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The effect of decerebration on the reflex response to left atrial distension Albrook, Sally Milton 1971

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THE EFFECT OF DECEREBRATION ON THE REFLEX RESPONSE TO LEFT ATRIAL DISTENSION  •by SALLY MILTON ALBROOK B.Sc.  (Honours) Chatham C o l l e g e ,  1969  A t h e s i s submitted i n p a r t i a l f u l f i l l m e n t o f the requirements f o r t h e degree o f Master o f S c i e n c e  i n the Department o  f  Physiology  We accept t h i s t h e s i s as conforming t o the r e q u i r e d standard  The U n i v e r s i t y o f B r i t i s h Columbia September, 1971  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 requirements f o r  an advanced degree at the U n i v e r s i t y of B r i t i s h Columbia, I agree that the L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r reference and study. I f u r t h e r agree that permission f o r extensive copying of t h i s thesis f o r s c h o l a r l y purposes may by h i s representatives.  be granted by the Head of my Department or 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 gain s h a l l not be allowed without my w r i t t e n permission.  Department The U n i v e r s i t y of B r i t i s h Columbia Vancouver 8, Canada  Date rffnjLnJujv3£', /j>/  i • ABSTRACT An  i n c r e a s e i n heart r a t e brought about by s t i m u l a t i o n  of the re c e n t e r s at the  j u n c t i o n o f the pulmonary v e i n s and  l e f t atrium  been reported by  i n dogs ha?  (1964). Although e x t e n s i v e  Led some and  experimentation  has  the  Linden,  shown the  a f f e r e n t pathway f o r such t a c h y c a r d i a i s i n the vagus nerve, and  e f f e r e n t impulses a r p e a r to t r a v e l v i a the  sympathetics,  the  l o c a t i o n of c e n t r a l synapses, and  o f c e n t r a l c o n t r o l necessary A l s o unknown i s the  designed  animal.  s e r i e s of experiments d e s c r i b e d i n t h i s paper were  b r a t i n g mongrel dogs (#-13 devised which avoided  q u e s t i o n s . A method f o r  Kg)  traumatic  p r e p a r a t i o n . The  by e l e c t r o c o a g u l a t i o n l o s s of blood,  v e i n s with the l e f t a t r i u m was  j u n c t i o n of the  c h a r a c t e r i s t i c s of the i n c r e a s e i n h e a r t However, c a r e f u l s t u d i e s o f these  inflation J  pulmonary such  neural  c h a r a c t e r i s t i c s with  both  discrepancy  t a c h y c a r d i a produced by  could not be t o t a l l y a b o l i s h e d by the  balloon  i n f u s i o n o f the  sympathetic b l o c k i n g agent p r o p r a n o l o l , e i t h e r b e f o r e  after decerebration. creases at  the  r a t e were u n a l t e r e d .  l e s i o n s of the s p i n a l c o r d , r e v e a l e d a  n r e v i o u s r e p o r t s . The  was  found to be unchanged by  a m i d c o l l i c u l a r d e c e r e b r a t i o n . Both magnitude and  with  decere-  leaving a stable  t a c h y c a r d i a i n i t i a t e d by  i n f l a t i o n o f s m a l l b a l l o o n s at the  drugs and  degree  s i g n i f i c a n c e of t h i s c a r d i o v a s c u l a r c o n t r o l  to answer both these  decerebrate  the  f o r i t s e x i s t e n c e are not known.  mechanism i n the unanaest.hetized The  cardiac  the  In a d d i t i o n s m a l l , but  significant, in-  i n h e a r t r a t e remained upon s e c t i o n of the l e v e l o f the  first  or  s p i n a l cord  c e r v i c a l v e r t e b r a . These r e s u l t s  ii  i n d i c a t e d t h a t the e f f e r e n t pathway f o r t h i s r e f l e x , predominantly r e l a y e d by the c a r d i a c sympathetica, a vagal  though  may  rossess  component.  U s i n g the same d e c e r e b r a t e  p r e p a r a t i o n , two  volatile  a n a e s t h e t i c s were used t o study the e f f e c t s o f a n a e s t h e t i c s  on  the response to b a l l o o n i n f l a t i o n . Halothane, or a n i t r o u s oxide-sodium p e n t o t h a l combination were a d m i n i s t e r e d decerebration,  then d i s c o n t i n u e d at completion  p r i o r to  o f the s e c t i o n .  Throughout the d u r a t i o n o f both a n a e s t h e t i c s , c a r d i o v a s c u l a r r e f l e x e s such as the left atrial  carotid  sinus r e f l e x , were depressed.  r e f l e x vras s i m i l a r l y s m a l l o r absent as  compared  t o dogs under c h l o r a l o s e a n a e s t h e s i a . Removal o f the c i r c u i t a f t e r successful decerebration appearance of s m a l l but b a l l o o n i n f l a t i o n , and  significant typical  coincided with  anaesthetic the  i n c r e a s e s i n h e a r t r a t e at  carotid  sinus a c t i v i t y at  o c c l u s i o n o f the c a r o t i d a r t e r i e s . N e i t h e r r e f l e x a t t a i n e d magnitudes  observed i n dogs under c h l o r a l o s e  d e s p i t e prolonged  The  the  anaesthesia,  w a i t i n g , up to s i x hours a f t e r  decerebration.  iii  TABLE OF CONTENTS Page ABSTRACT TABLE OF CONTENTS  i i i i  LIST OF TABLES LIST OF FIGURES ACKNOWLEDGEMENTS INTRODUCTION Review o f c e n t r a l c a r d i o v a s c u l a r c o n t r o l Review o f l e f t a t r i a l r e c e p t o r s Scone o f present i n v e s t i g a t i o n METHODS General s u r g i c a l p r e p a r a t i o n Method o f d e c e r e b r a t i o n Spinal Transection Protocol RESULTS Results of i n d i v i d u a l series E f f e c t s o f i n f l a t i n g the b a l l o o n s a t t h e pulmonary v e i n l e f t a t r i a l j u n c t i o n E f f e c t s of decerebration Effects of propranolol E f f e c t s of atropine Effects of spinal section E f f e c t s of anaesthetics DISCUSSION Introduction C e n t r a l c o n t r o l o f the l e f t a t r i a l r e f l e x R e l a t i v e r o l e s o f t h e sympathetic-parasympathetic d i v i s i o n s i n the response t o b a l l o o n i n f l a t i o n The l e f t a t r i a l r e f l e x i n the a n a e s t h e t i z e d i n t a c t o r unanaesthetized d e c e r e b r a t e dog C e n t r a l nervous system i n t e g r a t i o n o f c a r d i o vascular reflexes BIBLIOGRAPHY VITA  iv v vi 1 1 6 # 9 9 11 13 16 20 20 27 27 32 34 41 43 46 46 47 48" 54 55 59  iv  LIST OF TABLES' Table  Title  Page  I  Experimental  II  Summary of r e s u l t s o f S e r i e s I  ?1  III  Summary of r e s u l t s o f S e r i e s I I  22  IV  Summary of r e s u l t s of S e r i e s  III  23  V  Summa r y of r e s u l t s o f S e r i e s  IV  2U  VI  Summary of r e s u l t s o f S e r i e s V  25  VII  Summary of r e s u l t s o f S e r i e s VI  26  VIII  Changes i n h e a r t at decerebration  r a t e and  IX  Changes i n heart a f t e r v/ receptor isoprenaline  r a t e and blood p r e s s u r e stimulation with  XI  XII  protocol  19  blood  pressure  29  LO  A b i l i t y of nropranolol to block e f f e c t of i s o p r e n a l i n e and the response t o pulmonary vein distension -  50  E f f e c t s o f d e c e r e b r a t i o n , ^ blockade, and vagotomy on t h e changes i n h e a r t r a t e and b l o o d p r e s s u r e caused by d i s t e n s i o n o f the pulmonary v e i n s  51  Percent o f c o n t r o l response'to pulmonary v e i n d i s t e n s i o n r e m a i n i n g a f t e r 4 blockade with propranolol  52  LIST OF FIGURES  Title S a g i t t a l section of a dog's brain Tyr>ical response to pulmonary vein l e f t a t r i a l distension T y p i c a l response to pulmonary vein l e f t a t r i a l distension i n a decerebrate dog Response to pulmonary vein l e f t distension  atrial  Response to pulmonary vein l e f t distension a f t e r ^ blockade  atrial  Response to pulmonary vein l e f t a t r i a l distension a f t e r decerebration and J blockade The e f f e c t of $ blockade with propranolo on the response to isoprenaline T y p i c a l r e s p o n s e to pulmonary vein l e f t a t r i a l distension following | blockade with propranolol  ACKNOWLEDGEMENTS  The  author wishes t o express  following  her a p p r e c i a t i o n t o the  people:  to J.R. Ledsome f o r ideas and c r i t i c i s m t o Olenda Bennion and Mort C l a r k e f o r t h e i r t e c h n i c a l a s s i s t a n c e and p a t i e n c e to  Kurt Henze f o r photography and r e p r o d u c t i o n o f r e c o r d  to Dr. F. G a r r e t t f o r advice on neuroanatomy and i n t e r pretation to James Mason f o r unusual  encouragement  to Yvonne Heap f o r a d v i c e on d e c e r e b r a t i o n to R i a O r r f o r p a t i e n t t y p i n g .  techniques  1  INTRODUCTION C l a s s i c a l l y , c e n t r a l neural c o n t r o l of c a r d i o v a s c u l a r r e f l e x e s has been r e l e g a t e d t o t h e "vasomotor c e n t e r s " of m e d u l l a . The nineteenth  a b l a t i o n s t u d i e s o f Owsjannikow and  century,  consolidated  D i t t m a r i n the  f o l l o w e d by those o f P o r t e r i n the  a formidable  experimental  fied  i n 1946  and  existence  a "depressor  fourth v e n t r i c l e ,  seemed l i t t l e  of a "pressor  c e n t e r " more m e d i a l l y i n the (Alexander,  puts from these c e n t e r s  clari-  r e b u t t a l to  center" l y i n g  could be demonstrated by  the  laterally,  f l o o r of  1946). Both t o n i c and  as  (Dittmar,  P o r t e r , 19X5). As reviewed and  by Alexander, t h e r e  c l a i m f o r the  twentieth,  b a s i s f o r the medulla  c h i e f r e p o s i t o r y of c e n t r a l c a r d i o v a s c u l a r c o n t r o l . 1#73 ; Owsjannikot^, 1^71;  the  the  phasic  out-  s t i m u l a t i o n of  the m e d u l l a , r e c o r d i n g from p e r i p h e r a l n e r v e s , or t r u n c a t i o n (Wang and  Ranson, 1939;  contentious as 1963,  voices,  Chai  Alexander, 1946). D e s p i t e  (Manning, 1965;  and Wang repeated  are  many of the  Such repeated  success  does not of course p r e c l u d e m o d i f i e r s and this f i e l d ,  conclusion that and  and  cardio-  other a f f e r e n t s  level". at c o n f i r m i n g  this single fact  the e x i s t e n c e o f d i s s e n t e r s ,  t h e o r i s t s . These s c i e n t i f i c p r e f e c t s f l u o r i s h i n  p r i m a r i l y as a r e s u l t of the  other d e t a i l e d information processes  earlier studies,  from b a r o r e c e p t o r s  i n t e g r a t e d at the m e d u l l a r y  few  P e i s s , I960), as r e c e n t l y  were a b l e t o come to the " i n e s c a p a b l e vascular reflexes e l i c i t e d  a  concerning  extreme  p a u c i t y of  any  the nervous pathways and  i n v o l v e d i n c e n t r a l c a r d i o v a s c u l a r c o n t r o l . I f the  medulla a c t s as the keystone i n an i n t r i c a t e  s t r u c t u r e of  2  cardiovascular  c o n t r o l , the nature o f t h e o t h e r  yet d i s c e r n a b l e . In a recent cardiovascular  stones i s not  review o f the c e n t r a l c o n t r o l o f  events, the s t a t e o f our knowledge was  revealed  by a l i s t i n g of f i v e major areas o f u n c e r t a i n t y : 1)  we do not know the s i t e  of c e n t r a l sympathetic  i n h i b i t i o n induced by b a r o r e c e p t o r  stimulation;  2)  we do not know t h e s i t e o f o r i g i n o f v a g a l  3)  we do not know the l o c a t i o n o f b a s i c s i t e s i n baroreceptor  synaptic  a c t i v a t i o n o f the autonomic  system, nor the p r o c e s s e s 4)  neurons;  involved;  we do not know the t r u e i n f l u e n c e o f more r o s t r a l s t r u c t u r e s on m e d u l l a r y a c t i v i t y .  Granted t h a t we i n f a c t know so l i t t l e  (Gebber, 1970). about the  d e t a i l s o f c e n t r a l o r g a n i z a t i o n , i t i s not s u r p r i s i n g t h a t p a r a l l e l t o t h e development o f t h e staunch c l a s s i c a l  viewpoint,  t h e r e e x i s t e q u a l l y long h i s t o r i e s o f s t u d i e s o f other  central  nervous system s t r u c t u r e s and t h e i r p o s s i b l e i n f l u e n c e s on cardiovascular  events.  Foremost among these s t r u c t u r e s i s t h e hypothalamus, w i t h i t s r o l e as h i g h e s t  c e n t e r o f autonomic i n t e g r a t i o n ,  r e g u l a t i n g such v i s c e r a l f u n c t i o n s as temperature, food  intake,  f l u i d b a l a n c e , sugar and f a t metabolism, i t i s o n l y normal t h a t it  should  be a s s o c i a t e d with c a r d i o v a s c u l a r r e f l e x e s . E a r l y  s t u d i e s , i n v o l v i n g crude s t i m u l a t i o n o f p a r t s o f the hypothalamus w h i l e m o n i t o r i n g nerve impulses i n sympathetic nerves i n c o n j u n c t i o n revealed  w i t h blood  marked i n c r e a s e s  pressure  and h e a r t  i n a l l parameters  ardiac rate,  ( P i t t s et a l . , 1 9 4 1 ) .  3  More discrete stimulation of the hypothalamus designed to e l i c i t the "defence reaction" i n cats produces large  increases  in heart rate and c o n t r a c t i l i t y with only s l i g h t r i s e s i n systemic blood pressure, (Hilton, 1963). Such a response could not be possible i f some c e n t r a l l y mediated i n h i b i t i o n or a l t e r a tion of the normal baroreceptor response pattern had place. Djojosugito  not taken  has recently demonstrated that such hypo-  thalamically induced i n h i b i t i o n of baroreceptor impulses i s indeed highly s p e c i f i c , acting p r i m a r i l y on heart performance as r e f l e c t e d i n a o r t i c blood flow and  l e f t v e n t r i c u l a r work  load, rather than p e r i p h e r a l l y (Djojosugito,  et.al.,1970).  