rate with  ever,  f a s h i o n s from the g a s t r i c  (BER) was r e c o r d e d  A significant  after  division  over  o f t h e stomach h a s b e e n r e c o r d e d i n  monopolar and b i p o l a r  Basic  with  activity  a d i s o r g a n i z e d BER was  c o m p l e t e vagotomy.  However, t h i s  observed  i r r e g u l a r i t y was  91 not  only  temporary, but  following traction  division on  the  of  could  only  vagi.  also  one  vagal  has  Some i n v e s t i g a t o r s have r e p o r t e d BER  trunk,  or  following pathognoN e l s e n . 93  b e e n s u g g e s t e d by  that  f o l l o w i n g vagotomy i s n o t  develops  spontaneously,  Hence i t i s c e r t a i n l y n o t  monic o f c o m p l e t e vagotomy, as  the  occur  the  J %  disorganization  observed immediately,  only  after a latent period  This  may  of s e v e r a l hours or  of  but even  71 days.  e x p l a i n why  more f r e q u e n t l y  i n the  If  onset  delay  i n the  principle operative  could  not  present o f BER  be  disorganization  stimulation  of the  trunk generally  tion  and  activity.  BER  In the  initial  response  central  stituting has  peripheral  increase  electrical vagal (5 ma,  and  i t was  not  (Group I )  possible  mixture  0.1  msc,  stimulation.  low  the  intra-  end  of  using  elicit by  other  vagal  thiopental  be  achieved  Alterations in gastric were p r o d u c e d by  second);  a  i n v e s t i g a t i o n sub-  f o r sodium  i n t e n s i t y , low  5 impulses per  to  or motor a c t i v i t y  However, s u b s e q u e n t  contractile activity  stimulation using  this  in antral contractile  s u g g e s t e d t h a t v a g o - v a g a l r e f l e x e f f e c t s can  means o f a f f e r e n t v a g a l  f o r an  or d i s t a l  d i v i d e d vagus w h i l e  a chloralose-urethane  rule,  vagotomy.  experimental s e r i e s  o f one  trunk remained i n t a c t .  i s the  of  observed  experiments.  a sound b a s i s  in gastric electrical  stimulation  not  r e s u l t e d i n a marked d i s t o r -  considerable  sodium t h i o p e n t a l a n a e s t h e s i a , reflex  as  completeness  a divided vagal of the  s e r i e s of acute  applied  t e s t t o a s s e s s the  Electrical  t h i s phenomenon was  frequency  the  afferent impulses  e f f e c t s were  by  presumably mediated v i a pathways t h r o u g h the s y s t e m and the on  a l o n g the  stomach. the  The  c e n t r a l nervous  remaining i n t a c t e f f e r e n t vagal  reported  potentiating  g a s t r i c response to vagal  e f f e c t of  stimulation  may  f i b r e s to  chloralose have b e e n i n -  o fluential sults way  do  i n achieving  these  demonstrate the  whereby  activity  one  by  The  may  existence  of  of a f f e r e n t vagal  the  BER  several  r e s p o n s e was  no  means c o n s i s t e n t  tractile  was  the  activity  occasions,  increase  observations  conduct the  muscle  subsequent to a f f e r e n t v a g a l  hand, i t d o e s n o t  appear that  effect  o f vagotomy on  effect  of p e n t a g a s t r i n  vagotomy w i l l at  of the  the on  contribute  this  Far  small  light  search f o r a r e l i a b l e  contractile force  was  more  bowel  stimulation.  i n the  t o a s s e s s c o m p l e t e n e s s o f vagotomy by  changes i n the  stimulation  unfortunately,  afferent vagal  seem more a p p r o p r i a t e  test  contractile  or r e p r o d u c i b l e .  would t h e r e f o r e to  but  and  i n b o t h a n t r a l and  following  re-  fibres.  to r e f l e x vagal  on  consistent  the  of a vago-vagal r e f l e x path-  very convincing by  Nevertheless,  modify g a s t r i c e l e c t r i c a l  stimulation  response  results.  