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An analysis of the mechanisms of pentobarbital induced myocardial depression by a study of electrolyte.. Robertson, Anne Cochrane 1956

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OF  AN ANALYSIS OF THE MECHANISMS PENTOBARBITAL INDUCED MYOCARDIAL DEPRESSION BY A STUDY OF ELECTROLYTE DISTRIBUTION  by ANNE COCHRANE ROBERTSON B.A., U n i v e r s i t y  of B r i t i s h  Columbia,  1952.  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE  REQUIREMENTS FOR THE DEGREE OF MASTER OF ARTS  in  the Department of Pharmacology  We a c c e p t t h i s required  THE  thesis  as conforming  to the  standard  UNIVERSITY OF B R I T I S H COLUMBIA October  1956  In presenting the  thesis i n p a r t i a l fulfilment of  r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y  of B r i t i s h it  this  freely  C o l u m b i a , I a g r e e t h a t .the L i b r a r y a v a i l a b l e f o r r e f e r e n c e and s t u d y .  agree t h a t p e r m i s s i o n f o r extensive  shall  make  I further  copying of t h i s  t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d b y t h e Head o f my D e p a r t m e n t o r b y h i s r e p r e s e n t a t i v e . stood that financial  copying or p u b l i c a t i o n of t h i s gain  of  The U n i v e r s i t y o f B r i t i s h V a n c o u v e r 8, Canada. Date  (\ tiJM\ (  thesis f o r  s h a l l n o t be a l l o w e d w i t h o u t my  permission.  Department  I t i s under-  "  , »  Columbia,  written  ii  Abstract  Continuous i n f u s i o n s of b a r b i t u r a t e s respired with  animals r e s u l t i n profound  terminal  cardiac  nature of t h i s electrolyte failure  arrest.  analyses  following  pentobarbital.  The  patterns  c o u n t e r e d were compared saline  i n f u s i o n s , and  myocardial artery.  ischemia  basis and  pattern  myocardial barbital  i n the  exerted  m e t a b o l i s m w h i c h may activity.  values  the  provided  subjected  and  the  left  to  control  partial  coronary-  were o b s e r v e d .  probably not c a t and  to  On  the  the  electrolytedistribution  conclusion  the  was  reached  responsible dog.  that  for  pento-  In cat a u r i c l e s ,  a s e l e c t i v e a c t i o n on e l e c t r o l y t e have been r e l a t e d t o d e p r e s s i o n I n a d d i t i o n , e v i d e n c e was  action of pentobarbital  i n d e p e n d e n t o f Na  sodium  differences i n resistance  i n e f f e c t s on  i s c h e m i a was  pentobarbital  direct  to those i n cats  of f a i l u r e ,  in  o f e l e c t r o l y t e d i s t r i b u t i o n en-  e f f e c t of pentobarbital  failure  electrical  i n t a c t animal w i t h  the  tissue  on mammalian h e a r t s  through l i g a t i o n of  of differences  level,  to those i n animals r e c e i v i n g  S i g n i f i c a n t species  cardiolethal  depression  attempt to e l u c i d a t e  at a cellular  were p e r f o r m e d  i n f u s i o n o f the  artificially-  cardiovascular  I n an  cardiac depression  in  on  cardiac  K distribution.  s u p p o r t f o r the  found of  atrial a  contractility  Control e l e c t r o l y t e  hypothesis  d i s t r i b u t i o n i s r e l a t e d to c a r d i a c  of  that e l e c t r o l y t e  automaticity.  vi  ACKNOWLEDGEMENTS  The a u t h o r w i s h e s t o t h a n k D r . E . E . D a n i e l and D r . J . G . F o u l k s f o r t h e i r e n c o u r a g e m e n t and a s s i s t a n c e i n t h e p r e p a r a t i o n o f t h i s paper.  The f i n a n c i a l a s s i s t a n c e p r o v i d e d b y t h e N a t i o n a l R e s e a r c h C o u n c i l o f Canada and the Banting Research F o u n d a t i o n i s a l s o g r a t e f u l l y acknowledged.  iii TABLE OF  ABSTRACT L I S T OF TABLES L I S T OF FIGURES ACKNOWLEDGEMENTS  CONTENTS  i i iv v v i  INTRODUCTION  1  II.  METHODS  3  1III.  RESULTS  8  I.  IV. V. VI.  DISCUSSION  23  SUMMARY  30  BIBLIOGRAPHY  31  iv  L I S T OF  TABLES  TABLE I. II.  III. IV.  V.  VI.  VII.  VIII.  IX.  Tissue blood preparations  content of various  animal 6  Comparison o f the a n e s t h e t i c , respiratoryd e p r e s s a n t , and c a r d i a c l e t h a l d o s e s o f PB i n c a t s , d o g s , and r a b b i t s .  10  E f f e c t s o f c o r o n a r y l i g a t i o n on v a s c u l a r s t a t u s .of c a t s  13  the  cardio-  E f f e c t s o f PB i n f u s i o n and c o r o n a r y l i g a t i o n on t h e e l e c t r o l y t e d i s t r i b u t i o n i n c a t hearts 15 D a t a d e r i v e d f r o m T a b l e IV, CI t o be e x t r a c e l l u l a r . E f f e c t s o f PB i n f u s i o n s on d i s t r i b u t i o n i n dog h e a r t s D a t a d e r i v e d f r o m T a b l e VT, CI t o be e x t r a c e l l u l a r  assuming a l l 16 the  electrolyte 18  assuming a l l 19  E f f e c t s o f s a l i n e and PB i n f u s i o n s , and c o r o n a r y l i g a t i o n on w h o l e b l o o d e l e c t r o l y t e s i n the c a t  21  E f f e c t s o f s a l i n e and PB i n f u s i o n s , and e o r o n a r y l i g a t i o n on p l a s m a e l e c t r o l y t e s i n c a t s and d o g s  22  V TABLE OF  FIGURES  FIGURE I.  II.  III.  IV.  