This d i f f e r e n t i a t e d i n t e r a c t i o n between hypothalamus and  medulla-  ry centered baroreceptor reflexes indicates a very high degree of i n t e g r a t i o n . Much work has been done stimulating s p e c i f i c areas of the cerebral cortex and noting the e f f e c t s evoked on both phasic and tonic cardiovascular various  events. The  f r o n t o - o r b i t a l cortex,  structures of the "limbic system", including the  the  septal  area, preoptic area, amygdala, and hippocampus, have a l l been shown to have possible modulating effects on reflexes (Hochman et.al.,1969; Klevans and et.al.,1960). However i t i s d i f f i c u l t  cardiovascular  Gebber, 1Q70;  Newman  to interpret the physio-  l o g i c a l s i g n i f i c a n c e of these reports. Whether such evoked responses are normally active i s not known. In addition, a l l of these areas have both afferent and hypothalamus, and  efferent connections to the  perhaps the e f f e c t s noted are being mediated  primarily v i a a c t i v a t i o n of hypothalamic-medullary pathways. Taken together the hypothalamus and these more r o s t r a l  4  s t r u c t u r e s cannot be denied an important r o l e i n c a r d i o v a s c u l a r c o n t r o l . The very f a c t that d e c e r e b r a t i o n  at the c o l l i c u l a r  plane causes d r a s t i c changes i n h e a r t • r a t e and blood emphasizes the e x i s t e n c e  o f such a f u n c t i o n . The p r e c i s e nature  of t h a t r o l e cannot be s t a t e d w i t h c e r t a i n t y a t t h i s An area  pressure,  point.  r e c e i v i n g renewed i n t e r e s t r e c e n t l y i s the  c e r e b e l l u m , l y i n g d i r e c t l y over the vasomotor c e n t e r s  i n the  f l o o r o f the f o u r t h v e n t r i c l e . The experiments o f M o r u z z i , d a t i n g from the 1940's, showed t h a t s t i m u l a t i o n o f the p a l e o cerebellum  could a l t e r c a r d i o v a s c u l a r r e f l e x e s evoked by stimu-  l a t i o n of sensory nerves, p a r t i c u l a r l y i n h i b i t i n g responses (Moruzzi,  pressor  1940). H i s t o l o g i c a l s t u d i e s have confirmed  a l a r g e network o f both a f f e r e n t and e f f e r e n t between t h e vasomotor c e n t e r s  connections  and t h e m e d u l l a r y r e t i c u l a r forma-  t i o n , and the pyramis, u v u l a , a n t e r i o r lobe and f a s t i g i a l nucleus o f t h e cerebellum  ( B r o d a l , 1954; Miura and R e i s ,  Cerebellectomy, f o l l o w i n g decerebration, s i g n i f i c a n t l y increase sinus r e f l e x i n c a t s ,  heart  (Reis and Cuenod, 1965). D i r e c t  responses i n c a t s Considering  i t s intimate  can be shown t o  r a t e , as w e l l as modify the c a r o t i d  t i o n o f the f a s t i g i a l nucleus can e l i c i t pressor  (Miura  the a n c i e n t  connection  large  and R e i s ,  stimula-  ( i . e . +100 mm.Hg.)  I969).  o r i g i n s o f the c e r e b e l l u m , and  w i t h the r e t i c u l a r f o r m a t i o n  o f the  medulla i t i s p r o b a b l y not u n l i k e l y t h a t some s i g n i f i c a n t grative function f o r cardiovascular present,  1969).  inte-  c o n t r o l may e x i s t . At  a l t h o u g h we can o n l y r e p o r t a few s c a t t e r e d  would be wise t o observe more c a u t i o n  facts,i t  i n d e c e r e b r a t e s t u d i e s to  5  avoid damage t o the c e r e b e l l u m , as i s f r e q u e n t l y done. We can not i g n o r e t h e p o s s i b l e e f f e c t s o f such damage without a b e t t e r u n d e r s t a n d i n g o f the cerebellum's r o l e i n c a r d i o v a s c u l a r r e g u l a tion . Caudal t o the medulla  i s t h e s p i n a l cord, c e n t e r o f  r e f l e x a c t i v i t y , which, i n the absence o f the b r a i n , appears t o be canable o f i n c r e a s i n g l y comolex c i r c u l a t o r y  adjustments.  C a r e f u l measurements o f l a t e n c i e s o f sympathetic responses  vasomotor  evoked by s t i m u l a t i o n o f c a r d i a c and r e n a l nerves have  r e v e a l e d t h a t the l a t e n c y o f type I I response  remains  i n s p i n a l c a t s , as i n c a t s w i t h an i n t a c t b r a i n  the same  (Katunsky and  K h a y u t i n , 1970; Khayutin and Lukoshkova, 1970). I f t h e s e  vaso-  motor responses were n o r m a l l y r e l a y e d v i a t h e m e d u l l a r y c e n t e r s such a r e s u l t would not be p o s s i b l e . D e s p i t e the problems attendant w i t h t h e s p i n a l a n i m a l , v i z . the l o n g d e l a y i n the r e t u r n o f v i s c e r a l r e f l e x e s , and the profound trauma o f s p i n a l shock, t h e r e i s no doubt a t p r e s e n t t h a t many autonomic r e f l e x a r e a s , i n c l u d i n g c a r d i o v a s c u l a r r e f l e x e s , possess both l o n g circuiting  ( s u p r a s p i n a l ) and s h o r t c i r c u i t i n g  the l o n g o r s h o r t c i r c u i t i s not y e t determined.  ( s p i n a l ) . Whether  i s predominant i n the normal animal  Indeed,  t h e r e i s evidence t h a t  both  pathways may be capable o f f u n c t i o n i n g , d e p e n d i n g on the c o n d i t i o n which the animal f a c e s , (Coote and Downman, 1966). In summary, i t i s p r o b a b l y f a i r t o say t h a t , g i v e n our c u r r e n t u n d e r s t a n d i n g , we cannot  deny the e x i s t e n c e o f a v e r y  powerful i n t e g r a t i n g c e n t e r f o r c a r d i o v a s c u l a r r e f l e x e s  located  i n t h e m e d u l l a . T h i s can be based, as i t o r i g i n a l l y was, on the  6  simple f a c t t h a t b a s i c w i t h o u t an enjoinder center  cardiovascular  i n t a c t medulla. However, we to a p p r e c i a t e  the  r e f l e x e s do not  function  should r e c a l l  Alexander's  r e t i c u l a r nature of t h i s c o n t r o l  (Alexander, 1946). A c o n s t a n t barrage of c o r t i c o -  hypothalamic, s p i n a l and cardiovascular  c e r e b e l l a r impulses impinges on  these  neurons i n the b r a i n stem, c e r t a i n l y p l a y i n g a  v i t a l r o l e i n c e n t r a l s e t t i n g of autonomic tone and  responsive-  ness . The  study r e p o r t e d  determine the exerted  l e v e l and  vein  r a t e i n i t i a t e d by l o c a t e d i n the  produced by d i s t e n s i o n of the  j u n c t i o n s . Although the  specific  stimulation  l e f t a t r i u m had  w i t h v a g a l a f f e r e n t s , and nerves, i t had  of b a r o r e c e p t o r  e f f e r e n t s i n the  cardiac  not yet been determined whether the  l e v e l . Before d e s c r i b i n g the methods and  a t r i a l r e f l e x under d i s c u s s i o n w i l l be Reports of r e f l e x changes i n heart  the a t r i a a l l stem d i r e c t l y from the B a i n b r i d g e i n 1915,  in  endinfrs  sympathetic central  protocol  h i s t o r y of  rate i n i t i a t e d  by  . i n f u s i o n experiments o f  r a t i o n a l explanation  r e f l e x . T a c h y c a r d i a could  the  included.  (Bainbridge,1915). Years o f c o n f u s i o n  the development of any  heart  i n the medulla or at some  used i n t h i s endeavor, a b r i e f review of the left  increase  left  been shown to be r e f l e x i n nature,  connections o f the a r c were l o c a t e d o t h e r CNS  undertaken to  extent of c e n t r a l nervous sytem c o n t r o l  on the t a c h y c a r d i a  atrial-pulmonary  i n t h i s t h e s i s was  marred  for t h i s so-called  be produced i n a v a r i e t y of ways such  as the  i n f u s i o n of l a r g e q u a n t i t i e s of f l u i d  i n the venous s i d e  of the  c i r c u l a t i o n o r i n f l a t i n g " u m b r e l l a s " and  other  7  contrivances  i n the r i g h t a t r i u m . U n f o r t u n a t e l y ,  increases i n  heart r a t e were not c o n s i s t e n t ; i n f a c t b r a d y c a r d i a was observed, (Aviado the evidence  e t . a l . ,1951). Indeed, an examination o f a l l  up t o 195$  than Heymans and  brought no l e s s eminent a u t h o r i t i e s  N e i l , i n t h e i r chapter  c e r t a i n o r i g i n " , to the t h a t any  on " R e f l e x e s  a c c e l e r a t o r y r e f l e x e s " , (Heymans and Despite that p o n t i f i c a l  Neil,  evidence  i n i t i a t e cardio-  l a y i n g t o r e s t of t h e  r e f l e x " , t h e r e i s no disagreement as t o the  p a r t i c u l a r l y concentrated  un-  195$).  ence o f nerve endings i n the- s u b e n d o c a r d i a l  junctions,  of  c o n c l u s i o n t h a t " t h e r e was no  of the r e c e p t o r s so f a r d e s c r i b e d can  "Bainbridge  often  exist-  t i s s u e o f the  atria,  a t the r e g i o n o f the pulmonary v e i n  ( C o l e r i d g e et.al.,1957;  Nonidez, 1937). Although  t h e r e are no r e c e n t experiments s u p p o r t i n g the c o n t e n t i o n l a r g e s c a l e i n f u s i o n s of the B a i n b r i d g e  type  could  these r e c e p t o r s s p e c i f i c a l l y , t h e r e i s evidence  that  stimulate  that tachycardia  can be produced by t h e i r d i s c r e t e s t i m u l a t i o n . Ledsome and Linden  i n 1962  reported that small balloons  i n s e r t e d through the  pulmonary veins so as t o l i e at the j u n c t i o n with the  left  a t r i u m could c o n s i s t e n t l y b r i n g about an i n c r e a s e i n heart of approximately  ?0 beats/minute. Nervous pathways were demon-  s t r a t e d i n the vagus ( a f f e r e n t ) and No  rate  the c a r d i a c  sympathetics.  p e r i p h e r a l changes i n v a s c u l a r r e s i s t e n c e have been r e v e a l e d  to e x p l a i n t h i s i n c r e a s e ,  ( C a r s w e l l , Hainsworth and  Ledsome,  1970). R e c o r d i n g s from a t r i a l r e c e p t o r s have shown them to active with the CMS  each h e a r t beat,  concerning  be  c o n t i n u a l l y r e l a y i n g messages t o  the s t a t e o f a t r i a l f i l l i n g and  performance,  (HakumSki, 1970; The the CMS  Korner, 1971).  present  connections  i n v e s t i g a t i o n was of the a t r i a l  i n c r e a s e i n h e a r t r a t e observed at  to  determine the l o c i  r e c e p t o r s i n v o l v e d i n the  junction i n anaesthetized  c o l l i c u l a r and  s p i n a l l e v e l s was  pathways. F i n a l l y , a study was under v a r i o u s a n a e s t h e t i c s , and dog.  dogs.  used  of c e n t r a l c o n t r o l . V a r i o u s drug regimens  were imposed on the p r e p a r a t i o n s t o exrose  unanaesthetized  clarify  unon i n f l a t i o n o f s m a l l b a l l o o n s  the pulmonary v e i n l e f t a t r i u m  Simple t r u n c a t i o n at the  c a r r i e d out t o  specific  autonomic  made of the l e f t a t r i a l i n the  decerebrate  response  9  METHODS One  h a l f hour p r i o r t o a d m i n i s t r a t i o n o f a n a e s t h e t i c ,  mongrel dogs o f e i t h e r sex, #-16  kg, were given 0.5  mg/kg  morphine s u l f a t e subcutaneously. Under l o c a l a n a e s t h e s i a (Winthrop L a b o r a t o r i e s ; c a r b o c a i n e - 1%), a cannula was i n serted  i n the saphenous v e i n and c ^ - c h l o r a l o s e  Houses: 1% s o l u t i o n i n 0.9$  ( B r i t i s h Drug  sodium c h l o r i d e ) i n f u s e d i n a dose  of 10 ml/kg o f body weight. The l e v e l o f a n a e s t h e s i a was maint a i n e d throughout t h e experiment  by t h e a d d i t i o n o f a p p r o x i -  mately 10/o o f the o r i g i n a l dose every h a l f hour. The dog's oesophageal heated  temperature  was kept constant a t 37°C (+2)  by a  table. Tn those animals not r e c e i v i n g c h l o r a l o s e , no p r e -  a n a e s t h e t i c was g i v e n , but 300  mg o f sodium p e n t o t h a l (Abbott  L a b o r a t o r i e s ; p e n t o t h a l ) was a d m i n i s t e r e d i n t r a v e n o u s l y a t t h e onset t o p e r m i t t h e i n s e r t i o n o f an e n d o t r a c h e a l tube and t h e c o n n e c t i o n o f the tube t o a F l u o t e c 3 (Cyprene  Ltd.)  volatile  a n a e s t h e t i c machine. Those animals r e c e i v i n g halothane (Ayerst L a b o r a t o r i e s : Fluothane) were maintained on a c l o s e d  circuit  of halothane and oxygen a t a f l o w r a t e o f 200-300 ml/minO^ w i t h l^-2/o h a l o t h a n e . No f u r t h e r p e n t o t h a l was r e a u i r e d and a d j u s t ments i n the flow r a t e o r t h e percentage o f halothane could be made throughout  s u r g e r y t o a l l o w an adeouate  and steady s t a t e  of a n a e s t h e s i a . The animals r e c e i v i n g n i t r o u s oxide and p e n t o t h a l , a f t e r t h e i n i t i a l dose of p e n t o t h a l , were kept a n a e s t h e t i z e d  10  w i t h a mixture and  20$  o f #0$  n i t r o u s oxide a t a f l o w r a t e of 2 L/min  oxygen a t 500 ml/min i n a semi-closed  s u r g i c a l purpose, f u s i o n of 30 mg  t h i s was  circuit.  