of  con-  It  these  intraoperative  investigation  of  g a s t r o i n t e s t i n a l smooth  stimulation.  further evaluation  On of  the  other  either  the  c o n d u c t i o n v e l o c i t y of the  BER  or  electrical  and  after  activity  v e r y much o f  before  s i g n i f i c a n c e t o the  the  search  hand. What t h e n a r e  we  left  with?  doubt p r o v i d e s a r e a s o n a b l e guide current  ulceration following  The as  Hollander i n s u l i n t o who  vagotomy.  The  i s at  risk  test of  intraoperative  no  retests  93 developed t o date have been n e i t h e r c o n c l u s i v e n o r pathognomonic o f complete vagotomy. denervation  Perhaps complete  parasympathetic  i s an i m p o s s i b l e g o a l i n v i e w o f t h e e x t r a v a g a l  c h o l i n e r g i c o u t f l o w v i a s p l a n c h n i c s and t h o r a c i c d o r s a l r o o t ganglia.  Perhaps complete anatomic vagotomy i s n o t 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 a g a i n s t 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 t h e i n c o m p l e t e  b u t "adequate"  vagotomy which o c c u r s when o n l y a t e r m i n a l g a s t r i c f u n d i c b r a n c h remains u n d i v i d e d .  Perhaps any o f these t e s t s has as  i t s major v i r t u e a s t i m u l u s t o t h e surgeon t o be more m e t i c u l o u s and e x a c t i n g i n h i s t e c h n i q u e  of performing  vagotomy,  knowing t h a t h i s work w i l l be p u t t o the " a c i d " t e s t tively.  Nevertheless,  postopera-  t h e development o f 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 p e r a t i o n i n the treatment and w i l l h e l p p r e v e n t  of p e p t i c u l c e r d i s e a s e ,  t h i s method from f a l l i n g i n t o d i s r e p u t e  because o f a c o n t i n u e d h i g h r a t e o f r e c u r r e n t u l c e r a t i o n .  9  TABLES  k  95 TABLE I BASIC ELECTRIC RHYTHM BEFORE AND AFTER VAGOTOMY  Dog  Vagi Intact  BER ( c y c l e s p e r minute) One vagus d i v i d e d Both v a g i  divided  2.76 4.11 4.54 3.99 4.95 4.05 3.76 3.91 4.16 4.19 4.57  4.40  3.13 4.47 4.56 4.17 4.72 4.36 , 4.05 3.79 4.65 4.07 4.43 3.60 4.21 4.03 4.12 4.13 4.37 3.65 5.60 5.20  4.4l  4.27  4.08  s t a n d a r d ±0.40 deviation  ±0.55  ±0.51  1 2  3.95 4.13 4.57 4.21 4.83 4.78 4.13  3 4 5 6 7 8 9 10 11 12 13  4.51 4.93 3.97 4.77 4.75 4.46  14  3.91 4.44  15 16 17  4.42  4.20 3.57 5.20  18  19 20 mean  3.84  3.75 3.74 4.01 3.95 3.93 3.60 5.00 4.75  Each r e c o r d i n g r e p r e s e n t s t h e BER i n c y c l e s p e r minute, a v e r aged o v e r a randomly chosen f i v e minute sequence o f r e c o r d i n g . The d i f f e r e n c e i n t h e BER w i t h t h e v a g i i n t a c t and t h a 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 t h e BER w i t h one vagus d i v i d e d and t h a t f o l l o w i n g complete vagotomy a l s o a c h i e v e d s i g n i f i c a n c e ( p < 0 . 0 1 ) . S t a t i s t i c a l a n a l y s i s performed by W i l c o x o n ' s S i g n e d Ranks T e s t .  96 TABLE I I THE EFFECT OF LAPAROTOMY AND TIME ON THE BER  Dog  BER  ( c y c l e s p e r minute) a t 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 o f c o v a r i a n c e 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 s l o w i n g o f t h e BER over t h e two hour t e s t p e r i o d (p <0.05). data obtained  Slopes f i t t e d f o r  from each dog r e v e a l t h a t t h e r a t e o f r e d u c t i o n  i n t h e BER r a t e i s s i m i l a r i n each a n i m a l 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 p e r minute Course o f p e n t a g a s t r i n i n f u s i o n Baseline  Vagi  intact  One vagus divided  Both v a g i divided  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 o f a c o n t i n u o u s i n f u s i o n o f p e n t a g a s t r i n (4 ugm./kg./hr.) on t h e BER o f t h e c a n i n e a f t e r vagotomy,  Pentagastrin resulted  the BER f r e q u e n c y .  