C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n s on t h e h e a r t r a t e o f c a t s , d o g s , and r a b b i t s  9  C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n s on t h e b l o o d p r e s s u r e o f c a t s , d o g s , and r a b b i t s  9  C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n s and c o r o n a r y l i g a t i o n on t h e h e a r t r a t e o f c a t s  12  C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n s and c o r o n a r y l i g a t i o n on t h e b l o o d p r e s s u r e o f c a t s  12  I.  INTRODUCTION  The a b i l i t y of large doses of barbiturates to produce profound depression and eventual cardiac arrest i n dogs has been attributed to a d i r e c t depressant action on the c o n t r a c t i l e force of the myocardium (Daniel et a l . 1956).  Electrocardio-  graphic (ECG) recordings during sodium pentobarbital (PB) i n fusion showed l i t t l e change i n pattern other than a terminal bradycardia.  However, when the negative i n o t r o p i c action of PB  was antagonized by i n f u s i o n of sympathomimetic amines, permitting large amounts of the barbiturate to be administered, s t a n d s t i l l and A-V block occurred.  atrial  Holland (1954) nas reported  that PB a l t e r s the rate of K transport i n i s o l a t e d r a b b i t and guinea pig a u r i c l e s i n concentrations which produce a 50-80$ reduction i n the amplitude of contraction.  In a d d i t i o n , the  changes encountered i n the i n t r a c e l l u l a r amounts of Na and K following previous stimulation (Hajdu, 1953), and the administ r a t i o n of d i g i t a l i s (Szent-Gyorgyi, 1953,  and Conn, 1956) and  epinephrine (Szent-Gyorgyi, 1953) have been suggested to underl i e changes i n cardiac c o n t r a c t i l i t y . The present i n v e s t i g a t i o n was undertaken i n order to discover whether or not the cardiac f a i l u r e induced by PB was associated with alterations i n tissue electrolytes animal..  i n the i n t a c t  In the dog, no s i g n i f i c a n t changes were encountered, i n  keeping with the e a r l i e r finding of l i t t l e change i n e l e c t r i c a l activity.  In the cat, however, the response to  continuous  2 infusions lethal  o f PB  d o s e was  c a r d i a was  followed  a d i f f e r e n t course,  s i g n i f i c a n t l y greater  cardiac  t h a n i n the dog.  pronounced, even w i t h o u t i n f u s i o n s  m i m e t i c a m i n e s , and t e r m i n a l  and t h e  of  Brady-  sympatho-  e l e c t r o l y t e c h a n g e s were  marked.  The e v i d e n c e s u g g e s t s a s e l e c t i v e a c t i o n o f PB o n c a t a u r i c l e s .  3 II.  METHODS  Cats PB I n f u s i o n . thetized,  1-3.5  Cats weighing  Kgm. were  i n t r a p e r i t o n e a l l y and i n t r a v e n o u s l y , w i t h  mgm./Kgm. PB ( P e n t o b a r b i t a l Sodium, U.S.P., B r i t i s h H o u s e s , 60 mgm./ml. i n 10$ e t h y l the l e f t  carotid  a r t e r y were c a n n u l a t e d ,  e t e r was a r r a n g e d trol  blood  t o measure a r t e r i a l  sample was w i t h d r a w n f r o m  f u s i o n s were made i n t o  0.95$ N a C l  the femoral  (0.5 ml./min.).  Heart  r a t e were r e c o r d e d failure,  and a m e r c u r y manompressure.  the c a r o t i d  A  con-  artery.  In-  v e i n b y means o f a n a d j u s t -  C o n t r o l animals  rate,  every  artificial  5-10 m i n u t e s .  r e s p i r a t i o n was p r o v i d e d  pressure  fell  b e l o w 15 mm.  mination  o f the experiment i n c o n t r o l s ) ,  infused with  PB.  respiratory a t the r a t e o f  When t h e b l o o d  o f Hg ( o r i m m e d i a t e l y  before  opened.  In control  PB i n f u s e d a n i m a l s , visible  by h e a r t p u n c t u r e  animals,  ter-  1000 I v U», H e p a r i n  ( C o n n a u g h t L a b o r a t o r i e s ) were g i v e n i n t r a c a r d i a l l y . sample was t a k e n  0.5  and r e s p i r a t o r y  After  i n animals  received  a n e s t h e t i c doses o f  blood pressure,  16 r e s p . / m i n .  blood  Drug  The t r a c h e a a n d  blood  m l . / m i n . o f 0.95$ N a C l and s u p p l e m e n t a l PB i n a l c o h o l .  30-^5  PB was g i v e n a t t h e r a t e o f 3 mgm./Kgm./min.  a b l e r a t e pump. in  alcohol).  anes-  A terminal  and t h e c h e s t  was  t h e h e a r t was removed a t o n c e .  In  i t was memoved when t h e r e was no l o n g e r a  heartbeat. Coronary L i g a t i o n .  I n one g r o u p o f c a t s , p r e p a r e d f o r  i n f u s i o n as above, p a r t i a l m y o c a r d i a l interference with  the coronary  blood  ischemia supply.  was p r o d u c e d b y The c h e s t and  4  p e r i c a r d i u m were opened a f t e r r e s p i r a t o r y c o r o n a r y a r t e r y was d i s s e c t e d major b r a n c e s . tory  failure  arrest,  and t h e l e f t  o u t abovce t h e l e v e l  ofits first  When f i f t e e n m i n u t e s h a d e l a p s e d  since  respira-  and i n s t i t u t i o n o f a r t i f i c i a l r e s p i r a t i o n , t h e l e f t  c o r o n a r y was l i g a t e d , t h e PB i n f u s i o n was d i s c o n t i n u e d ,  and t h e  p e r i c a r d i u m and c h e s t were c l o s e d .  #13)  the In  e x p e r i m e n t was a l l o w e d the remaining  ventricle  animals,  I n one a n i m a l  t o proceed  t o complete  (Cat  cardiac  failure.  t h e h e a r t was removed when t h e l e f t  failed.  Dogs PB I n f u s i o n . tized  i n t h e same manner  experimental animals,  as the c a t s .  o f 1.5  ml./min.  right auricular  Kgm. were  anesthe-  and p r e p a r e d and I n both c o n t r o l and  a r t i f i c i a l r e s p i r a t i o n was s t a r t e d a t  same t i m e a s t h e i n t r a v e n o u s  a rate the  7-16  w i t h 2$-h0 mgm./Kgm. PB i n a l c o h o l  infused  the  Dogs w e i g h i n g  infusions  A t termination  w h i c h were g i v e n a t  o f the experiment,  appendage a n d t h e apex o f t h e l e f t  only  ventricle  were r e m o v e d .  Rabbits PB I n f u s i o n . for  tissue blood  manner  R a b b i t s whose h e a r t s were t o be u s e d  c o n t e n t e s t i m a t i o n s were p r e p a r e d  a s PB i n f u s e d  cats.  The a n e s t h e t i c  i n t h e same  d o s e r e q u i r e d was  35-55 mg$./Kgm. PB, a n d t h e r a t e o f t h e i n f u s i o n s v a r i e d  from  0.5-1.56 m l . / m i n . Isolated effects  Hearts.  o f PB p e r f u s i o n  A n a t t e m p t was made t o s t u d y t h e  i s o l a t e d r a b b i t h e a r t s by a m o d i f i e d  5 Langendorff  procedure.  Owing t o l a r g e l o s s e s o f K a n d h e a r t  f a i l u r e i n control preparations, the r e l i a b i l i t y technique  e m p l o y e d was q u e s t i o n e d . .  ofthe  Therefore, this  phase  o f t h e p r o j e c t was abandoned i n f a v o u r o f more d e t a i l e d studies i n intact  animals*  A n a l y t i c a l Methods Tissue Blood timated  Content..  Tissue blood  c o n t e n t was e s -  b y a m o d i f i c a t i o n o f t h e method o f Lowry and H a s t i n g s  (194-2) •  R e a d i n g s o f h e m o g l o b i n c o n c e n t r a t i o n w e r e made o n  t h e Beckman DU S p e c t r o p h o t o m e t e r .  S i n c e no a t t e m p t was made  t o d i s t i n g u i s h between b l o o d h e m o g l o b i n and t i s s u e the  concentrations reported are probably higher than  actually present. and  myoglobin,  left  ventricles  The a v e r a g e b l o o d  content  o f v a r i o u s animal  those  of the auricles  preparations are l i s t e d  i n T a b l e I ( s e e f o l l o w i n g page) . The  maximum c h a n g e i n c o n c e n t r a t i o n o f a n y t i s s u e  e l e c t r o l y t e w h i c h c o u l d be p r o d u c e d b y t h e o b s e r v e d in  blood  blood  c o n t e n t w o u l d b e l e s s t h a n 3$.  electrolytes  sidered negligible,  to total  tissue  The c o n t r i b u t i o n o f  c o n c e n t r a t i o n s was  T i s s u e s were d i s s e c t e d f r e e  f r o m g r o s s d e p o s i t s o f f a t and c o n n e c t i v e and minced w i t h  scissors into  tissue,  d e s c r i b e d b y D a n i e l and Boyes  determined  blotted  s m a l l weighed v e s s e l s .  T i s s u e w a t e r a n d e l e c t r o l y t e s were d e t e r m i n e d niques  con-  a n d c o r r e c t i o n s were n o t a p p l i e d .  Tissue Electrolytes.  lightly,  variations  (1956).  b y t h e method o f L o w r y a n d H a s t i n g s  by t h e t e c h F a t c o n t e n t was (194-2) *  TABLE I  T I S S U E BLOOD CONTENT OF VARIOUS ANIMAL  Animal  Preparation  ?f o f t e s t s  Ml.  b l o o d p e r Kgm. Auricles  Rabbit  Control  —»  19.7 t  Rabbit  PB  5  14.8  Cat  Control  5  22.3 t  Cat  PB  l  45.3  failure  failure  Combined A v e r a g e  14  PREPARATIONS  2.4  t i s s u e (wet wt.) Left Ventricle  32.5^  1.6  r 1,5  29.7T 4.9  2.1  23.0 • 2.4  20.7 !  20.4 2.3  27.3 - 2.2  7 Blood and Plasma E l e c t r o l y t e s .  Whole blood samples  were measured, weighed and dried for water and e l e c t r o l y t e analysis by the same methods as t i s s u e s .  Plasma C l was de-  termined by the method of Asper, Schales, and Schales (1947)• Ha and K were determined by i n t e r n a l standard flame analysis on d i l u t e d plasma with the Janice flame  spectrophotometer  (Hald, 1951). Calculations A l l tissue e l e c t r o l y t e i n terms of fat free weights.  concentrations are reported Formulae for the d e r i v a t i o n  of i n t r a - and e x t r a c e l l u l a r water and electrolytes were taken from Manery (1954) •  I t nas been reported that the  absolute  values of e x t r a c e l l u l a r volume derived from plasma and t i s s u e electrolyte  concentrations are u n r e l i a b l e for cardiac muscle  (Robertson and Peyser, 1956).  Therefore, conclusions a r i s i n g  from the data to be presented are based on comparisons of the r e l a t i v e sizes of the chloride and sodium spaces, and are subject to quantitative r e v i s i o n pending further evidence. Formulae for s t a t i s t i c a l analysis were obtained from Snedecor (1946).  V a r i a b i l i t y i s expressed as the standard  error of the mean*  t was calculated, and the p r o b a b i l i t y of  a higher value of t of l e s s than 0.05  (P =<0.05) i s con-  sidered to be s i g n i f i c a n t i n the comparison of any two groups.  8 III.  