For  augmented by the i n t r a v e n o u s  of p e n t o t h a l every h a l f hour, o r l e s s ,  r e q u i r e d by the i n d i v i d u a l a n i m a l . The  inas  r i g h t femoral a r t e r y  cannulated w i t h a 6 i n c h l e n g t h of t e f l o n t u b i n g ( l mm. and  f e m o r a l a r t e r i a l pressure measured by a Statham  gauge manometer (model p23Gb). Pressure was d i r e c t w r i t i n g Honeywell u l t r a v i o l e t  Mean p r e s s u r e was  113  flat  1505,  amplifier.  {±5%)  t o 35  HZ.  obtained e l e c t r i c a l l y . C a l i b r a t i o n with a  mercury and water p r e s s u r e system was  done p r i o r t o each  iment. Samples o f a r t e r i a l blood were taken a t throughout  strain  r e c o r d e r (Model  o f such a system was  bore)  recorded on a  V i s i c o r d e r ) a f t e r a m p l i f i c a t i o n by an Accudata The f r e o u e n c y response  was  the experiment  and PQQ  a p p r o p r i a t e e l e c t r o d e s and  , PQ  exper-  intervals  ,and pH measured u s i n g  an I n s t r u m e n t a t i o n L a b o r a t o r i e s  blood gas a n a l y s i n g system. A d d i t i o n s o f sodium b i c a r b o n a t e (1 M.)  or adjustments  were used ranges  to attempt  i n the r e s p i r a t o r y pump s t r o k e volume t o keep pH and PQQ  of 7.3 - 7.4, and The animal was  35-40 mm Hg,  w i t h i n the normal  respectively.  then t u r n e d so t h a t the l e f t  exposed and the chest opened a t the 5th i n t e r c o s t a l Harvard  r e s p i r a t o r was  was  space. A  a t t a c h e d t o the t r a c h e a l cannula w i t h a  s t r o k e volume of approximately r a t e o f l#/min. One  side  50 ml./3kg o f body weight a t a  l i t r e per minute o f oxygen was  i n s p i r e d a i r t o ensure adequate oxygenation. opened a r e s i s t a n c e o f 3 cm.  of H 0 9  was  added t o the  Once the c h e s t  was  added to the e x p i r a t o r y  11  o u t l e t . Blood  volume l o s t d u r i n g s u r g e r y was r e p l a c e d by the  i n f u s i o n of dextran blood  (Travenol) t o approximate 10% o f estimated  volume. A f t e r d e f l e c t i n g the l e f t  lungs so as t o expose the  pulmonary v e i n s , small b a l l o o n s , w i t h a c a p a c i t y o f one ml, were i n s e r t e d i n the v e i n s so t h a t when i n f l a t e d they l a y a t the j u n c t i o n o f the v e i n s and the l e f t  a t r i u m . The l e f t  were then t i e d o f f w i t h s t o u t cord t o prevent i n t e r f e r e n c e i n the l e f t animal  lungs  backflow and  a t r i u m . The chest was c l o s e d and the  p l a c e d i n an u p r i g h t p o s i t i o n . For d e c e r e b r a t i o n , t h e head was f i x e d  t a x i c frame  i n a stereo-  (La P r e c i s i o n Cinematographique; P a r i s ) by i n s e r t i n g  the e a r bars through the e x t e r n a l a u d i t o r y meatus. A f t e r c e n t e r ing  the head by moving the ear b a r s , t h e angle o f the head was  determined by l o w e r i n g t h e jaws u n t i l the eyes were i n the same h o r i z o n t a l plane w i t h the e a r b a r s , a f t e r which t h e jaw was immobilized The  by the use o f the f a c e p l a t e and mandibular clamps.  e a r b a r s , which were a t 40 on the frame, were then taken as  the 0 p o i n t o f r e f e r e n c e . A standard  2 l e a d ECG was a t t a c h e d t o the chest and  a f t e r p r e - a m p l i f i c a t i o n (Grass Instruments Model P15 f i e r ) displayed simultaneously  on t h e u l t r a - v i o l e t  r e c o r d e r and  d u a l beam o s c i l l o s c o p e ( T e k t r o n i x type RM 565). Heart a l s o recorded  u s i n g a Honeywell Cardiotachometer  Preampli-  r a t e was  t r i g g e r e d by  the R wave o f t h e ECG. A l l h e a r t r a t e s used i n t h e experimental r e s u l t s were counted from the ECG r e c o r d over p e r i o d s o f a t l e a s t 0.5 min.  1?  Decerebration frequency fastened  was accomplished by the means o f a h i g h  c o a g u l a t i o n system c o n s i s t i n g of nine  electrodes  t o g e t h e r t o form a f o r k - l i k e apparatus t a p e r e d  a t both  ends so as t o f i t the base o f t h e s k u l l . The e l e c t r o d e s were constructed  o f s i z e 23 s t a i n l e s s s t e e l t u b i n g approximately  17  cm l o n g , and coated with a t h i n even l a y e r o f i n s u l a t i o n . To i n s u l a t e t h e e l e c t r o d e s they were s l o w l y lowered i n t o a beaker o f Insul-X  ( I n s u l - X , O s s i n i n g , New Y o r k ) , then baked f o r one  hour a t 70°C. The procedure was repeated which 2-3 mm. a t t h e t i n s were scraped o f c u r r e n t between adjacent  three times,  bare t o permit  after passage  t i p s o n l y . Checks f o r breaks i n t h e  i n s u l a t i o n were made p r i o r t o each experiment w i t h an AVO meter ( H i o k i E l e c t r i c Works - Model AF-105) and r e c o a t i n g s made as necessary. A f t e r exposing approximately  the s k u l l , a s m a l l r e c t a n g u l a r  hole,  40 mm x 10 mm, was made u s i n g a hand d r i l l . The  hole was made i n t h r e e s e c t i o n s , a s m a l l square on e i t h e r s i d e b e i n g removed f i r s t . The b r i d g e o f bone remaining c e n t e r was t h e n c a r e f u l l y d r i l l e d  across the  at each end and l i f t e d  of with  bone c l i p p e r s t o a v o i d damage t o t h e l a r g e s a g i t t a l s i n u s i n the mid l i n e . Bone wax was used t o stop b l e e d i n g from t h e p e r i meter o f t h e r e c t a n g l e . The p o s i t i o n o f t h e hole was determined by p l a c i n g the e l e c t r o d e s i n t h e i r h o l d e r a t 0, p e r p e n d i c u l a r to t h e s u r f a c e o f t h e s k u l l . E x p e r i e n c e the e l e c t r o d e s a t these brainstem  had shown t h a t  lowering  c o o r d i n a t e s would e f f e c t i v e l y sever t h e  a t a m i d - c o l l i c u l a r l e v e l i n dogs o f #-13 kg, w i t h  small heads o f normal s k u l l s t r u c t u r e .  1?  To lower the e l e c t r o d e s , the dura was  removed w i t h  f i n e s c i s s o r s on both s i d e s o f the s a g i t t a l s i n u s . Care had t o be taken when l o w e r i n g the e l e c t r o d e s t h a t they separated over the s i n u s , y e t entered w i t h o u t undue s p l a y i n g . They were then lowered u n t i l the r e s i s t a n c e o f the bone a t the base o f the brainstem was  felt;  u s u a l l y around  C o a g u l a t i o n was  40 mm  from the b r a i n  surface.  then performed w i t h a Wyss C o a g u l a t o r  (Geneva; J . Monti) i n t e n 2 mm  steps, passing approximately  100  m Amps, f o r 15 seconds between the t i p s o f n e i g h b o u r i n g e l e c t r o d e s a t each l e v e l . Decerebrate r i g i d i t y was but muscular  seldom  observed,  e x t e n s i o n , b l a d d e r i n c o n t i n e n c e , and a l a r g e  i n h e a r t r a t e were common o c c u r r e n c e s . S m a l l e r , but  fall  significant  r e d u c t i o n s i n femoral a r t e r i a l b l o o d p r e s s u r e were a l s o f r e q u e n t l y noted. The was  success o f the d e c e r e b r a t i o n procedure  assessed a t the completion o f each experiment  the animal and  removing  the b r a i n stem f e l l  the c e r e b r a l hemispheres.  by b l e e d i n g I f decerebrate,  away i n a c l e a n l i n e between the  w i t h evidence o f b u r n i n g shown by darkened  colliculi,  spots and s o f t e n e d  t i s s u e . A s a g i t t a l s e c t i o n o f such a d e c e r e b r a t i o n i s presented i n F i g u r e 1. The at  s e c t i o n was  prepared from a dog's head removed  the completion o f an experiment  a f t e r b l e e d i n g . The head  was  then f r o z e n , f o r one week, skinned and s e c t i o n e d w i t h a handsaw. In  the 4th s e r i e s , where s p i n a l s e c t i o n s were  performed, the animals were a l s o f i x e d i n the s t e r e o t a x i c frame for  convenience and  i n t h e m i d l i n e and  s t a b i l i t y . The neck muscles were separated r e t r a c t e d . In some animals s i m p l y opening  the dura over the foramen magnum a l l o w e d s u f f i c i e n t a c c e s s to  14  the cord to permit first  safe s e c t i o n . In o t h e r s , the cap o f the  c e r v i c a l v e r t e b r a was  removed w i t h bone c l i p p e r s a f t e r  d r i l l i n g w i t h a hand d r i l l .  A f t e r p a r a l y z i n g the animal w i t h  0.5  mg/kg (IV) s u c c i n y l c h o l i n e (E.R.  Souibb & Sons; S u c o s t r i n  C h l o r i d e ) t r a n s e c t i o n o f the cord was  accomplished by means of  a s p a t u l a and  s c i s s o r s , t a k i n g care to a v o i d the b a s i l a r a r t e r y  on the v e n t r a l s i d e o f the c o r d . G e l foam (Upjohn Co.) i n t o the c a v i t y staunched any l e v e l s were maintained and  severe  bleeding.  packed  Anaesthetic  throughout the p r e p a r a t i o n , t r a n s e c t i o n ,  p o s t s e c t i o n p e r i o d s by the i n f u s i o n of 10% o f the  dose of c h l o r a l o s e every  original  \ hour.  In a l l s e r i e s where drugs were used they were administered  i n t r a v e n o u s l y through the  saphenous v e i n  cannula  f o l l o w e d by a 5 ml wash o f s a l i n e . An e x c e p t i o n was  s e r i e s 5,  where the f e m o r a l  the same.  P r o p r a n o l o l , 0.5  v e i n was  used, the wash remaining  mg/kg (Ayerst L a b o r a t o r i e s ; Ay-64043) was  t o b l o c k sympathetic ^ r e c e p t o r s and was if  i t was  s u c c e s s f u l i n b l o c k i n g 90$  ft s t i m u l a t i o n by 0.5*/ Inc.; I s o p r e n a l i n e s a l t and  g/kg  judged t o have done so  or more o f the response to  of I s o p r e n a l i n e  s u l f a t e ) . Atropine  Sons, Ltd.) used i n s e r i e s I I , was  dosage.  used  (K.&  K.  Laboratories  s u l f a t e (E.R.Squibb  g i v e n i n an 0.4  mg/kg  i  15  scale  i  1 lcm  Figure 1.  S a g i t t a l section of a dog's brain made decerebrate by the electrocoagulation method.  A midsaggital section of a dog's brain approximately 1.2 x enlarged. The l e s i o n i s the darkened area just r o s t r a l to the cerebellum and destroying the c o l l i c u l a r region. In the actual specimen the l e s i o n extended 0.5 cm i n width.  16  EXPERIMENTAL PROTOCOL In t h e f i r s t s e r i e s o f experiments,  after  general  surgery and opening o f the s k u l l and dura had been  completed,  the animal was allowed t o r e c o v e r f o r a t l e a s t 10 minutes, o r u n t i l a steady s t a t e had been a c h i e v e d , b e f o r e b e g i n n i n g the p e r i o d o f e x p e r i m e n t a t i o n . T e s t i n g f o r the presence  o f the l e f t  a t r i a l r e f l e x was always done i n the same manner. F o l l o w i n g a c o n t r o l p e r i o d , t h e pulmonary b a l l o o n s were i n f l a t e d minutes,  f o r two  a f t e r which a p e r i o d of i n f l a t i o n was r e c o r d e d , and  the b a l l o o n s d e f l a t e d . A f t e r a two minute r e c o v e r y p e r i o d another r e c o r d was taken, and changes i n heart r a t e and blood p r e s s u r e c a l c u l a t e d from mean v a l u e s b e f o r e and a f t e r b a l l o o n i n f l a t i o n . When t h r e e such t r i a l s had been completed, t h e animal was made d e c e r e b r a t e u s i n g t h e h i g h frequency e l e c t r o d e system and, a f t e r e o u i l i b r a t i o n t h e r e f l e x t e s t i n g  procedure  repeated. To study t h e nature o f the r e f l e x , v a r i o u s drug regimens were a p p l i e d and t h e i r e f f e c t s on the r e f l e x noted. I n s e r i e s I , t h i s c o n s i s t e d o f f i r s t b l o c k i n g the response r e c e p t o r s t i m u l a t i o n by i s o p r e n a l i n e (0.5 pranolol  g/kg IV) w i t h p r o -  (0.5 mg/kg I V ) . The b a l l o o n s were then i n f l a t e d , and  the response  recorded as b e f o r e . At the completion o f each t e s t  p e r i o d a repeat dose o f i s o p r e n a l i n e (0.5 to  t o ft  a s c e r t a i n t h e degree o f $  blockage.  g/kg IV) was given  I f necessary a f u r t h e r  dose o f p r o p r a n o l o l was a d m i n i s t e r e d . A f t e r 3 such c e r v i c a l vagotomy was performed  trials  and the r e f l e x t e s t e d once more.  17  In s e r i e s I I , g e n e r a l procedures were the same as i n s e r i e s I but i n place o f p r o p r a n o l o l , a t r o p i n e  (0.4 mg/kg IV)  was g i v e n . A f t e r t e s t i n g the r e f l e x three times,  i f any  i n c r e a s e i n h e a r t r a t e remained upon i n f l a t i o n o f the b a l l o o n s , p r o p r a n o l o l was given and the t e s t The  third  repeated.  group of experiments c o n s i s t e d o f i n i t i a -  t i n g a ^ r e c e p t o r blockade p r i o r t o d e c e r e b r a t i o n , c o n t r o l r e f l e x had been r e c o r d e d .  