stomach b e f o r e and  i n a 34% i n c r e a s e i n  Vagotomy d i d n o t 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.  Jl  millivolt=15  Basic electrical rhythm with associated action potentials recorded at antrum.  F i g u r e 1. B a s i c e l e c t r i c a l rhythm (BER) r e c o r d e d 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 t h e e l e c t r i c a l p o t e n t i a l i n t h e r e s t i n g s t a t e . Demonstration of associated action potentials.  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.  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 .  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.;  BER,  anterior vagus divided; stimulation of central end divided vagus, 120 V., 0.1 msc, 10 impulses/sec, x 9 0 " ; note absence of effect on BER.  period of stimulation  *  note slight irregularity of BER BER,  F i g u r e 3.  posterior vagus divided; stimulation of_central end of divided vagus 120 V., 0.1 msc, 10 impulses/sec, for 120 sees.  The e f f e c t on BER o f 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 ) .  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 .  103  BER (antrum), vagi intact  Effect of dissection of cervical vagi on BER.  1  BER,  following section of right cervical vagus.  BER,  following section of left cervical vagusi.e. complete cervical vagotomy.  BER 30 minutes after complete cervical vagotomy.  F i g u r e 5. The e f f e c t o f 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 n e r v e s 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 60 seconds No contractile response in antrum. No change in BER. x  •  •  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  F i g u r e 6.  The e f f e c t on BER o f 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 section (chloralose-urethane anaesthesia).  BER (antrum);Chloralose-urethane anaesthesia with succinylcholine. vagi intact.  if—••X • 4  —"V-—l-^v^r^V^VVKN'^^Ar-—•——~^\~——  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-^^* ^^—^Hf^T-—^——— 1  ^  ^—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  F i g u r e 7.  antral contractions.  T h e _ e f f e c t on BER o f a 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 (chloralose-urethane anaesthesia, stimulus isolator).  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.  _ |—, |[— | — | — , BER,  |u_  (  I Ui. I— |u_  |(U-  both vagi divided.Conduction velocity  |u_ |u_- |L  1.6 cm./sec.  figure B  BER and  F i g u r e 8.  recorded at antrum using a short time constant (0.03 sec.) higher amplication (1 millivolt= 20 mm. deflection) Note distortion of BER.  A . B i p o l a r r e c o r d i n g o f BER, demonstrating c o n d u c t i o n v e l o c i t y o f the p a c e s e t t e r p o t e n t i a l b e f o r e and a f t e r vagotomy. B. BER r e c o r d e d 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 .  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.  F i g u r e 9.  T-he e f f e c t on BER o f a p e n t a g a s t r i n i n f u s 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 . o  BIBLIOGRAPHY  109 BIBLIOGRAPHY 1.  A g o s t o n i , E., J . E . Chinnock, M. DeBurgh D a l y , 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 o f the vagus nerve and i t s branches t o t h e h e a r t , l u n g s , and abdominal v i s c e r a i n t h e c a t . J . P h y s i o l . (London) \T£_\ 182-205, 1957.  2.  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