Cardiovascular The anesthesia,  RESULTS  D e p r e s s a n t E f f e c t s ; o f PB I n f u s i o n s . c o m p a r a t i v e d o s e s o f PB r e q u i r e d  r e s p i r a t o r y a r r e s t , and c a r d i a c  dogs, and r a b b i t s a r e l i s t e d The  cardiac l e t h a l  compares t o t h a t culated  reported  on t h e b a s i s  The r a t i o  o f heart  The r a t i o s o f c a r d i a c  r a t e and b l o o d  t o the species.  Figures  r a t e and blood  mgm./Kgm. o f PB i n f u s e d .  pressure  pressure,  I n the c a t , heart  throughout the course  also differed  expressed as  rate  cardiac  and  the h e a r t  arrest.  a t a slower  a t 65$ o f t h e c o n t r o l r a t e  and hQ% i n t h e r a b b i t when a r r e s t o c c u r r e d . the blood  w i t h the f i r s t rate  until  pressure  fell  I n the rate, i n the  In a l l  r a p i d l y t o 20-30$ o f n o r m a l  100 mgm./Kgm. o f PB.  of fall  decreased  o f t h e i n f u s i o n and r e a c h e d a  and t h e r a b b i t , the d e c r e a s e o c c u r r e d was b e a t i n g  The p a t t e r n o f  plotted against the  dog  species,  lethal  I and I I o n the f o l l o w i n g  minimum o f 32% o f n o r m a l j u s t b e f o r e  the  of respiratory  d o s e was l e s s i n t h e r a b b i t , b u t  percentage o f the c o n t r o l values,  dog,  lower  d o s e s were m a r k e d l y d i f f e r e n t , b e i n g  page show t h e h e a r t  steadily  (1956) when c a l -  et a l  i n t h e r a b b i t and l o w e s t i n t h e dog.  according  page)  d o s e o f PB i n t h e d o g , w h i c h  by D a n i e l  was s i m i l a r i n a l l s p e c i e s .  depression  i n cats,  o f the f r e e base, i s s i g n i f i c a n t l y  a r r e s t dose t o a n e s t h e t i c  highest  failure  i n Table I I . (see f o l l o w i n g  than i n the c a t o r the r a b b i t .  doses t o a n e s t h e t i c  t o produce  I n t h e c a t and t h e r a b b i t ,  then d e c r e a s e d markedly and the animal  a considerably  l a r g e r d o s e o f PB h a d been  infused.  survived  9  MGM./ KGM.PB  F i g u r e I. C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n s o n t h e h e a r t r a t e o f c a t s , d o g s , and r a b b i t s . ( R a t e o f i n f u s i o n , 3.jngm.PB/Kem. /min.)  MGM./KGM. PB  Figure II. C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n s o n t h e b l o o d p r e s s u r e o f c a t s , d o g s , and r a b b i t s . ( Rate o f i n f u s i o n , 3 mgm.PB/Kgm./min.)  TABLE I I  COMPARISON OF THE ANESTHETIC,  RESPIRATORY DEPRESSANT, AND SARDIAC  LETHAL DOSES OF PB I N CATS, DOGS, AND RABBITS Animal  6  Cat  Dog  Rabbit  a  # of tests  Duration min.  Anesth. Dose mgm./Kgm,  43.4  94.9 19.9  tl.2  43.9 14.1  30.0  118.3 129.9  42.9  From D a n i e l e t a l Rate o f i n f u s i o n ,  ro.O  :5.6  (1956) 3 mgm. PB/Kgm./min.  Resp.  Depressant Dose mgm./Kgm. R a t i o n t o Anesth. Dose  74.4 *5.9 (55.0)'  53.3 t8.5  Cardiac Lethal Dose mgm./Kgm. R a t i o t o Anesth. Dose  1.72  326.1 129.5  7.52  (1.84)  170.6 113.7  5.69  1.24  403.7 J82.6  9.42  .11 In  t h e dog,  and  the b l o o d p r e s s u r e  the animal  Effect  their that  t o PB  reduced  Flow i n Cats.  difference  infusions  of the c a t h e a r t coronary  With c i r c u l a t i o n reaching  between c a t s and  indicated  the  to withstand  obviously impaired, the femoral  the  dogs i n  possibility  m i g h t be due prolonged  f l o w a t t e n d a n t upon the  the h e a r t from  descent  time.  the g r e a t e r r e s i s t a n c e o f the former  the a b i l i t y of  observed  response  i t s rapid  succumbed w i t h i n a s h o r t  o f Reduced Coronary The  continued  to  periods  extreme  hypotension.  concentration of  infusion  s i t e might  PB  be  c o n s i d e r a b l y reduced  o r n o n - e x i s t e n t , and  eventual cardiac  f a i l u r e m i g h t be due  to myocardial  alone.  d i s c o v e r whether or not the e f f e c t s  observed  reduced  i n PB PB  the p l a t e a u l e v e l  were t h e n  left  coronary.  ( s e e page  The  coronary  infused cats,  were g i v e n s u f f i c i e n t and  to depress  results  anoxia  are  summarized  a l l cases,  the  animals  animals to the  i n Table I I I .  subjected to  coronary  infused with  PB  those  the  t h a t they maintained  a similar  the l e f t  ventricle  had  failed,  degree o f  F i g u r e s I I I and  the d i f f e r e n c e  despite  hypotension.  t h e h e a r t was  s t r o n g l y enough t o p r o d u c e f l u c t u a t i o n s  pressure.  of  subjected to l i g a t i o n of  s u r v i v e d longer than  beating  a series  produce  the b l o o d p r e s s u r e  ligation  Although  flow could  to  13).  In  fact  In order  I V on page 12 p r e s e n t  still  i n blood graphically  i n the p a t t e r n o f c a r d i o v a s c u l a r d e p r e s s i o n .  12  MINUTES  F i g u r e I I I . C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n l i g a t i o n on t h e h e a r t r a t e o f c a t s .  and  coronary  MINUTES  F i g u r e IV. C o m p a r a t i v e e f f e c t s o f PB i n f u s i o n and l i g a t i o n on t h e b l o o d p r e s s u r e o f c a t s .  