a f t e r the  The same i s o o r e n a l i n e -  p r o p r a n o l o l check was used as p r e v i o u s l y w i t h f r e q u e n t  admini-  s t r a t i o n o f i s o p r e n a l i n e t o i n s u r e adequate b l o c k i n g . S i n c e the p r o p r a n o l o l d i d not wear o f as evenly o r r a p i d l y as d e s i r e d , f u r t h e r doses o f p r o p r a n o l o l were g i v e n as r e q u i r e d t o m a i n t a i n the ^ blockade a f t e r d e c e r e b r a t i o n . any  increase  After 3 further t r i a l s , i f  i n h e a r t r a t e remained upon i n f l a t i o n o f t h e  b a l l o o n s , c e r v i c a l vagotomy was performed and the b a l l o o n s r e inflated. Where halothane or n i t r o u s oxide  and p e n t o t h a l were  used as a n a e s t h e t i c s , t h e procedures were simply I with  the removal o f the v o l a t i l e a n a e s t h e t i c  those o f s e r i e s  and t h e d i s -  continuence o f p e n t o t h a l upon s u c c e s s f u l completion o f the decerebration. anaesthetic  At l e a s t 10 min. - 1 hour were n e c e s s a r y f o r the  t o be blown o f f and i t s e f f e c t s reduced. A f t e r  t e s t i n g t h e r e f l e x , 1 hour w a i t s were i n t e r j e c t e d t o attempt t o augment f u l l r e c o v e r y  from a n a e s t h e s i a .  The same procedure o f  (5> blockade and c e r v i c a l vagotomy was then c a r r i e d o u t . The  group o f experiments i n c l u d e d  t r a n s e c t i o n , followed  i n s e r i e s 4, s p i n a l  a somewhat d i f f e r e n t course.  After  IS  s u r g e r y was The  complete, three  s n i n a l cord was  dura over the  c o n t r o l i n f l a t i o n s were performed.  then prepared as d e s c r i b e d  foramen magnum and  first  by opening  the  c e r v i c a l vertebra.  Because t h i s o f t e n a l t e r e d the p h y s i o l o g i c a l s t a t e as r e f l e c t e d by heart was  r a t e and  femoral a r t e r i a l blood p r e s s u r e ,  again t e s t e d a f t e r a new  steady s t a t e had  A f t e r t r a n s e c t i o n o f the c o r d ,  been  the  reflex  established.  i n f l a t i o n o f the b a l l o o n s  was  done i n s e r i e s as r a p i d l y as p o s s i b l e i n an attempt to remain w i t h i n the p e r i o d  i n which the animal e x h i b i t e d a steady  w i t h a degree o f v a g a l  t o n e . C e r v i c a l vagotomy was  a s s e s s the degree o f vagal inflated.  tone r e m a i n i n g and  state  done t o  the b a l l o o n s  again  Series Number Anaesthetic Number o f dogs Protocol  I  II  III  Chloralose  Chloralose  Chloralose  6  6  7  IV  V  C h l o r a l o s e Halothane  7  VI  N 0 and 2  Pentothal  4  7  Control  Control  Decerebration Decerebration Decerebration S p i n a l Section  Decerebration  Decerebration  Decerebrate control  No a n a e s t h e t i c No a n a e s t h e t i c  Control  Blockade Vagotomy  Control  Decerebrate control  Control § Blockade  £ Blockade  Spinal Control  Decerebrate control  Decerebrate control  Atropine  4  $  Vagotomy  Vagotomy  Atropine  Decerebrate control  Vagotomy  TABLE I .  Control  Vagotomy  EXPERIMENTAL PROTOCOL  Blockade  Blockade  Vagotomy  RESULTS  The results of a l l s i x series of experiments are summarized  separately below i n tables  II - VII. A  discussion  the significance of these r e s u l t s i n terms of the r e f l e x response and i t s nervous pathways follows.  21  CONTROL Number o f dogs Number o f trials HR Mean Standard error of the mean  10  AFTER DECEREBRATION  AFTER PROPRANOLOL  AFTER VAGOTOMY  6  6  6  6  ia  is  18-  17  BP 0.1  1.48 0.96  HR  BP  BP  HR  HR  BP  15  0.3  10  0.6  -0.3 -1.5  1.60  0.70  1.45  0.37  0.76 0.94  A) Heart r a t e (beats/min.) and blood p r e s s u r e (mm.Hg.) changes o c c u r r i n g a t d i s t e n s i o n o f the pulmonary v e i n l e f t a t r i a l j u n c t i o n f o r 2 minutes.  CONTROL VS DECEREBRATE HR Standard e r r o r of d i f f e r e n c e T Level of Significance  BP  DECEREBRATE VS J> BLOCKED  BLOCKED VS VAGOTOMY  HR  BP  HR  BP  10.3  2.2  3.9  0.6  4.4  0.2  1.605  0.349  1.783  0.195  NS  NS  NS  NS  B) R e s u l t s o f T t e s t f o r p a i r e d s t u d e n t i z e d range. NS = not s i g n i f i c a n t .  5.168 2.594 2p^0.01 2p<i0.05  data u s i n g a  TABLE I I . SUMMARY OF RESULTS OF SERIES  I.  22  CONTROL Number o f dogs Number o f trials  Mean Standard error o f the mean  AFTER DECEREBRATION  AFTER ATROPINE  AFTER PROPRANOLOL  7  7  7  4  21  21  21  10  HR  BP  HR  BP  HR  BP  HR  BP  27  -2.0  32  0.5  2.5  -0.5  -0.4  -0.7  3.57  0.79  0.71 0.65  1.00  1.05  2.92 1.12  A) Heart r a t e (beats/min.) and blood p r e s s u r e (mm.Hg.) changes a t d i s t e n s i o n o f the pulmonary v e i n l e f t a t r i a l j u n c t i o n f o r 2 minutes.  Standard e r r o r of d i f f e r e n c e T Level of significance  CONTROL VS DECEREBRATE  DECEREBRATE VS ATROPINE  ATROPINE VS $ BLOCKED  HR  BP  HR  BP  HR  BP  4.1  2.4  25.3  1.0  5.1  0.4  0.660  1.572  2.924  0.571  NS  NS  4.633 0.624 2p<0.01 NS  2p<0.10  B) R e s u l t s o f T t e s t f o r p a i r e d data s t u d e n t i z e d range. NS = not s i g n i f i c a n t .  TABLE I I I .  NS  using  SUMMARY OF RESULTS OF SERIES I I .  CONTROL Number o f dogs Number o f trials  6  ( ! > BLOCKADE + DECEREBRATION  6 13  19 HR  Mean Standard error of the mean  AFTER b BLOCKADE  BP  AFTER ATROPINE  6  4  20  12  HR  BP  HR-  BP  HR  BP  0.7  3  0.4  -3  -1.9  1.25  0.57  3.33 0.74  23  -2.2  6  .3.49  0.52  1.27 0.63  A) Heart r a t e (beats/min.) and blood p r e s s u r e (mm.Hg.) changes o c c u r r i n g a t d i s t e n s i o n of the pulmonary v e i n l e f t a t r i a l j u n c t i o n f o r 2 minutes.  Standard e r r o r of d i f f e r e n c e T Level o f significance  CONTROL VS 4 BLOCKED  0 BLOCKED VS DECEREBRATE  DECEREBRATE VS ATROPINE  HR  BP  HR  BP  HR  BP  13  -2.9  2  0  19  3.5  1.795  0.042  3.321  7.269  3.511  3.655  2p<0.0 5 2p<0£5 NS  NS  2p^0.05 2p<0.01  F) R e s u l t s o f T t e s t f o r p a i r e d data u s i n g a s t u d e n t i z e d range. NS = not s i g n i f i c a n t .  TABLE IV.  SUMMARY OF RESULTS OF SERIES I I I .  ?4  CONTROL  AFTER SPINAL SECTION  7  7  7  29  30  14  Number o f dogs Number o f t r i a l s  Mean Standard e r r o r o f the mean  AFTER VAGOTOMY  HR  FTP  HR  BP  HR  12  -0.2  6  -1.8  -0.6 -4.8  1.27  1.00  0.48 1.82  '1.73  0.79  BP  A) Heart r a t e (beats/min.) and blood p r e s s u r e (mm.Hg.) changes a t d i s t e n s i o n o f the pulmonary v e i n l e f t a t r i a l j u n c t i o n f o r two minutes.  CONTROL VS SPINAL SECTION  SPINAL SECTION VS VAGOTOMY  HR  BP  HR  BP  Standard e r r o r o f difference  7.0  0.8  6.3  2.5  T  1.897  0.663  3.270  2.457  Level o f s i g n i f i c a n c e  NS  NS  2p^0.05  2p<0.05  B) R e s u l t s o f T t e s t s f o r p a i r e d data u s i n g a s t u d e n t i z e d range. NS = not s i g n i f i c a n t .  TABLE V.  SUMMARY OF RESULTS OF SERIES IV.  NO ANAESTHETIC DECEREBRATE  CONTROL Number o f dogs Number o f t r i a l s  4 13 HR  X SEM  I HOUR LATER  4 13 BP  4 -2.3 0.93 1.37  AFTER & BLOCKADE  AFTER VAGOTOMY  4 10  4 9  4 9  HR  BP  HR  BP  HR  BP  HR  5 1.34  -2.4 1.13  7 1.02  0.4 1.29  3.5 1.22  1.3 1.57  0 -3.9 0.46 2.37  A) Heart r a t e (beats/min.) and blood p r e s s u r e (mm.Hg.) changes at d i s t e n s i o n o f t h e pulmonary v e i n l e f t a t r i a l j u n c t i o n f o r two minutes. A f t e r the c o n t r o l p e r i o d and d e c e r e b r a t i o n , no f u r t h e r a n a e s t h e t i c was used i n these dogs.  Standard e r r o r o f difference T Level o f s i g n i f i c a n c e  CONTROL VS DECEREBRATE  DECEREBRATE VS I HOUR LATER  DECEREBRATE VS ^ BLOCKED  DECEREBRATE VS VAGOTOMY  HR  BP  HR  BP  HR  BP  HR  1.9 0.363 NS  0.9 0.799 NS  1.4 0.341 NS  1.9 2.509 NS  3.7 1.496 NS  2.5 1.393 NS  6.9 2.3 3.749 1.037 2p<0.10 NS  B) R e s u l t s of T t e s t f o r p a i r e d data u s i n g a s t u d e n t i z e d NS = not s i g n i f i c a n t .  TABLE V I .  SUMMARY OF RESULTS OF SERIES V.  BP  range.  BP  NO ANAESTHETIC DECEREBRATE  CONTROL Number o f dogs Number o f t r i a l s  X SEM  AFTER p BLOCKADE  AFTER VAGOTOMY  7 14  5 15  6 18  7 22  7 21 HR  I HOUR LATER  BP  2 -3.8 0.65 1.08  HR  BP  HR  BP  HR  9 1.02  -1.3 0.83  8.5 0.98  -1.3 1.18  3 -3.0 1.68 1.74  BP  HR  0 -2.2 0.22 0.64  A) Heart r a t e (beats/min.) and blood pressure (mm.Hg.) changes at d i s t e n s i o n o f t h e pulmonary v e i n l e f t a t r i a l j u n c t i o n f o r 2 minutes. A f t e r the c o n t r o l p e r i o d and d e c e r e b r a t i o n , no f u r t h e r a n a e s t h e t i c was used i n these dogs.  Standard e r r o r o f difference T Level of significance  CONTROL VS DECEREBRATE  DECEREBRATE VS I HOUR LATER  DECEREBRATE VS 4 BLOCKED  DECEREBRATE VS VAGOTOMY  HR  HR  BP  HR  HR  0.3 0.308  0.2 0.260  NS  NS  BP  6.8 2.4 5 . 0 1 9 1.412 2 p ^ 0 . 0 1 NS  7.5 3.206 2T><0.05  BP 2.4 1.943 NS  9.5 6.055 2t><0.01  B) R e s u l t s o f T t e s t s f o r p a i r e d data u s i n g t h e s t u d e n t i z e d NS = not s i g n i f i c a n t .  TABLE V I I .  SUMMARY OF RESULTS OF SERIES VI  BP  BP 0.2 0.099 NS  range.  27  I _Brrects_or_inflatinig; the b a l l o o n s a t t h e pulmonary v e i n i  lert_atrial_junction I n f l a t i n g t h e pulmonary v e i n b a l l o o n s w i t h 0.5 (3-11 Kg.)  - 1.0 ml s a l i n e  a significant  (12-13 Kg.) f o r two minute p e r i o d s produced  i n c r e a s e i n mean heart r a t e without a s i g n i f i c a n t  change i n femoral  a r t e r i a l blood p r e s s u r e .  dogs under c h l o r a l o s e a n a e s t h e s i a  In 94 t r i a l s i n 23  the mean i n c r e a s e i n h e a r t  r a t e was 17 beats/min.(SEM + 1.4), w i t h a mean blood  pressure  change o f -0.9 mmHg(SEM + . 5 ) . T h i s i n c r e a s e i n h e a r t r a t e was s i g n i f i c a n t a t p 0.001 u s i n g a T t e s t f o r p a i r e d data w i t h the studentized  range. Because o f the r a o i d onset  o f the increase i n  heart r a t e , and t h e f a c t t h a t i t c o u l d be p a r t i a l l y o r w h o l l y blocked  by v a r i o u s combinations o f sympathetic and parasympathe-  t i c b l o c k i n g agents, i t was presumed to be o f r e f l e x o r i g i n . The i n c r e a s e i n heart r a t e was s i m i l a r t o t h a t r e p o r t e d by Ledsome and  Linden  (1964) and there was no doubt t h a t d i s t e n s i o n o f the  pulmonary v e i n - a t r i a l j u n c t i o n s i n the c o n t r o l s t a t e d i d indeed cause an i n c r e a s e i n h e a r t r a t e .  Because i t i s o f importance i n a s s e s s i n g the r e l a t i v e magnitude o f any change i n heart  r a t e o r blood  p r e s s u r e , we  should d i s c u s s the e f f e c t s o f d e c e r e b r a t i o n on c o n t r o l values o f these  parameters, b e f o r e  decerebration  considering i n d e t a i l the influence of  on t h e l e f t a t r i a l r e f l e x d e s c r i b e d above. In the  31 dogs made d e c e r e b r a t e  by the e l e c t r o c o a g u l a t i o n method, mean  h e a r t r a t e f e l l from 142 beats/min. (SEM + 7.5, Range 34-223) t o  123 beats/min. (SEM + 9.4, Range 43-240). a f t e r d e c e r e b r a t i o n .  ?8  Blood  p r e s s u r e f o l l o w e d a s i m i l a r p a t t e r n , d e c r e a s i n g from  c o n t r o l v a l u e s o f 120.2 106.9  mmHg (SEM  mmHg (SEM ± 3 . 6 ,  range 80-174) t o  + 2.9; range 72-113). R e f e r to t a b l e VIII.These  changes o c c u r r e d immediately  upon s e c t i o n o f the brainstem a t  the m i d - c o l l i c u l a r l e v e l and were i n general s u s t a i n e d d u r i n g the 4-6 hours o f experimentation  a f t e r " r e c o v e r y " from  decere-  b r a t i o n . Even i n dogs from S e r i e s I I I , which had been t r e a t e d p r i o r to d e c e r e b r a t i o n with p r o p r a n o l o l (0.5 mg/Kg), changes of  the same magnitude were observed,  i n d i c a t i n g t h a t much o f  the change i n h e a r t r a t e was due t o a change i n v a g a l  tone.  When the pulmonary v e i n b a l l o o n s were i n f l a t e d a t these new p o s t - d e c e r e b r a t i o n c o n t r o l l e v e l s , the mean i n c r e a s e i n h e a r t r a t e was s l i g h t l y augmented w h i l e blood changes were n e g l i g i b l e . In 39 t r i a l s and  pressure  i n 13 dogs, from S e r i e s I  I I , the r e f l e x i n c r e a s e i n h e a r t r a t e d u r i n g b a l l o o n  t i o n rose, from a mean o f 19 beats/min (SEM + 2.2) b r a t i o n t o 24 beats/min  (SEM + 2.5)  before  mmHg (SEM  +0.6)  decere-  a f t e r d e c e r e b r a t i o n . Blood  p r e s s u r e changed from a c o n t r o l mean o f -1 mmHg (SEM 0.4  infla-  +0.3)  to  f o l l o w i n g d e c e r e b r a t i o n . However, when  compared s t a t i s t i c a l l y  with a T t e s t f o r p a i r e d d a t a , there was  no s i g n i f i c a n t d i f f e r e n c e between the r e f l e x changes i n h e a r t r a t e and blood p r e s s u r e b e f o r e and a f t e r d e c e r e b r a t i o n i n these dog^i. An example o f the r e c o r d i n a r e p r e s e n t a t i v e experiment is  shown i n f i g u r e s 2 and 3. I t was concluded  from these  t h a t the c e n t r a l c o n t r o l mechanism f o r the l e f t a t r i a l was  data  reflex  not r o s t r a l t o the s u p e r i o r c o l l i c u l u s as i t s t i l l e x i s t e d  i n the d e c e r e b r a t e  a n i m a l . To determine i f the  characteristics  ?9  CONTROL HEART RATE  PROPRANOLOL BEFORE > DECEREBRATIONI  CHLORALOSE  HALOTHANE  NITROUS OXIDE AND PENTOTHAL  I  SEM RANGE  TABLE V I I I .  BLOOD PRESSURE  AFTER DECEREBRATION HEART RATE  BLOOD PRESSURE  120 123 110 123 124 132  144 74 72 30 160 54  102 112 112 110 116 126  114 190 130 113 156 111 114 193 117 130 130 96 163 103  143 106 126 146 130 124 152 140 133 106 112 122 103  76 119 150 30 114 114 64 193 90 210 152 170 106 96  113 72 90 116 116 112 116 116 100 91 100 112 102 90  116 126 96 102  100 103 90 116  43 34 73 36  106 104 126 105  162 150 210 225 130 144 136  100 132 100 174  177 90 204 240 163 120 163  142 7.5 34-223  120.2 3.6 30-174  144 57  92  54 130 35  92  126  30 114  123  9.4 43-24C  72  116  104 156 100 50 114 106. 9 2.9 72-il5  CHANGES IN HEART RATE (beats/min.) AND BLOOD PRESSURE (mm.Hg.) AT DECEREBRATION.  160 r -  Heart Rate Beats/min. 100  I40r—  Femoral Arterial Blood Pressure (mm.Hg.) >°  IOOI—  'Figure 2.  mum  A t y p i c a l r e c o r d o f t h e response t o d i s t e n s i o n o f the pulmonary v e i n l e f t a t r i a l j u n c t i o n i n a dog a n a e s t h e t i z e d w i t h c h l o r a l o s e . In sequence from l e f t t o r i g h t are shown s e c t i o n s o f a c o n t r o l p e r i o d , d u r i n g . i n f l a t i o n o f the pulmonary b a l l o o n s , and two minutes a f t e r d e f l a t i o n . Each v e r t i c a l time l i n e r e p r e s e n t s t e n seconds.  31  E C G  Heart  Rate  Beats/min.  Femoral Blood (mm.  Arterial Pressure Hg.)  •Figure 3.  A . t y p i c a l r e c o r d of the response to d i s t e n s i o n o f the pulmonary v e i n l e f t a t r i a l j u n c t i o n i n a d e c e r e b r a t e dog a n a e s t h e t i z e d w i t h c h l o r a l o s e . From l e f t t o r i g h t are shown s e c t i o n s o f a control period, during i n f l a t i o n of the pulmonary b a l l o o n s , and two minutes a f t e r d e f l a t i o n . Each v e r t i c a l time l i n e r e p r e s e n t s t e n seconds. T h i s r e c o r d v/as taken from t h e same dog as i n F i g u r e 2.  3?  o f the r e f l e x had been a l t e r e d by the removal o f h i g h e r a c l o s e r study o f the nature  o f the r e f l e x i n the  s t a t e was undertaken u s i n g drugs, vagotomy and III.  centers,  decerebrate  spinal section.  The e f f e c t s of p r o p r a n o l o l I t was noted i n S e r i e s I , t h a t the ^ sympathetic  b l o c k i n g agent, p r o p r a n o l o l  (0.5 mg/Kg) d i d not a b o l i s h the  l e f t a t r i a l r e f l e x , and i n f a c t d i d not even s i g n i f i c a n t l y a l t e r the magnitude o f the h e a r t r a t e i n c r e a s e . In 1$ t r i a l s i n 6 decerebrate  dogs, the mean i n c r e a s e i n h e a r t r a t e d u r i n g  b a l l o o n i n f l a t i o n was 15 beats/min. (SEM  + 1.6).  After  blockade w i t h p r o p r a n o l o l , the r e f l e x i n c r e a s e i n h e a r t had  a m e a n v a l u e of 10 beats/min. (SEM  significantly different p a i r e d d a t a . Blood statistically  from the  pressure  rate  + 1.4), which was not  c o n t r o l value i n a T t e s t f o r  changes were n e g l i g i b l e and not  d i f f e r e n t . T h i s f i n d i n g was i n c o n f l i c t w i t h  o f Ledsome and Linden  that  (1969) who had shown t h a t the same dose  of p r o p r a n o l o l a d m i n i s t e r e d  to chloralose anaesthetized  dogs  could s i g n i f i c a n t l y reduce the heart r a t e i n c r e a s e a s s o c i a t e d with balloon  inflation.  To determine whether we were indeed  o b s e r v i n g an  a l t e r e d r e f l e x , a study was made i n which p r o p r a n o l o l was g i v e n both b e f o r e and a f t e r d e c e r e b r a t i o n  (see Methods - S e r i e s I I I ) .  In t h i s p a r t i c u l a r group o f 6 dogs we observed very marked i n crease  rate during c o n t r o l balloon i n f l a t i o n ,  ranging  from 7-53 beats/min. w i t h a mean o f ?3 beats/min. (SEM  + 3.5).  Blood  i n heart  pressure  f e l l an average o f  mmHg (SEM  + 0.8). The  i n f u s i o n o f 0.5 mm/Kg. o f p r o p r a n o l o l a b o l i s h e d most o f the  33  i n c r e a s e i n h e a r t r a t e , as w e l l as a l t e r i n g b l o o d  pressure  changes. A f t e r p r o n r a n o l o l , the mean i n c r e a s e i n h e a r t r a t e was 6 beats/min.  (SEM + 1.3), w h i l e blood p r e s s u r e i n c r e a s e d 0.7  mrnHg (SEM + 0.6). Both v a l u e s were s i g n i f i c a n t l y d i f f e r e n t  from  c o n t r o l i n f l a t i o n v a l u e s i n a T t e s t f o r p a i r e d data at2p^.0.05. D e c e r e b r a t i o n a t t h i s p o i n t , w i t h t h e l e v e l o f $ b l o c k i n g kept constant by a d d i t i o n a l doses o f p r o p r a n o l o l , d i d not s i g n i f i c a n t l y a l t e r t h i s response. Mean h e a r t r a t e i n c r e a s e was 3 beats/min.(SEM + 1.?); blood p r e s s u r e i n c r e a s e was 0.4 mrnHg (SEM  + 0.6). A t y p i c a l  left  atrial  r e f l e x blocked with  propra-  n o l o l both b e f o r e and a f t e r d e c e r e b r a t i o n i s shown i n f i g u r e s 4, 5 and 6. I t might be argued a t t h i s p o i n t t h a t the i n c r e a s e s i n h e a r t r a t e observed  at balloon i n f l a t i o n  after propranolol,  were i n f a c t , a r e f l e c t i o n o f an incomplete of  ^ b l o c k a d e . The use  i s o p r e n a l i n e i n t h i s case, can be used as an index o f the  e f f e c t i v e n e s s o f the b l o c k a d e . I f i s o p r e n a l i n e i s a d m i n i s t e r e d p r i o r t o (} blockade, l a r g e changes i n h e a r t r a t e and blood p r e s s u r e can be  observed.  R e f e r r i n g t o t a b l e IX, i n 20 dogs h e a r t r a t e i n c r e a s e d an a v e r age  o f 90 beats/min.  p r e s s u r e decreased  (SEM + 11.7, range 27-136) as b l o o d  -41.6 mrnHg. (SEM + 3 . 9 , range -10 t o - 7 2 ) 30  seconds a f t e r t h e i n f u s i o n o f i s o p r e n a l i n e . A f t e r p r o p r a n o l o l however, changes i n both parameters were e i t h e r a b o l i s h e d o r n e g l i g i b l e . F i g u r e s 7 and 3 i l l u s t r a t e a t v p i c a l response t o i s o p r e n a l i n e b e f o r e and a f t e r (i blockade w i t h p r o p r a n o l o l . S i n c e the same dose o f i s o p r e n a l i n e c o u l d be a d m i n i s t e r e d a t any time  34  throughout the experiment, any e a s i l y be d e t e c t e d  by an  increase i n p a c t i v i t y  increased  could  response to i s o p r e n a l i n e .  F u r t h e r doses o f p r o p r a n o l o l c o u l d then be g i v e n t o ensure complete (J b l o c k i n g . I t i s i n t e r e s t i n g t h a t w h i l e the f i r s t s t r a t e d t h a t p r o p r a n o l o l was  s e r i e s demon-  a b l e t o a b o l i s h o n l y about 1 / 3  the t o t a l i n c r e a s e i n heart r a t e d u r i n g b a l l o o n i n f l a t i o n , second s e r i e s showed t h a t p r o p r a n o l o l was 2/3  o f the  of the  a b l e t o a b o l i s h over  i n c r e a s e i n heart r a t e . However, the amount o f  r e f l e x remaining  i n both cases,  10 beats/min. i n S e r i e s I  versus  7 beats/min. i n S e r i e s I I , i s not v e r y d i f f e r e n t . The d i f f e r e n c e may  t h e r e f o r e a r i s e i n the magnitude of the  self;  control reflex i t -  14 beats/min. i n S e r i e s I as opposed t o 2 3 beats/min. i n  Series I I . This i s suggestive r o l e s o f the  sympathetic and  the magnitude o f the under d i f f e r e n t  o f the v a r i a t i o n i n the v a g a l components i n  i n heart r a t e remaining the i n f u s i o n o f 0.4  determining  left a t r i a l reflex in different  circumstances.  relative  animals  In a l l cases t e s t e d , the  increase  a f t e r p r o p r a n o l o l could be a b o l i s h e d  by  mg/kg a t r o p i n e .  IV._The e f f e c t s _ o f _ a t r o p i n e To f u r t h e r i n v e s t i g a t e the c o n t r i b u t i o n o f parasympat h e t i c and  sympathetic components t o the l e f t a t r i a l r e f l e x , t h e  o p p o s i t e procedure to t h a t d i s c u s s e d b l o c k i n g the m u s c a r i n i c f i r s t with atropine preceptors  above was  followed v i z .  p o s t g a n g l i o n i c parasympathetic  (0.4 mg/Kg I V ) , then b l o c k i n g  with propranolol,  activity  sympathetic  (Methods - S e r i e s I I ) . R e s u l t s  from t h i s procedure are given i n Table H I .  There i s no doubt  35  Heart  Rate  Beats /min.  ECG  Femoral Blood  Arterial Pressure  (mm. Hg.)  F i g u r e l+* Response t o pulmonary v e i n l e f t a t r i a l d i s t e n s i o n i n a dog a n a e s t h e t i z e d w i t h c h l o r a l o s e . In sequence from l e f t t o r i g h t are shown s e c t i o n s o f a c o n t r o l p e r i o d , d u r i n g i n f l a t i o n o f the nulmonary b a l l o o n s , and two minutes a f t e r d e f l a t i o n . V e r t i c a l time l i n e s r e p r e s e n t 10 seconds.  36  F i g u r e 5.  T y p i c a l response t o pulmonary v e i n l e f t a t r i a l distension following blockade w i t h p r o p r a n o l o l (0.5 mg/Kg I V . ) . From l e f t t o r i g h t are shown s e c t i o n s o f a c o n t r o l p e r i o d , i n f l a t i o n o f the pulmonary b a l l o o n s , and two minutes a f t e r d e f l a t i o n . Each v e r t i c a l time l i n e r e p r e s e n t s 10 seconds. T h i s r e c o r d was taken from the same dog as t h a t i n F i g u r e 4.  37  F i g u r e 6.  T y p i c a l response t o pulmonary v e i n l e f t a t r i a l d i s t e n s i o n i n a d e c e r e b r a t e dog f o l l o w i n g $ blockade w i t h p r o p r a n o l o l (0.5 mg./Kg.IV.). T h i s r e c o r d was taken from the same dog as F i g u r e s L and 5. From l e f t t o r i g h t a r e shown s e c t i o n s o f a c o n t r o l p e r i o d , d u r i n g i n f l a t i o n o f the pulmonary b a l l o o n s , and two minutes a f t e r d e f l a t i o n . V e r t i c a l time l i n e s r e p r e s e n t 10 seconds.  33  ECG Heart Rate Beats/min.  Femoral Arterial Blood Pressure (mm. Hg.)  Figure  1 2 0  100  7.  The e f f e c t o f $ blockade on the response to i s o p r e n a l i n e . In s e c t i o n 1, the marker i n d i c a t e s the i n f u s i o n o f 0.5 *fg/Kg IV. of i s o p r e n a l i n e . V e r t i c a l time l i n e s r e p r e s e n t 10 seconds. S e c t i o n 2 o f t h e r e c o r d i l l u s t r a t e s the e f f e c t o f t h e same dose o f i s o p r e n a l i n e i n f u s e d a p p r o x i m a t e l y two minutes a f t e r blockade w i t h p r o p r a n o l o l (0.5 mg/Kg IV.) i n the same dog.  39  F i g u r e #.  A r e c o r d o f the response to d i s t e n s i o n o f the pulmonary v e i n l e f t a t r i a l j u n c t i o n following blockade w i t h p r o p r a n o l o l (0.5 mg./Kg.IV.). T h i s r e c o r d was taken from the same dog as i n F i g u r e 7, immediately f o l l o w i n g s e c t i o n 2. From l e f t t o r i g h t a r e shown s e c t i o n s o f a c o n t r o l p e r i o d , d u r i n g i n f l a t i o n o f the pulmonary b a l l o o n s , and two minutes a f t e r d e f l a t i o n , v e r t i c a l time l i n e s r e p r e s e n t 10 seconds.  CONTROL HEART RATE +150 +72 +99 +114 +33 +24 +46 +30 +136 +120 +173 +135 +156 +48 +62 +111 +108 +66 +27 +36  X SEM RANGE TABLE IX.  89.300 11.684 24-136  BLOOD PRESSURE -32 -72 -32 -26 -46 -24 -56 -24 -60 -60 -62 -10 -20 -44 -60 -48 -32 -24 -46 -54  -41.600 3.878 (-10)-72  AFTER BLOCK WITH PROPRANOLOL HEART RATE  BLOOD PRESSURE  +12 0 +6 -2 0 -6 0 0 +16 +6 -9 +5 -1 0 0 +3 +6 +6 0 0  0 +2 +2 -2 0 -4 +4 0 -6 0 -4 0 +2 -2 -16 -4 -4 0 0 +6  2.100 1.263 (-9)-16  -1.300 1.013 +6-(-16)  CHANGES IN HEART RATE AND BLOOD PRESSURE AFTER 4 RECEPTOR EXCITATION BY ISOPRENALINE.  Heart r a t e and blood p r e s s u r e a r e i n beats/min. and mm.Hg. r e s p e c t i v e l y , and r e p r e s e n t changes i n h e a r t r a t e and blood p r e s s u r e r e c o r d e d 3 0 seconds a f t e r the i n f u s i o n i n the f e m o r a l v e i n o f 0 . 5 ^ g / K g i s o o r e n a l i n e . The changes a f t e r $ blockade were recorded s i m i l a r l y , approximately 2 - 5 minutes a f t e r i n f u s i o n o f 0 . 5 mg/Kg o f p r o p r a n o l o l .  41  that a t r o p i n e was a b l e t o v i r t u a l l y a b o l i s h the r e f l e x . However, i f we take  i n t o c o n s i d e r a t i o n the o v e r a l l e f f e c t s o f a t r o p i n e ,  as r e f l e c t e d  i n changes i n c o n t r o l v a l u e s o f heart r a t e and  blood p r e s s u r e , completely  i t i s obvious t h a t we are d e a l i n g w i t h a  new p h y s i o l o g i c a l s t a t e . In seven d e c e r e b r a t e  dogs,  heart r a t e i n c r e a s e d from a mean c o n t r o l value o f 172 beats/min. (SEM  + 10, range 133-222) to 214 beats/min. (SEM + 12, range  156-246) with the a d m i n i s t r a t i o n o f a t r o p i n e . Blood  pressure  a l s o i n c r e a s e d , though o n l y s l i g h t l y , from a c o n t r o l l e v e l o f 91 mrnHg (SEM + 4.9, range 76-103) t o 100 mrnHg (SEM + 5 . 4 , range 72-114). I f we now r e c o n s i d e r the amount o f r e f l e x a f t e r a t r o p i n e , i t must be admitted,  remaining  t h a t though 3 beats/min.  i s a v e r y small i n c r e a s e , i t i s s i g n i f i c a n t t h a t t h e heart i s able t o c o n s i s t e n t l y i n c r e a s e i t s r a t e a t a l l from a b a s e l i n e of 214 beats/min.  