coronary  •TABLE  III  E F F E C T S OF CORONARY LIGATION ON :  Animal  # of tests  PB i n f u s e d cats  6  Coronary ligated cats  6  Cat  A  #13  CARDIOVASCULAR  THE  STATUS OF CATS  Control Heart Rate beats/min.  Control Blood Press, mm. Hg.  Terminal Heart Rate beats/min.  165 - 4  110 .* 4  0  Terminal Blood Press. mm. Hg,  Survival A Time min.  69.5  I 8.8 H  165 * 6  110  180  107  S u r v i v a l time a f t e r l i g a t i o n  t  12  89 * 20  111.9  0  248.0  o f t h e c o r o n a r y , o r f r o m 15  t 21.5  min. a f t e r r e s p i r a t o r y a r r e s t .  l.h The  blood  pressure  same c o u r s e the  after  coronary  l i g a t i o n f o l l o w e d the  as i n PB f a i l u r e , b u t t h e p l a t e a u p o r t i o n o f  c u r v e was c o n s i d e r a b l y e x t e n d e d .  exhibit  the gradual  slowing  The h e a r t d i d n o t  t h a t was c h a r a c t e r i s t i c o f  PB f a i l u r e i n c a t s , b u t was m a i n t a i n e d control analyses did  value.  The r e s u l t s ,  reported  as w e l l as t h e e l e c t r o l y t e  below, i n d i c a t e d  that myocardial  o f PB  not d u p l i c a t e the e f f e c t s  Effects  above 60% o f t h e  infusion.  o f PB I n f u s i o n and C o r o n a r y L i g a t i o n  Electrolytes.  Results  of electrolyte  ischemia  on T i s s u e  analyses  are l i s t e d  i n T a b l e s I V (pagel5) and V I (pagel8) D a t a d e r i v i n g f r o m t h e assumption t h a t CI i s c o n f i n e d are  reported  i n Tables  most i m p o r t a n t  Cat. by  V (pagel6) and V I I (page 19).  observations  a r e summarized  In cat auricles,  space The  below.  PB f a i l u r e was  accompanied  s i g n i f i c a n t i n c r e a s e s i n t h e Na and CI c o n c e n t r a t i o n s ,  together no  t o the e x t r a c e l l u l a r  with  a s l i g h t decrease  change i n t h e K c o n t e n t .  i n total tissue  water, but  The sum o f t h e c a t i o n s was  markedly i n c r e a s e d .  Na s p a c e was i n c r e a s e d , as was C I s p a c e  to  The c o n t e n t  a lesser  extent.  o f i n t r a c e l l u l a r w a t e r was  l o w e r and t h e i n t r a c e l l u l a r c a t i o n s a p p e a r e d creased occurred  i n concentration. i n excess  o f the  The i n c r e a s e i n t o t a l t i s s u e increase  In c a t v e n t r i c l e s . similar,  but s t a t i s t i c a l l y  t o have i n -  i nCI.  PB f a i l u r e was a s s o c i a t e d  i n s i g n i f i c a n t , changes o f a  magnitude..However, t o t a l t i s s u e  Na  water i n the r i g h t  with lesser  ventricle  TABLE I V E F F E C T S OF PB INFUSION AND CORONARY LIGATION ( C L . ) ON THE ELECTROLYTE DISTRIBUTION I N CAT HEARTS Tissue  # of Total tests H 0 Gm./Kgm. wot wt.  Control PB CL.  Control PB CL.  Auricles  Right Ventricle  5 6  6 Left Ventricle  Control PB CL.  5  6 6  6  6  Cl mSq./Kgm. w e t wt.  Na mEq./Kgm. . w e t wt.  819 ? 4  811 i 6 783 i 21  6 3 . 6 : 3.3 370 2 14 76.41 473 • 33* 52.11 1.2*'ft384+ 12*  66.8 t 3.2 89.I • 6,4* 70.3 * 1.9*  799-2 804*4 797 i 3  42.8! 1.9 2391 10 50.7: 1.9* 275* 13 41. 5! 0.7ft 234 t 6*  48.2 * 2.4 3381 9 53.7 r 2.3 390! 5 47.5 * l . l * 373 i 9  78.1i 2.3 76. 5 *- 2.3 75.6 s 1.9  794 - 1 778 t 23 796 • 3  33.4- 1.6 203: 9 40. 5 * 1.3** 2171 10 31.4 * 1.2ff 199 i 7  41.8*1.6 45.8• 3.2 40.6 1.2  78.9 * 1.4 79.6 1.8 7 5 . 5 - 2.4  K raEq./Kgra. d r y wt.  mEq./Kgm, wet w t .  351*12 345133 335 i 12  63.4 13.2 65.2 * 6,4 61.2 * 2.4  383 t 7 397 t 4 3712 11t  *• S i g n i f i c a n t c h a n g e (P=0.01-o.05) w i t h r e s p e c t t o c o n t r o l v a l u e . * * H i g h l y s i g n i f i c a n t change (P*<0.01) w i t h r e s p e c t t o c o n t r o l v a l u e T, ft  K  Na mEq./Kgm. d r y wt.  2  S i g n i f i c a n c e o f changes w i t h  respect  t o PB i n f u s i o n v a l u e s .  TABLE V DATA DERIVED FROM TABLE  I V , ASSUMING A L L C I TO B E  EXTRACELLULAR Tissue  Control PB C.L. Control PB C.L. Control PB C.L. a  Auricles  Right Ventricle  ' c i space Gm. EC H 2 0  Na s p a c e Gm. EC H 2 0  'IC H20 Gm./Kgm. wet w t .  t 25 t 27 389 ! 7 - M  ifl 6 : 21 555 t 3k*** M+3 t l i t *  1+03 t 2h 282 t 23*** ^07 1 l 8 * t *  h?6 5kh  t t *  320 : 12 362 I 15* 31 * - 8 t t  301 t 16 33^ - 12 295 * 6 *+  501 - 15 ^70 13 502 ; 6 t  1 11 289 • 11** 23^ 1 9  261 t 10 285 t 19 2h9 t 7  5h6 i 10 1+99 + 29 562 • 6 t  1  Left Ventricle  2h9  ft*  Absence o f a value  for intracellular  I C Na Gm./Kgm. IC H20 a  f  f  4tfSignificance  o f changes w i t h  respect  29.6 t 21.0 13.0 - 7.0  15k t  161 t 7 ll+8 ! 5  !  5.08 t 1.55 1^3 - k 5.95 * ^.10 161 t ih if.95 i 1.13 133 t 6  Na i n d i c a t e s t h a t a n e g a t i v e  t o PB i n f u s i o n v a l u e s .  156 - 15 228 t 2h ** 150 i 19 tT +  value  was c a l c u l a t e d .  * Change o f b o r d e r l i n e s i g n i f i c a n c e ( P - 0 . 0 5 - 0 . 1 ) w i t h r e s p e c t t o c o n t r o l v a l u e . S i g n i f i c a n t change ( P « 0 . 0 1 - 0 . 0 5 ) w i t h r e s p e c t t o c o n t r o l v a l u e , j - * * H i g h l y s i g n i f i c a n t change ( P » < 0 . 