C e r t a i n l y we c o u l d not conclude from  these  experiments a l o n e , t h a t the l e f t a t r i a l r e f l e x i s s o l e l y mediated by t h e vagus. V_._Effects o f _ s p i n a l s e c t i o n A t r a n s e c t i o n o f the s p i n a l cord o f the dog a t the l e v e l o f the foramen magnum does two major t h i n g s t o the p h y s i o l o g i c a l s t a t e o f the animal;  one, i t i n i t i a t e s a p e r i o d o f  " s p i n a l shock" o f unknown d u r a t i o n ; and, two, i t severs the sympathetic c e n t r a l connections t o and from the h i n d b r a i n the f i r s t blood  l e a v i n g v a g a l pathways  intact. It i s d i f f i c u l t  o f these two events,  pressure  while  t o assess  though changes i n h e a r t r a t e and  can give us an i d e a o f the v a s t l y a l t e r e d s t a t e  w i t h which we a r e d e a l i n g .  42  Immediately following; s e c t i o n o f the cord a t the l e v e l o f the f i r s t  c e r v i c a l v e r t e b r a i n 10 dogs, the h e a r t  rate  f e l l d r a s t i c a l l y from a c o n t r o l mean o f 123 beats/min. (SEM + 13, range 66-174) t o #0 beats/min. (SEM + 11.7, range  43-135),  w h i l e b l o o d p r e s s u r e decreased from 139 mmHg (SEM + 2.2, range 128-15?) t o 116.7 mmHg (SEM + 10.2,  range 60-164). The h e a r t  r a t e change was however not s u s t a i n e d , w i t h i n a h a l f hour, mean h e a r t r a t e was even h i g h e r than c o n t r o l v a l u e s , a t 135 b e a t s / min.  (SEM + 11.3, range 77-177). Blood p r e s s u r e , however,  continued t o f a l l ,  r e a c h i n g 86 mmHg (SEM + 5.9, range  58-112).  T h i s was a c u r i o u s phenomena t o observe, as the i n c r e a s e i n h e a r t r a t e seemed t o be c o r r e l a t e d w i t h the disappearance o f " v a g a l t o n e " . I f c e r v i c a l vagotomy was performed w i t h i n the p e r i o d o f decreased h e a r t r a t e , h e a r t r a t e i n c r e a s e upon s e c t i o n o f the nerve could be observed. However, i f the h e a r t r a t e had s t a b i l i z e d the  at the 120-150 beats/min. range,  vagus had l i t t l e  e f f e c t on h e a r t  cutting  rate.  C o r r e l a t e d w i t h t h i s l o s s o f " v a g a l tone" was the absence o f the c a r o t i d the  s i n u s r e f l e x i n i t i a t e d by o c c l u s i o n o f  common c a r o t i d a r t e r i e s . In 22 t r i a l s  seconds a f t e r c a r o t i d  i n 6 dogs,  o c c l u s i o n i n the c o n t r o l p e r i o d  thirty heart  r a t e i n c r e a s e d an average o f 15 beats/min. (SEM + 5.30, range -19 t o + 107.5) as blood p r e s s u r e i n c r e a s e d 18.2 mmHg (SEM +  5.30, range -2 t o +32). Approximately one hour a f t e r  t r a n s e c t i o n i n these same s i x dogs, nine t r i a l s o c c l u s i o n produced no change i n h e a r t r a t e + 1.39,  range -6 t o +7.5)  spinal  of carotid  (0 beats/min. SEM  w h i l e b l o o d p r e s s u r e i n c r e a s e d 5 mmHg.  U3  (SEM  + 1.34, range +1 to +13). T h i s created  left  atrial  some d i f f i c u l t y  i n t h e examination o f the  r e f l e x f o r what was presumed t o be a D o s s i b l e  vagal  component. The o b j e c t was to observe the r e f l e x , a f t e r s p i n a l s e c t i o n , d u r i n g some degree o f steady period of vagal a c t i v i t y . Obviously  state, yet within the  from the data  above i t was not p o s s i b l e t o meet a l l these Despite  these  presented  conditions.  problems, i n 31 t r i a l s  i n 7 dogs, a mean  i n c r e a s e i n heart r a t e d u r i n g b a l l o o n i n f l a t i o n was 6 b e a t s / min.  (SEM + 1.3), w h i l e blood n r e s s u r e  decreased-1.7 mrnHg (SEM  + 1.0). T h i s i n c r e a s e could be a b o l i s h e d i n a l l cases c a l vagotomy, or i f s u f f i c i e n t time was allowed heart  r a t e t o reach a steady  t o elapse f o r  s t a t e i n the 120-150 range, the  r e f l e x could be observed t o d i s a p p e a r w i t h the disappearance o f " v a g a l  i n approximate  correlation  tone".  A l l o f the above r e s u l t s were obtained chloralose anaesthesia.  by c e r v i -  from dogs under  I t was thought t h a t i t might be o f  i n t e r e s t t o oberve the l e f t a t r i a l r e f l e x under the i n f l u e n c e o f o t h e r a n a e s t h e t i c s , and e s p e c i a l l y v o l a t i l e  anaesthetics,  which might be d i s c o n t i n u e d upon d e c e r e b r a t i o n . Two a l t e r n a t i v e a n a e s t h e t i c s were used: halothane, combination The  and a n i t r o u s  oxide-nentothal  (see Methods, S e r i e s V - V I ). f o u r dogs i n c l u d e d i n the halothane study  t e n t l y presented  consis-  us w i t h a c o n d i t i o n i n which c a r d i o v a s c u l a r  r e f l e x e s were d e p r e s s e d . The c a r o t i d  sinus r e f l e x , i n i t i a t e d by  o c c l u s i o n o f the c a r o t i d a r t e r i e s , was absent o r very  small i n  44  12 t r i a l s  i n the f o u r dogs d u r i n g the c o n t r o l n e r i o d . Mean  changes i n h e a r t r a t e 20 seconds a f t e r o c c l u s i o n were -2 min.  (SEM  + 1.13,  2.3  mmHg. (SEM  was  nresent,  range -9 to +6)  + 0.78,  as blood  range -2 t o +7).  though s m a l l , and  The  f o l l o w e d the  pressure  increased  left atrial  reflex  characteristic  p a t t e r n observed p r e v i o u s l y i n c h l o r a l o s e a n a e s t h e t i z e d (see t a b l e V I ) . D e c e r e b r a t i o n  and  the removal o f the  c i r c u i t a l t e r e d t h i s p i c t u r e o n l y s l i g h t l y . The r e f l e x was  now  present.  In seven t r i a l s  dogs  halothane  carotid  sinus  i n 3 dogs, twenty  seconds a f t e r c a r o t i d o c c l u s i o n , heart r a t e i n c r e a s e d  an  average o f 6 beats/min. (SEM  as  pressure atrial  rose 4.7  r e f l e x was  + 2.26,  mmHg.(SEM + 2.68,  range -3 t o +12) range -2 to +8).  augmented, though not  not change the magnitude or d i r e c t i o n of these  left  Waiting circuit  left  junction. With n i t r o u s oxide we  difficulty  surgery was pentothal  hoped t o a v o i d t h i s same  o f l o n g l a s t i n g d e p r e s s i o n but the n e c e s s i t y of adding  pentothal to achieve  a s a t i s f a c t o r y depth of a n a e s t h e s i a  d e t r i m e n t a l . The  combination of n i t r o u s oxide  c o n s i s t e n t l y gave us an animal i n which a h i g h  r a t e tended to obscure the l e f t a t r i a l p e n t o t h a l was During  blood  responses to  c a r o t i d o c c l u s i o n or d i s t e n s i o n o f the pulmonary v e i n atrial  The  significantly.  as l o n g as s i x hours a f t e r removal o f the a n a e s t h e t i c did  beats/  administered,  r e f l e x . The  the more severe  range 144-228), the  r a t e t o 21 b a l l o o n i n f l a t i o n s i n 7 dogs was  and heart  more o f t e n  t h i s problem.  the c o n t r o l p e r i o d , where heart r a t e had  beats/min.(SEM + 11.7,  for  a mean o f  180  i n c r e a s e i n heart o n l y 2 beats/min.  45  (SEM  + 0.6).  Blood  pressure  changed -3.3  mmHg. (SEM  + 1.1).  c o n t i n u i n g the n i t r o u s oxide f o l l o w i n g d e c e r e b r a t i o n d i d always change t h i s p a t t e r n . In 22 t r i a l s  (SEM  + 1.0),  c o n t r o l value  which was  at 2n 0.01.  significantly different  significantly different  Blood  pressure  9  changes were not  from c o n t r o l changes. Prolonged  waiting, alter  t h i s resnonse. P r o p r a n o l o l a b o l i s h e d most o f the r e f l e x ,  while  + 1.7)  remaining  beats/  from the  up t o s i x hours a f t e r removal of n i t r o u s o x i d e d i d not  3 beats/min. (SEM  not  i n 7 dogs, mean  r e f l e x i n c r e a s e i n heart r a t e t o b a l l o o n i n f l a t i o n was min.  Dis-  i n 15 t r i a l s  c e r v i c a l vagotomy t o t a l l y a b o l i s h e d i t .  only  i n 5 dogs,  h6  DISCUSSION A p e r u s a l of the r e s u l t s r e v e a l s t h r e e major areas of concern which m e r i t f u r t h e r d i s c u s s i o n : 1) The  l o c a t i o n o f the c e n t r a l synapse f o r the  atrial 2)  The  left  reflex;  p o s s i b i l i t y o f the e x i s t e n c e of a vaeral  e f f e r e n t component; 3) The  r o l e of the l e f t a t r i a l r e f l e x i n the  unanaesthetized Although  animal.  the data presented  above can not w i t h  p r e c i s i o n answer the f i r s t o f these q u e s t i o n s , t h e y a t t e l l us w i t h a degree of c e r t a i n t y where the c e n t r a l of  the l e f t a t r i a l  least  connections  r e f l e x are n o t . D e c e r e b r a t i o n a t the  mid-  c o l l i c u l a r plane d i d not s i g n i f i c a n t l y a l t e r the magnitude or n e u r a l c h a r a c t e r i s t i c s of the response distension  (see T a b l e  X).  t o pulmonary v e i n  Thus i t does not seem l i k e l y  that  s t r u c t u r e s r o s t r a l to the s u p e r i o r c o l l i c u l u s , such as the hypothalamus, are n e c e s s a r y f o r the appearance o f the reflex effect.  full  T h i s l e a d s us t o b e l i e v e t h a t the r e g i o n o f  c e n t r a l nervous system  (CSN)  c o n t r o l i s l o c a t e d e i t h e r i n the  medulla, a l o n g w i t h o t h e r c a r d i o v a s c u l a r c e n t e r s , o r , a t the s p i n a l l e v e l . The  presence  o f the c a r d i o v a s c u l a r c e n t e r s , and  the r e t i c u l a r nature of the medulla, w i t h i t s m u l t i s y n a n t i c infinity  o f c o n n e c t i o n s , serve t o p r e j u d i c e us i n i t s f a v o r . More c o n c r e t e evidence may  C a l a r e s u and  exist  i n the work o f  Henry i n t h e i r study of the e f f e c t s o f s t i m u l a t i o n  47  of the " p a r a h y n o g l o s s a l  area"  ( HA) i n the medulla o f the P  cat  3  ( C a l a r e s u and. Henry, 1971). T h i s r e g i o n o f the f l o o r o f the f o u r t h v e n t r i c l e i n c l u d e s the h y n o p l o s s a l  interfascicular  n u c l e i , t h e medial l o n g i t u d i n a l f a s c i c u l u s (MLF), and t h e paramedian r e t i c u l a r nucleus s t u d i e s by B r o d a l  (PMRN). C a r e f u l nerve  have demonstrated e x t e n s i v e  degeneration a f f e r e n t s t o the  PMF.N. from the f r o n t o - p a r i e t a l c o r t e x , the v e s t i b u l a r n u c l e i , f a s t i g i a l nucleus,  the r e t i c u l a r n u c l e i o f the b r a i n s t e m , and  some a s c e n d i n g f i b e r s from the d o r s a l f u n i c u l u s o f the s p i n a l cord,  ( B r o d a l , 1957). D i r e c t p r o j e c t i o n s o f c a r o t i d s i n u s  nerve  f i b e r s have been found t o t h e PMRN. (Homma, M i u r a , and. R e i s , 1970). E l e c t r i c a l s t i m u l a t i o n o f the PHA i n t h e cat caused short latency pressure  (1-5 seconds) i n c r e a s e s i n heart  e i t h e r simultaneously  not e f f e c t e d by d e c e r e b r a t i o n , creased  r a t e and blood  o r s i n g l y . These i n c r e a s e s were and could be s i g n i f i c a n t l y de-  by i n f u s i o n s o f p r o p r a n o l o l , o r a b o l i s h e d by c e r v i c a l  vagotomy. Evoked p o t e n t i a l s were recorded c a r d i a c sympathetic n e r v e s . Although t h e r e  p e r i p h e r a l l y i n the i s no evidence t h a t  t h i s r e g i o n i s the s i t e o f c e n t r a l synapses f o r the  tachycardia  observed a t d i s t e n s i o n o f the pulmonary v e i n s , the s i m i l a r i t i e s i n the response a r e s t r i k i n g , and i t would be i n t e r e s t i n g t o t e s t t h e l e f t a t r i a l response a f t e r d i s c r e t e l e s i o n s o f the PHA,  s p e c i f i c a l l y t h e PMRN. As to the e x i s t e n c e  o f a s n i n a l c o n t r o l center f o r t h i s  r e f l e x , while we cannot deny t h a t such a c e n t e r may e x i s t , i s no r e a l evidence s u p p o r t i n g limited  such a c o n c l u s i o n . While  i n scope, the experiments i n s e r i e s IV showed a 50%  there  48  r e d u c t i o n i n the response to pulmonary v e i n d i s t e n s i o n a f t e r s e c t i o n of the cord at the Admittedly,  l e v e l of the f i r s t  cervical  vertebra.  the d r a s t i c changes i n the p h y s i o l o g i c a l s t a t e of  the animal a f t e r s e c t i o n , as w e l l as s e v e r i n g c e n t r a l sympathetic  connections  may  e x p l a i n p a r t o f t h i s r e d u c t i o n . However,  the f a c t t h a t the t a c h y c a r d i a  t h a t remained at b a l l o o n  inflation  seemed t o p e r s i s t o n l y as long as v a g a l a c t i v i t y , and a b o l i s h e d by b i l a t e r a l  c e r v i c a l vagotomy, tends to  was  contra-  i n d i c a t e b e l i e f i n a s p i n a l c e n t e r o f c o n t r o l . More c o n t r o l l e d experiments r e g a r d i n g  s p i n a l m e d i a t i o n of l e f t  would be n e c e s s a r y b e f o r e this  r e a c h i n g any  atrial  assured  impulses  conclusions  in  case. What the s p i n a l s e r i e s does do  s t u d i e s , i s t o add weight to the  f o r the purpose of these  evidence i n f a v o r o f a  vagal  e f f e r e n t component. The  f a c t t h a t p r o p r a n o l o l , g i v e n i n doses  s u f f i c i e n t to b l o c k 9$%  o f the p r e c e p t o r  p r e n a l i n e , could  not a b o l i s h the  e x c i t a t i o n by  iso-  response t o pulmonary v e i n  d i s t e n s i o n s t r o n g l y i n d i c a t e s t h a t the remaining i n c r e a s e s heart  r a t e do not r e s u l t from sympathetic a c t i v i t y . The  native explanation,  t h a t the b a l a n c e of the  caused by |» r e c e p t o r s not The  chance o f "wearing o f f " , or  alter-  increase could  e f f e c t e d by p r o p r a n o l o l  in  i s not  be  likely.  incomplete blockage i s s l i m  when u s i n g i s o p r e n a l i n e f r e q u e n t l y . In a d d i t i o n , the dose of p r o p r a n o l o l used, 0.5  mg/Kg TV.,  i s t h a t recommended as capable o  d i s t i n g u i s h i n g sympathetic from parasympathetic a c t i v i t y t o h e a r t , and than 90%  b l o c k i n g " c e r t a i n l y more than 75%,  and  probably  the more  o f changes i n h e a r t r a t e caused by r e f l e x changes i n  sympathetic nervous a c t i v i t y . "  (Ledsome e t . a l . ,  1Q65).  In a l l  49  cases, as seen i n tables  X and  XI, we  have over ?$% of the i n -  crease i n heart rate at pulmonary vein distension remaining; after P r o p r a n o l o l .  It should be remembered that t h i s f i g u r e i s  a mean of many t r i a l s in many animals; i n d i v i d u a l l y , the  percent  of control response remaining a f t e r propranolol varied from 0#-100# (see tableXII). The fact that an increase i n heart rate of approximately the same magnitude remains a f t e r s p i n a l section at the f i r s t c e r v i c a l vertebra can only add weight to the i n creasing suspicion that part of the r e f l e x may  be mediated by  efferent a c t i v i t y i n the parasympathetic nerves. Although cardioacceleration caused by the vagus nerve has been reported  by Smith, such f i b e r s have been shown to  terminate i n intracardiac adrenergic would also be blocked  by propranolol,  ganglia, so presumably they (Smith, 1970). Therefore,  i f cardioacceleration caused by the vagus e x i s t s , i t must be brought about by the usual mechanism of reducing vagal  inhibi-  t i o n . From our records, the e a r l i e r claim by Ledsome and  Linden  that the efferent pathway f o r the l e f t a t r i a l r e f l e x resides s o l e l y in the cardiac sympathetics cannot be supported, (Ledsome and  Linden, 1969). Their experiments were performed on  only a few animals, and bretylium tosylate c h i e f l y used as a sympathetic blocking agent. When one dog, a s l i g h t increase  i n fact propranolol vras used i n  (2 beats/min.) i n heart rate remained  upon stimulation of a t r i a l receptors. In a more recent paper,two dogs showed increases of 3 # beats/min., and  #1 beats/min. at  balloon i n f l a t i o n . These increases v/ere reduced to 1? beats/min. {Jlfo of control) and 16 beats/min. (?S)% of c o n t r o l ) , respectively following the administration of propranolol  (0.5 mg/Kg.),  1. CHANGE IN HEART RATE AND MEAN BLOOD PRESSURE 30 SECONDS AFTER ISOPRENALINE (0.5 <fg/Kg) HEART RATE (beats/min)  BLOOD PRESSURE (mm/Hg)  Control (n=20)  +90+11  -42+L  After  +2+1. ^  -1.3+1  Block.(n=?0)  2. CHANGE IN HEART RATE AND MEAN BLOOD PRESSURE DURING PULMONARY VEIN DISTENSION HEART RATE (beats/min)  BLOOD PRESSURE (mm/Hg)  Control (n=l3)  +23+3  -2.2+0.8  After  +6+1.2  -0.7+0.7  TABLE X.  Block.(n=l8)  ABILITY OF PROPRANOLOL (0.5 mg/Ktr) TO BLOCK EFFECT OF ISOPRENALINE AND THE RESPONSE TO PULMONARY VEIN DISTENSION.  HEART RATE (beats/min)  BLOOD PRESSURE (mm/Hg)  C o n t r o l (n=5*)  +^0+l. 86  -1.4+0.57  After  +24+2.46  +0.4+0.57  A f t e r Decerebration + $ -Blockade(n=33)  +9+0.95  +0.5+0.34  A f t e r Decerebration + J-Blockade + Vagotomy (n=44)  -0.1+0.31  -2.3+0.72  Decerebration  TABLE X I . EFFECTS OF DECEREBRATION,$ -BLOCKADE, AND VAGOTOMY ON THE CHANGES IN HEART RATE AND BLOOD PRESSURE CAUSED BY DISTENSION OF THE PULMONARY VEINS.  52  AFTER  AFTER PROPANOLOL AND DECEREBRATION  PROPRANOLOL  % RESPONSE INITIAL HEART RATE (beats/min)  % RESPONSE INITIAL HEART RATE (beats/min) 119  59  130  100  30  100  114  25  114  45  64  77  144  0  144  6  57  25  74  27  92  37  72  50  34  31  30  33  130  3  160  49  35  56  54  41  SERIES I  SERIES I I I  TABLE X I I . PERCENT OF CONTROL RESPONSE TO PULMONARY VEIN DISTENSION REMAINING AFTER J> BLOCKADE WITH PROPRANOLOL (0.5 mg/Kg.IV). ( % Resnonse" e a u a l s t h e p e r c e n t o f t h e control increase i n heart rate at pulmonary v e i n d i s t e n s i o n remaining a f t e r ^ blockade.) v  53  (Carswell e t . a l . , served  i n ^he  1970.). These amounts are s i m i l a r to those  decerebrate  s t u d i e s , and  a f t e r s p i n a l s e c t i o n . I f we ^3 b l o c k i n g agent, and  the  accent  the i n c r e a s e s  p r o p r a n o l o l as a  remaining reliable  s p i n a l s e c t i o n as a means o f  d i s t i n g u i s h i n g v a g a l ] y mediated responses,  then we  can  the f a c t t h a t a vagal e f f e r e n t component f o r the l e f t i n c r e a s e i n heart r a t e may C e r t a i n l y we e x i s t s . The  ob-  accent atrial  exist.  have not proved t h a t such a component  f a c t t h a t b r e t y l i u m t o s y l a t e which b l o c k s  post-  g a n g l i o n i c a d r e n e r g i c neurons, can t o t a l l y a b o l i s h the i n h e a r t r a t e at pulmonary v e i n d i s t e n s i o n , i s a argument a g a i n s t such a component. D e s p i t e the  increase  formidable  prolonged  sympathomimetic a c t i o n s of b r e t y l i u m , " v a g a l tone" i s markedly present  a f t e r subsidence  by the v i g o r o u s (Ledsome and a competitive  carotid  Linden,  o f sympathetic s i n u s and  e x c i t a t i o n , as  lung s t r e t c h  i n h i b i t o r of norepinephrine,  a l l o w high  local  t o accumulate. In such a  case,  the amount might be s u f f i c i e n t t o permit not d e t e c t a b l e by  reflexes,  1964). I t i s a l s o p o s s i b l e t h a t p r o p r a n o l o l ,  c o n c e n t r a t i o n s of n o r e p i n e p h r i n e  yet  evidenced  may  sympathetic  excitation,  i s o p r e n a l i n e . B r e t y l i u m , which b l o c k s  r e l e a s e of n o r e p i n e p h r i n e  would o b v i a t e t h i s problem, and  perhaps p r o v i d e more complete  blockade.  I t would be u s e f u l t o  observe the e f f e c t s o f b r e t y l i u m t o s y l a t e on the percent o f response remaining blockade  i n the d e c e r e b r a t e  the  preparation a f t e r  with p r o p r a n o l o l . As noted  above, the percent  h e a r t r a t e remaining widely  the  a f t e r <6 blockade  of c o n t r o l i n c r e a s e i n w i t h p r o p r a n o l o l may  i n a group of dogs. However, i n any  one  dog,  vary  the amount  54 tends t o s t a y r e l a t i v e l y the same b o t h i n the i n t a c t and decereb r a t e a n i m a l . I t i s l i k e l y that t h i s could degree of "autonomic  r e s u l t from the  t u n i n g " e x i s t i n g i n a s p e c i f i c animal a t  a s p e c i f i c t i m e . I f we suppose t h a t two p o s s i b l e e f f e r e n t  path-  ways f o r h e a r t r a t e i n c r e a s e s i n i t i a t e d by l e f t a t r i a l r e c e p t o r s t i m u l a t i o n might  f u n c t i o n , t h e predominance o f e i t h e r pathway  at any one time might  r e s u l t from the i n i t i a l  l e v e l of heart  r a t e and blood p r e s s u r e a t the moment o f s t i m u l a t i o n and the r e l a t i v e c o n t r i b u t i o n o f sympathetic o r parasympathetic to t h a t  activity  level.  Animal In t h e u n a n a e s t h e t i z e d d e c e r e b r a t e dog, the l e f t a t r i a l r e f l e x appears much reduced as compared t o i t s magnitude i n the c h l o r a l o s e a n a e s t h e t i z e d i n t a c t o r d e c e r e b r a t e dog. Whether t h i s i s the r e s u l t o f an exaggerated appearance  with  c h l o r a l o s e , o r a depressed appearance w i t h halothane o r n i t r o u s oxide and p e n t o t h a l cannot be determined. C e r t a i n l y  volatile  a n a e s t h e t i c s have been known t o depress c a r d i o v a s c u l a r w h i l e c h l o r a l o s e i s famous f o r p o t e n t i a t i o n o f s p i n a l  function, reflex  a c t i v i t y , v i z " c h l o r a l o s e j e r k s " . In our own experiments, the v o l a t i l e a n a e s t h e t i c s produced  a c o n d i t i o n i n which  the c a r o t i d  s i n u s r e f l e x as w e l l as the l e f t a t r i a l response to b a l l o o n i n f l a t i o n , was v e r y s m a l l or even absent. Blood p r e s s u r e could be lowered or r a i s e d a t w i l l by simply a l t e r i n g the depth o f a n a e s t h e s i a , i n d i c a t i n g a powerful involvement i n c a r d i o v a s c u l a r e v e n t s . Recovery from a n a e s t h e s i a , as judged by the r e t u r n o f r a p i d , normally patterned r e f l e x e s , i . e . c a r o t i d  sinus r e f l e x ,  55  wa?  slow. Indeed, w h i l e i t i s d i f f i c u l t  to b e l i e v e t h a t  e f f e c t s of halothane o r n i t r o u s oxide could h a l f hour a f t e r removal of the  anaesthetic  the  l i n g e r beyond circuit,  one  recovery  of  normal r e f l e x e s sometimes took up t o s i x hours. Perhaps a l l t h a t can  be  s t a t e d at present  i s that the  increase  i n heart  rate  brought about by pulmonary v e i n d i s t e n s i o n , does appear i n a v a r i e t y of c i r c u m s t a n c e s ; i . e . the i n t a c t or d e c e r e b r a t e dog, anaesthetized  i n t a c t dog,  chloralose  anaesthetized  the halothane or N^O-nentothal and  the u n a n a e s t h e t i z e d  decerebrate  dog. Cardiovascular  Reflexes  and  R e t u r n i n g to the c o n t r o l and  the  CMS  Integration  l a r g e r p i c t u r e of  r o l e of l e f t a t r i a l  cardiovascular  receptors  in particular,  these r e s u l t s can be i n t e r p r e t e d i n a broader manner. As p r e v i o u s l y , the  c u r r e n t view of the  central  noted  cardiovascular  c o n t r o l mechanism c o n s i s t s of a m e d u l l a r y c a r d i o v a s c u l a r r e t i c u l a r i n n a t u r e , and c o r t i c a l , c e r e b e l l a r , and  center,  r e c e i v i n g m u l t i p l e i n p u t s from s p i n a l , receptor  r e s u l t of the  neurons. The  output at  one  time i s the  the  degree o f i n t e g r a t i o n t h a t t a k e s p l a c e . I n c r e a s i n g l y ,  any  e n t i r e i n p u t from a l l sources  the  importance o f t h i s concept of i n t e g r a t i v e c o n t r o l i s b e i n g p r e c i a t e d as the key to the e x t e n s i v e adjustments p o s s i b l e i n normal and relatively rigid envisioned  range of  ap-  cardiovascular  emergency s i t u a t i o n s . The  barorecentor-vasomotor c e n t e r  simply  and  cannot e x p l a i n the  system  d i v e r s i t y of  previously  reactions  p o s s i b l e . While the newer u n d e r s t a n d i n g i s a t t r a c t i v e f o r i t s f l e x i b i l i t y and  range of responses, i t i s d i f f i c u l t  to approach  56 experimentally. Recently, some idea of the type of d i f f e r e n t i a t e d outnut that i s P o s s i b l e with t h i s system was  demonstrated by  Oberg and White (1970). Measuring rapid phasic  s h i f t s i n blood  flow by plethysmography, they examined the kinds of responses r e s u l t i n g from i n t e r r u p t i o n or stimulation of either cardiac vagal or carotid sinus afferents. Interruption of the  cardiac  vagal afferents by a cold block of the c e r v i c a l vagi i n a dog with sectioned  a o r t i c nerves resulted i n tachycardia  and i n -  creased renal blood flow resistance. A l e s s e r increase i n muscle blood flow resistance was  also recorded. However, reducing  baroreceptor inputs by carotid occlusion i n the same animal caused l i t t l e change i n heart rate with predominant e f f e c t s on the resistance to flow i n s k e l e t a l muscle. Similar o u a n t i t a t i vely d i f f e r e n t i a t e d responses were observed unon e l e c t r i c a l stimulation of the vagal afferents or carotid sinus nerve. Decreases i n heart rate and  vasodilatation i n the renal bed  predominated at stimulation of the c e r v i c a l vagi, while baroreceptor stimulation brought large changes i n s k e l e t a l muscle blood flow, with l a t e r , less s i g n i f i c a n t reductions heart rate and  i n both  renal flow. Such a d i s t i n c t l y d i f f e r e n t i a t e d  response pattern would not be possible without a r e t i c u l a r multisynantic The  neuron pool capable of a high degree of i n t e g r a t i o n . extent of overlap P o s s i b l e with such an arrangement  is exemplified  by the work of Calaresu and Thomas (1971). Stimu-  l a t i o n of the paramedian r e t i c u l a r nucleus could i n h i b i t sympat h e t i c drive i n anaesthetized, i n t a c t or decerebrate vagotomized cats, causing bradycardia.  