0 1 ) w i t h r e s p e c t t o c o n t r o l v a l u e . t ff  IC K Gm./Kgm, I C HpO  H ON  !7 was  s l i g h t l y increased,  and C I s p a c e i n c r e a s e d  Na s p a c e I n b o t h v e n t r i c l e s ,  so t h a t t h e r e  was no  increase  i n i n t r a c e l l u l a r Na c o n c e n t r a t i o n .  nificant  changes from c o n t r o l  tissue left was  CI i n b o t h v e n t r i c l e s ,  ventricle. of borderline  electrolyte  these  than  apparent  The o n l y  sig-  were i n t h e i n c r e a s e d  and i n c r e a s e d  The i n c r e a s e d  CI space i n t h e  CI space i n the r i g h t  ventricle  significance.  With coronary few  values  more  l i g a t i o n ^ cat hearts  alterations  were most p r o n o u n c e d  showed  from the c o n t r o l s , i n the a u r i c l e s .  very  but again  Tissue  C I was  s i g n i f i c a n t l y d e c r e a s e d , and m i n o r d e c r e a s e s o c c u r r e d i n t o t a l w a t e r and K. Na c o n c e n t r a t i o n was The  C I s p a c e was  s l i g h t l y increased.  s i g n i f i c a n t l y smaller while  Na  space  expanded s l i g h t l y .  In the v e n t r i c l e s . coronary  t h e changes o c c u r r i n g f o l l o w i n g  l i g a t i o n were m i n o r . When t h e e l e c t r o l y t e s  pared  t o those  concentrations and  i n PB f a i l e d h e a r t s ,  in  left  ventricles.  in  a l l but the l e f t  so  decrease  i n anoxic  and l o w e r c o n c e n t r a t i o n s Total  water  ventricle,  Na s p a c e was  i n the a u r i c l e  h e a r t s , were com-  s i g n i f i c a n t l y lower  o f C I and Na were f o u n d  right ventricles,  decreased.  i n anoxic  content  o f C I and K  tended  t o be  less  and K c o n c e n t r a t i o n was  smaller  i n a l l tissues,  and r i g h t v e n t r i c l e .  i n C I s p a c e was  auricles  An e v e n  o b s e r v e d , w h i c h was  also  significantly greater  significantly  TABLE V I  EFFECTS OF PB INFUSIONS  ON THE ELECTROLYTE  DISTRIBUTION  IN DOG HEARTS  Control  Tissue  #of tests  Auricles  PB  Total HpO Gm./Kgm. wet w t .  Cl mEq,/Kgm. wet wt.  Na Na mEq./Kgm, mEq./Kgm, d r y wt. 'wet w t .  K K mEq./Kgm, mEn./Kgm. d r y wt. wet wt.  5  819-6  54.9 - 0.9  369 -* 15  66.311.4  5  818 - 6  53.9 ! 2.0  400 1 27  72.0 1 2.1* .362 1 12  374 1 7  67.6^2.7 65.7 - 2.7  H  00 Left Control PB  A  Ventricle  5  5  Change o f b o r d e r l i n e  786 1 4  30.9 - 2 . 5  786 * 2 . 33.2 1 2.6  significance  196*15  4 1 . 9 * 2.9  202 110  (P* 0.05-0.1)  with  43.1 11.9  respect  420 1 27 89.71 5.5 419 1 13  to the control  89.6 12.7  value.  TABLE V I I DATA DERIVED FROM TABLE V I , ASSUMING A L L C I TO BE EXTRACELLULAR  Tissue  CI s p a c e Gm.EC H 0 p e r Kgm. wet w t .  Na s p a c e Gm. EC H 0 p e r Kgm. wet wt.  IC H 0 Gm./Kgm. wet w t .  I C Na mEq./Kgm. IC H 0  10  1+27 - 1*+  **13 t 11  10.6 Z 6.1  159 t 8  hZO t 16  1+58 • 13  398 ! 11  16.1+ * 2.0  161 * 5  23*+ - 20  269 * 19  552 t 18  10.2 t h.6  163 - 15  259 t 21  27!+ Z 11  53^ ! 16  11.1 I 2.0  167 t 8  2  Control  Auricles  PB  Control PB  Left Ventricle  hi?  r  2  2  2  IC K mEq./Kgm. IC K 0 2  20  less  i n a l l tissues.  A significant  w a t e r and d e c r e a s e i n i n t r a c e l l u l a r of anoxic  hearts,  and  this  increase  i n intracellular  K occurred  p a t t e r n was  i n the  repeated  auricles  to a l e s s e r  degree i n the other t i s s u e s .  Dog. was  the o n l y  change  i n PB  a b o r d e r l i n e i n c r e a s e i n t i s s u e Na u n a c c o m p a n i e d  increases  by  ventricles  showed o n l y m i n o r c h a n g e s f o l l o w i n g  failure.  Effects  o f S a l i n e and PB I n f u s i o n s ,  P l a s m a and B l o o d i n Tables  VIII  terminal blood  (page 21)  results  and I X (page 2 2 ) .  and p l a s m a samples  over the i n i t i a l  and C o r o n a r y L i g a t i o n on  Electrolytes. Analytical  and C l and, a f t e r  T h e r e was  little  reported  I n the c a t ,  showed a n i n c r e a s e  PB i n f u s i o n , a n i n c r e a s e samples.  are  i n Na  i n water  concentration  change i n K  concentration.  PB i n f u s i o n s were a c c o m p a n i e d by  increased  w a t e r and C l and p l a s m a C l as compared  control  blood  saline  infusions.  terminal  changes were s m a l l  opposite  i n direction  the  failure  i n water or C l .  Dog PB  I n dog a u r i c l e s ,  coronary  i n magnitude  to those  dog, the o n l y i m p o r t a n t  content  Following  significantly  ligation,  to the the  and t e n d e d t o be  o c c u r r i n g i n PB i n f u s i o n .  change was  an i n c r e a s e  In  i n water  o f t h e t e r m i n a l p l a s m a s a m p l e s f o l l o w i n g PB i n f u s i o n .  TABLE  VIII  EFFECTS OF SALINE AND PB INFUSIONS* AND CORONARY LIGATION ( C L ) ON WHOLE BLOOD ELECTROLYTES IN THE CAT Infusion or Procedure  H 0 Gm./Kgm. w e t wt.  Sample  CI mEq./Kgm. -wet wt.  2  Na mEq./Kgm. d r y wt.  Na mEq./Kgm. wet wt.  None  Initial  8281 h  9 3 . 8 ! 1.8  760*26  129  Saline  Terminal  8*f9 ! 9 '**  97.5 - 2.5  905+b%+*  PB  Terminal  877 J6*****"  111 + 2 *•*«*• 1180 - 9 0 •  CL  Terminal  833 i 8 H f  9^.9 - i M i i  K mEq./Kgm. d r y wt.  2  K mEq./Kgm. w e t wt.  25.5 - 0.8  *+.35-0.10  133 +  32.2 i 1 . 8  »+.82 i 0.37 *  lh2 -h++*  3*+.2 J1.8»*«  *f.08!0.12t  2 7 . 