However, i f both vagi were i n t a c t ,  57  s t i m u l a t i o n o f the same s t r u c t u r e caused  increases  r a t e . Such r e s u l t s l e d to the  t h a t two  might e x i s t w i t h i n the  D  suggestion one  MRN;  e x e r t i n g an  i n heart neuron  pools  inhibitory in-  f l u e n c e on sympathetic a c t i v i t y , the o t h e r an i n h i b i t o r y i n f l u e n c e on parasympathetic a c t i v i t y . Whatever the s p e c i f i c n i z a t i o n o f t h i s nucleus may  be,  these r e s u l t s emphasize  orga-  the  f a c t t h a t a l l - o r - n o n e type massive i n h i b i t i o n or e x c i t a t i o n to all  segments of the c a r d i o v a s c u l a r system are probably  u s u a l l y the  not  case.  The  response t o s t i m u l a t i o n of the l e f t a t r i a l  by pulmonary b a l l o o n i n f l a t i o n , r a t e and  receptors  i n which primary e f f e c t s are  r e n a l volume c o n t r o l mechanisms  ob-  served  on h e a r t  longer  seems untenable i n the l i g h t of such an u n d e r s t a n d i n g of  c e n t r a l c a r d i o v a s c u l a r c o n t r o l . Although a r e p o r t of  no  vascular  p e r i p h e r a l r e s i s t a n c e changes at pulmonary b a l l o o n i n f l a t i o n been p u b l i s h e d , applied our own.  ( E d i s , Donald and  to a t r i a l r e c e p t o r s  Shepherd, 1970)  could  the  stimulus  not have been comparable t o  They observed l a r g e changes i n a o r t i c blood  as w e l l as e i t h e r b r a d y c a r d i a  has  pressure  o r t a c h y c a r d i a , depending upon the  c o n t r o l heart r a t e . Pulmonary v e i n d i s t e n s i o n by our methods c o n s i s t e n t l y given t a c h y c a r d i a w i t h i n a r t e r i a l blood  pressure  has  insignificant fluctuations  from a l l l e v e l s o f c o n t r o l h e a r t rate.  I t has been p r e v i o u s l y demonstrated t h a t t h i s i n c r e a s e i n h e a r t r a t e i s not accompanied by a l t e r a t i o n s i n p e r i p h e r a l v a s c u l a r r e s i s t a n c e i n the hind limbs,  ( C r s w e l l , Hainsworth, and  1970). From the d e c e r e b r a t i o n  s t u d i e s , i t seems l i k e l y t h a t  a  d i f f e r e n t i a t i o n of t h i s response i s c a r r i e d out l e v e l , and  i s not  c o r t i c a l l y or h y p o t h a l a m i c a l l y  Ledsome the  at a m e d u l l a r y imposed. T h i s  53  is  somewhat s u r p r i s i n g a s  the  only  other  c a r d i o a c c e l e r a t i o n unaccompanied by or c a r d i a c points  c o n t r a c t i l i t y was  i n the  localization atrial  hypothalamus of  the  that  report  changes i n blood  p r o d u c e d by  ( F a n g and  of d i s c r e t e  stimulation  Wang, 1 9 6 ? ) . The  ventricle  during  t y of the  existence  pharmacological  receptor  and  of a vagal  P e r h a p s when we both the  low  pressure  and  details  high  the  appreciated.  possibili-  t o r e d i r e c t our nervous  both  attensystem"  of c e n t r a l o r g a n i z a t i o n  pressure  system r e c e p t o r s ,  f u n c t i o n i n c a r d i o v a s c u l a r h o m e o s t a s i s i n h e a l t h and fully  fourth  for substantiation.  " i n t e g r a t i v e a c t i o n o f the  r e a l i z e the  o f the  await  e f f e r e n t component r e q u i r e s  time course analyses  t i o n s o n c e more t o t h e  floor  stimulation. Similarly,  P r i m a r i l y t h e n these r e s u l t s have served  be  left  r e f l e x r e s p o n s e t o p u l m o n a r y v e i n d i s t e n s i o n must i n the  of  precise  c e n t r a l m e d u l l a r y synapses of the  more d e t a i l e d s t u d i e s o f a c t i v i t i e s  will  pressure  of  their  disease  59 BIBLIOGRAPHY Alexander, Robert S., (1946). T o n i c and R e f l e x F u n c t i o n o f M e d u l l a r y Sympathetic C a r d i o v a s c u l a r C e n t e r s . J . Neurophys. 9, 205-217. Albrook, S.M., and Ledsome, J.R. , (1971). E f f e c t s o f D i s t e n s i o n of the Pulmonary V e i n - L e f t A t r i a l J u n c t i o n s i n Decerebrate Dogs. Proceedings o f the XXV I n t e r n a t i o n a l Congress o f P h y s i o l o g i c a l S c i e n c e s , v o l . IX, Munich. Albrook, S., B n n i o n , G., and Ledsome, J.R., (1971). A Method f o r the D e c e r e b r a t i o n o f Dogs by E l e c t r o c o a g u l a t i o n . (Submitted f o r P u b l i c a t i o n ) . e  Aviado, D.M.,Jr., L i , T.H., Kalow.W., Schmidt, C.F., T u r n b u l l , G.L., P e s k i n , G.W. , Hess, M.E. , and Weiss, A . J . , (1951). R e s p i r a t o r y and C i r c u l a t o r y R e f l e x e s from the L e f t Side of the H e a r t . Amer. J . P h y s i o l . 165, 261-277. Aviado, D.M., J r . , and Schmidt, C.F., (1959). C a r d i o v a s c u l a r and R e s p i r a t o r y R e f l e x e s from the l e f t s i d e o f the H e a r t . Amer. J . P h y s i o l . 196, 726-730. B a i n b r i d g e , F.A., (1915). The I n f l u e n c e o f venous f i l l i n g the r a t e o f the H e a r t . J . P h y s i o l . 50, 65-34.  upon  B r o d a l , A l f , Anders, C., and Gogstad, (1957). A f f e r e n t connect i o n s o f the Paramedian R e t i c u l a r Nucleus o f the Medulla Oblongata i n the Cat. Acta Anatomica 3 0 , 133-151. B r o d a l , A l f , and T o r v i k , Amsgar, (1954). C e r e b e l l a r P r o j e c t i o n s of Paramedian R e t i c u l a r Nucleus of Medulla Oblongata i n Cat. J.Neurophys. 17, 434-495. C a l a r e s u , F.R., and Henry, J . L . , (1971). The Mechanism of the C a r d i o - A c c e l e r a t i o n e l i c i t e d by E l e c t r i c a l S t i m u l a t i o n of the P a r a h y n o g l o s s a l Area i n the C a t . J . h v s i o l . 210, 107-120. D  C a l a r e s u , F.R., and Thomas, M.R., (1971). F u n c t i o n of the Paramedian R e t i c u l a r Nucleus i n the C o n t r o l o f Heart Rate i n the C a t . J . h y s i o l . ?16, 143-153. D  - C a r s w e l l , F., Hainsworth, R. , and Ledsome, J.R., (1970). The E f f e c t s of D i s t e n s i o n o f the Pulmonary V e i n - A t r i a l J u n c t i o n s upon P e r i p h e r a l V a s c u l a r R e s i s t a n c e ; J . P h y s i o l . 207, 1-14. C h a i , C.Y., and Wang, S.C., (1963). I n t e g r a t i o n of Sympathetic C a r d i o v a s c u l a r Mechanism i n Medulla Oblongata o f the Cat. Am. J . P h y s i o l . 215, 1310-1315. C o l e r i d g e , J.C.G., Hemingway, A.,Holmes, R.L.,and Linden, R.J. (1957). The L o c a t i o n o f A t r i a l Recentors i n the Dog; a P h v s i o l o g i c a l and H i s t o l o g i c a l Study. J . P h y s . 1 3 6 , 174-197.  60  Coote, J.H., and Downman, C.B., ( 1 9 6 6 ) . Central Pathways of some Autonomic Reflex Discharges. J . Physiol. 133, 7 1 4 - 7 2 9 . Dittmar, C., (1370). Bin neuer Beweiss f u r die Reizbarkeit der Centripetalen Fasern des Rttckenmarks. Ber.SMchs. Ges. V/iss. (Math-Phys.) 22, 18 . Dittmar, C., ( 1 8 7 3 ) . Uber die Lage des sofrenannten Gefasszen^rums. i n der Medulla Oblongata. Ber. SSchs.Ges. V/iss. (Math-Phys.) 2 5 , 4 4 9 - 4 6 9 ) . Djpjosugito, A.M., Folkow, B., Kylstra, P.H., Lisander, B., and T u t t l e , R.S. (1970). D i f f e r e n t i a t e d Interaction between Hypothalamic Defence Reactions and Baroreceptor Reflexes. Acta. Physiol. Scand. 7 8 , 376-335. Edis,  Anthony J . , Donald, David E., and Shepherd, John T. (1970) Cardiovascular Reflexes from Stretch of ^ulmonary VeinA t r i a l Junctions i n the D O E . C i r c u l a t i o n Research 27, 1091-1100. :  Fang, H.S., and Wang, S.C. (1962). Cardioaccelebrator and Caroidauermentor Points i n Hypothalamus of the Doe. Am. J . Physiol. 2 0 3 , 147-150. Folkow, B j 8 r n , and N e i l , E r i c , (1971). C i r c u l a t i o n . Toronto, Oxford University Press, pp. 3 0 7 Gebber, G.L. , (1970). Central Organization of Baroreceptor Reflexes. J . Anesthes. 3 2 , 103-106. Gellhorn, E., ( 1 9 6 4 ) . The Significance of the State of the central Autonomic Nervous System f o r Quantitative and Q u a l i t a t i V ' Aspects of some Cardiovascular Reactions. Amer. H a r t J . 6 7 , 1 0 6 - 1 2 0 . e  HakumSki, M a r t t i , O.K., ( 1 9 7 0 ) . Function of the Left A t r i a l Receptors. Acta. P h y s i o l . Scand. Supplementum 3 4 4 . Heymans, C., and N e i l , E., (1Q53). R e f l exogenic Areas of the Cardiovascular System. London, J.& A. C h u r c h i l l Ltd., PP. 230-234.  H i l t o n , S.M., ( 1 9 6 3 ) . I n h i b i t i o n of Baroreceptor Reflexes on Hypothalamic Stimulation. J . Physiol. 165, 56-57. Hockman, Charles H., Talesnik, J . , and Livingston, K.E., (1Q69). Central Nervous System Modulation of Baroreceptor Reflexes. Am. J . Physiol.217, 1681-1689. Homma, S., Miura, M., and Reis, D.J., (1970). I n t r a c e l l u l a r Recording from Paramedian R e t i c u l a r Neurons Monosynaptically Excited by Stimulation of the Carotid Sinus Nerve. Brain Research 18, 185-183.  61  Katunsky, A., and K h a y u t i n , V.M., (1963). The R e f l e x Latency and L e v e l of M e d i a t i o n of S p i n a l A f f e r e n t Impulses o f the C a r d i o v a s c u l a r Sympathetic Neurons. P f l i i g e r s A r c h . 293,  294-304.  Khayutin, V l a d i m i r M., and Lukoshkova, E l e n a V., (1970). Spinal M e d i a t i o n o f Vasomotor R e f l e x e s i n Animals w i t h I n t a c t B r a i n S t u d i e d by E l e c t r o p h y s i o l o g i c a l Methods. P f l u g e r s A r c h . 3?1, 197-222. Klevans, L.R., and Gebber G.L., (1970). Influence of F o r e b r a i n Areas on B a r o r e c e n t o r R e f l e x e s . Fed.Proc. ? 9 , 1512. Kiussman, F.W., Van C i t t e r s , E.L., and Rushmer, R.F. , ( i 9 6 0 ) . C a r d i o v a s c u l a r E f f e c t s o f D i s t o r t i o n o f S t r e t c h Receptors i n the C a r d i a c W a l l s . Fed.Proc. 19, 9?. Korner, P a u l I . , (1971). I n t e g r a t i v e Neural C a r d i o v a s c u l a r Control. P h y s i o l . Rev. 51, 3 1 2 - 3 6 7 . Ledsome, J.R., and L i n d e n , R.J., (196?). The E f f e c t s o f D i s t e n s i o n o f the J u n c t i o n a l Regions o f the Pulmonary V e i n s and L e f t Atrium. J . of P h y s i o l . 165, 44-45?. Ledsome, J.R. , and Linden, R.J., (1964). The E f f e c t o f B r e t y l i u m T o s y l a t e on some C a r d i o v a s c u l a r R e f l e x e s . J . P h y s i o l . 170, Z , 4 ? - 4 5 5 . Ledsome, J.R., and Linden, R.J., (1964). R e f l e x Increase i n Heart Rate from D i s t e n s i o n of the P u l m o n a r y - V e i n - A t r i a l Junctions. J . P h y s i o l . 170, 456-473. Ledsome, J.R., and L i n d e n , R.J. , (1967). The E f f e c t o f D i s t e n d i n g a Pouch o f the L e f t Atrium on the Heart Rate. J . o f P h y s i o l . 193, 1?1-1?9. Ledsome, J.R., L i n d e n , R.J. , and Norman, J . , ( 1 9 6 5 ) . The use of Sympathetic -Receptor B l o c k i n g Agents i n the I n v e s t i g a t i o n o f R e f l e x Changes i n Heart Rate. B r i t i s h J . Pharm. and Chem. 24, 751-733. Manning, John W., ( 1 9 6 5 ) . Cardiovascular Reflexes Following L e s i o n s i n M e d u l l a r y R e t i c u l a r Formation. Am. J . P h v s i o l . ?03, ?53-?55. M i u r a , M. , and R e i s , D.J., ( 1 9 6 9 ) . Cerebellum: A P r e s s o r Response E l i c i t e d from the F a s t i g i a l Nucleus and i t s E f f e r e n t Pathway i n B r a i n s t e m . B r a i n Research 13, 595-599. M o r u z z i , 0., (1940). P a l e o c e r e b e l l a r I n h i b i t i o n of Vasomotor and R e s n i r a t o r y C a r o t i d Sinus R e f l e x e s . J . Neurophys. 5, ?0-3?. Newman, P.P., and W o l s t e n c r o f t , J.H., ( i 9 6 0 ) . I n f l u e n c e of the O r b i t a l Cortex on Blood P r e s s u r e Responses i n the Cat. J . Neurophys. ?3, ?11-?17.  62  Nonidez, J.F., (1937). I d e n t i f i c a t i o n o f the Receptor Area? i n the Venae Cavae and Pulmonary V e i n ? which I n i t i a t e R e f l e x Cardiac Acceleration (Bainbridge's R e f l e x ) . Amer. J . Anat. 61, 203-223. Oherg, B., and White, S., (1970). C i r c u l a t o r y E f f e c t ? o f I n t e r r u p t i o n and S t i m u l a t i o n o f C a r d i a c Vafral A f f e r e n t s . Acta P h y s i o l . Scand. 80, 383-394. Oberg, B., and White,. S., (1970). Role o f V a g a l C a r d i a Nerves and A r t e r i a l B a r o r e c e p t o r s i n C i r c u l a t o r y Adjustments t o Hemorrhage i n t h e Cat. Acta P h y s i o l . Scand. 80, 359-403. Owsjannikow, F., (1371). D i e Tonischen und R e f l e c t o r i s c h e n Z e n t r e n d e r OefSssnerven. Ber.SSchs. Ges.Wiss.,(math-ohys) 23, 135-147. P e i s s , C.N., (I960). C e n t r a l C o n t r o l o f Sympathetic C rriioA c c e l e r a t i o n i n the Cat. J . P h y s i o l . 151, 225-237. a  P i t t s , R.F., Larrabee, M.G., and Bronk, O.W., (1941). An a n a l y s i s o f Hypothalamic C a r d i o v a s c u l a r C o n t r o l . Am.J. P h y s i o l . 134, 357-383. P o r t e r , W.T., (1915). The V a s o t o n i c and the V a s o r e f l e x C e n t r e . Amer. J . P h y s i o l . 36, 413-422. R e i s , D.J., and Cuenod, M., (1965). C e n t r a l Neural R e g u l a t i o n of C a r o t i d B a r o r e c e p t o r R e f l e x e s i n t h e C a t . Am. J . P h y s i o l . 209, 1267-1275. Smith, Delmont C., (1970). S y n a p t i c s i t e s i n Sympathetic and Vagal C a r d i o a c c e l e r a t o r Nerves o f t h e Dog. Amer.J. o f Physiol. 213, 1618-1623. Wang, S.C., and Ranson, S.W., (1939). Autonomic Responses t o E l e c t r i c a l S t i m u l a t i o n o f the Lower B r a i n Stem. J . Comp. N e u r o l . 71, 437-455.  

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