0 ! 2.8?  l.^- 0.38  4  777 i & W • 128 -3 ^ +  +  tv>  * **  Change  o f borderline  Significant  * * + Highly  Significance  (Pr 0.05-0.1) w i t h  (PrO.01-0.05) w i t h  s i g n i f i c a n t change  * *T ^ t t Significance l.ff  change  significance  r e s p e c t t o i n i t i a l c o n t r o l sample (no i n f u s i o n ) .  respect to i n i t i a l  (P»<0.01) w i t h  sample  respect to i n i t i a l  o f changes w i t h  respect to control  saline  o f changes w i t h  r e s p e c t t o PB i n f u s i o n .  (no i n f u s i o n ) .  sample  infusion.  (no i n f u s i o n ) .  TABLE I X  E F F E C T S OF SALINE AND PB INFUSIOFS PON Animal  Infusion or Procedure  Cat  Dog  Sample  PLASMA ELECTROLYTES I N CATS AND DOG'S H 0 Gm./Kgm. wet wt.  Initial Terminal Terminal Terminal  921 935  •  930  - *  None Saline PB  Initial Terminal Terminal  * 2 925 * 930 3 934 4 2 *  942  * *  change  121 122 130 122  1 3 *• 3 ** 2** %  change (P*0.01-0.05)  *-* H i g h l y s i g n i f i c a n t  Cl 'mEq.A.  2  None Saline PB CL  * Significant  AND CORONARY LIGATION ( C L )  116 120 118  with  (P**0.Q1)  * * * •  * •+ 4  Na mEq;/L.  t  1 1 2 *+ t 2 %  159 160 162 161  1 * 1 • 1 * 4 3  3.67 3.83 3.70 3.98  2 2 1  157 153 156  f *  4*35  respect to i n i t i a l  with  K mEq./L.  w  1 2 1  4  sample  control  T  Significant  change ( P « 0 . 0 1 - 0 . 0 5 )  £  Significant  change (P--0.01-0.05,)' w i t h r e s p e c t t o PB i n f u s i o n .  with respect t o control  •  +  *  * •  4.08  control  respect to i n i t i a l  •  saline  0.12 0.40 0.12 0.86  0.17 0.23 0.31  (no i n f u s i o n )  sample  infusion.  (no i n f u s i o n )  23 IV.  DISCUSSION  Species V a r i a t i o n i n the C a r d i o v a s c u l a r E f f e c t s The centrations arrest of  o f PB.  r e s i s t a n c e o f c a t and r a b b i t h e a r t s  o f PB g r e a t e r t h a n  those  t o con-  r e q u i r e d t o produce  i n dog h e a r t s m i g h t be due i n p a r t t o t h e a b i l i t y  the former t o s u r v i v e i n the presence  pressure.  This a b i l i t y  flow a t low a r t e r i a l  could r e s u l t  blood  pressures,  demand f o r t h e m e t a b o l i t e s circulation.  coronary  or from a s m a l l e r  t a c h y c a r d i a has been  reported  to f o l l o w severe myocardial  tricular  fibrillation  (Harris,  et  1  from b e t t e r  blood  o r o x y g e n s u p p l i e d by t h e  I n dogs, v e n t r i c u l a r  al.,195 *-).  o f reduced  ensuing  ischemia, with  ven-  i n a h i g h percentage  o f cases  V e n t r i c u l a r t a c h y c a r d i a and  fibrilla-  t i o n were n o t ' e n c o u n t e r e d  d u r i n g PB i n f u s i o n .  This  fact,  t o g e t h e r w i t h t h e e l e c t r o l y t e d a t a d i s c u s s e d below, a r e taken  as an i n d i c a t i o n  occur  t o any s i g n i f i c a n t  in  favour  that decreased  degree i n dogs.  o f the p o s s i b i l i t y  coronary  blood  terminal  tissue  supply  cats subjected  to  one a n o t h e r .  i s presented  to  those  i n controls,  and t h e l e f t  the r i g h t v e n t r i c l e ,  decrease  with  i n d r y weight.K.  evidence  and l e f t  ligation  f o r both  presumably s e v e r e l y ischemic, in  Direct  less  by a c o m p a r i s o n o f t h e  i n the r i g h t  to l e f t , coronary The v a l u e s  flow d i d not  that cat hearts require  electrolytes  of  coronary  t o c o n t r o l s and  v e n t r i c l e s n©re  v e n t r i c l e , which  showed v a l u e s  similar  the e x c e p t i o n o f an  Therefore,  ventricles  similar was t o those  insignificant  i n c o n t r a s t t o t h e dog  2h  heart,  the metabolism o f these  reflected  by e l e c t r o l y t e  influenced  tissues,  by t h e d e g r e e o f t i s s u e  i n significant  as i t i s  c o n c e n t r a t i o n , appears anoxia.  a n o x i a w h i c h was p r e s e n t i n t h e l e f t result  insofar  alterations  little  Even the severe  ventricle  from  t o be  control  d i d not electrolyte  values.  These e l e c t r o l y t e  data,  combined w i t h t h e f a c t  that  b r a d y c a r d i a was much more p r o n o u n c e d d u r i n g PB i n f u s i o n , a r e evidence  t h a t PB i n f u s i o n s  i n producing  acted d i f f e r e n t l y  coronary  major f a c t o r  ligation,  the p o s s i b i l i t y  i n producing  mechanisms c o n c e r n e d excluded  cardiac arrest  by a l t e r i n g t h e  the terminal decrease  observed  o f the drug here  I n dog i n PB  i n i n t r a c e l l u l a r K which has o f reduced  ventricular  pO^  T h e r e f o r e i t seems p r o b a b l e  i n s p e c i e s r e s i s t a n c e t o PB  c a r d i o v a s c u l a r d e p r e s s i o n i s due t o some d i r e c t actions  be  t a c h y c a r d i a d i d n o t o c c u r , and  was n o t e n c o u n t e r e d .  the d i f f e r e n c e  cannot  ischemia i s probably unimportant  been r e p o r t e d i n the presence  that  t h a t a n o x i a was a  i n electrolyte distribution  depression since ventricular  (Conn, 1956)  In rabbits,  a s i t was i n c a t s  s i n c e e l e c t r o l y t e s were ,not a n a l y z e d .  hearts, myocardial  since  ischemia  c a r d i a c depression i n the c a t h e a r t .  where t h e h e a r t r a t e was w e l l m a i n t a i n e d , with  from  on h e a r t t i s s u e .  induced action or  The s p e c i e s  differences  a r e cause f o r s p e c u l a t i o n as t o t h e s u s c e p t i b i l i t y  o f t h e human h e a r t .  2? PB  and C a r d i a c Cat  Electrolytes. Heart.  PB  The c h a n g e s a c c o m p a n y i n g  were most marked i n t h e c a t a u r i c l e .  failure  The n e t e f f e c t was  an u p t a k e o f Na and C l b y t h e t i s s u e and a l o s s o f w a t e r from  the c e l l s  Since  t i s s u e K was u n a l t e r e d ,  creased, without these  water.  The q u e s t i o n  changes c o u l d space w i t h  hypertonic  a n d w a t e r was s l i g h t l y d e -  a r i s e s as t o whether o r n o t  an osmotic  shift  o f water  The most e x t r e m e  caused by the assumption  be made i s t h a t t h e i n f u s i o n f l u i d  milliosmols per l i t e r )  fluid,  and plasma.  be due t o a n e x p a n s i o n o f t h e e x t r a -  infusion fluid,  which could  auricle  fluid  t h e r e s u l t s must be due t o a n u p t a k e o f i o n s  cellular  hl8  i n t o the i n t e r s t i t i a l  i n the f a i l i n g thus forming  theoretically  heart  and r e p l a c e d  a hypertonic  infinite  auricle.  accumulated behind  the r i g h t  the i n t e r s t i t i a l  extracellular  volume s u r r o u n d i n g  fluid of  the c e l l s of  the  right  for  o n l y o n e - t h i r d o f the a c t u a l l o s s o f i n t r a c e l l u l a r  which occurred. illustrated  Even t h i s  (containing  The e x t r e m e n a t u r e  by (1) the f a c t  t a k e n by h e a r t  extreme c o n d i t i o n would  t h a t terminal plasma  (2) t h e f a c t  p e r f o r m e d o n t h e combined r i g h t fact in  although  samples,  and l e f t  Therefore  the e x t r a c e l l u l a r  increase  that t i s s u e analyses  t h a t K d i d n o t move o u t o f c e l l s  osmotic dehydration.  water  o f the assumption i s  puncture, d i d n o t e x h i b i t any g r e a t  i n Na c o n c e n t r a t i o n ,  account  auricles,  were  and (3) t h e  as i s u s u a l l y the case  i t c a n be c o n c l u d e d  space p r o b a h l y  that,  expanded a t t h e  26 expense o f i n t r a c e l l u l a r w a t e r i n r e s p o n s e tonicity  o f the i n f u s i o n ,  directly  on t h e mechanisms c o n t r o l l i n g  i n t r a c e l l u l a r water  An cussed the be  PB e x e r t e d  to the hyper-  some o t h e r a c t i o n the maintenance o f  content.  i n c r e a s e i n t i s s u e Na u n r e l a t e d t o t h a t  above a l s o o c c u r r e d .  absolute values  I t must be b o r n e i n mind  that  Peyser such  (1956), however, t h e r e  islittle  a r e v i s i o n w o u l d l e a d t o marked  r e l a t i v e volumes o f d i s t r i b u t i o n o f these c a l c u l a t e d Na s p a c e expanded more t h a n dicating  probably  the c e l l s .  reason  to believe  changes i n t h e two i o n s .  The  t h e CI space, i n -  Normally,  ion i s lost.  which  when Na e n t e r s  due t o some d e f e c t i n t h e t r a n s p o r t s y s t e m  e x c h a n g e s Na f o r K, t h e l a t t e r  may  Robertson  t h a t Na was p e n e t r a t i n g some compartment f r o m  CI was e x c l u d e d , cells,  that  f o r Na and C I s p a c e d i s c u s s e d h e r e  subject t o r e v i s i o n i n view o f the f i n d i n g s o f  and  dis-  which  However, s i n c e  t i s s u e K r e m a i n e d u n c h a n g e d , and e x t r a c e l l u l a r K was n o t increased, Either  one o f two p o s s i b i l i t i e s must h a v e  some a n i o n o t h e r  or a c a t i o n other  t h a n CI e n t e r e d  t h a n K was l o s t .  t h e c e l l w i t h Na,  Either  e x p l a i n the i n c r e a s e i n the e x t r a c e l l u l a r CI w h i c h was e n c o u n t e r e d , at present  t o determine  The  occurred.  possibility  concentration of  but there i s i n s u f f i c i e n t  the nature  and d i r e c t  systems which r e g u l a t e t h e i n t r a -  evidence  o f the ions involved.  f a c t s w h i c h c a n be c o n c l u d e d  a r e t h a t PB e x e r t s a s e l e c t i v e  would  from t h i s  study  a c t i o n on t h e  to extracellular  ratios  27 o f Na a n d w a t e r i n t h e c a t a u r i c l e . causes u l t i m a t e that  cardiac a r r e s t , although  the negative  inotropic effect  v e n t r i c l e s has a s i m i l a r  The  heart  failure  t o PB, c o u l d  (1954).  i n K-free  be due t o a  Heart.  found i n dog h e a r t  the tissue.  some o t h e r  dilution  r a t e o f l o s s o f K from  o f t h e e x t e r n a l medium  water.  raises thep o s s i b i l i t y  form o f s u p r e s s i o n This  fact,  that  b y PB, p r o b a b l y combined w i t h  changes  o f PB p r e s e n t  an impairment  thelack o f e f f e c t  emphasizes  the proba-  (1952) a n d H o f f m a n e t a l (1956)  changes i n t h e c o n t r a c t i l i t y  o f mammalian h e a r t may o c c u r  o f changes i n Na and K d i s t r i b u t i o n *  I n i n t a c t d o g s and i s o l a t e d  heart-lung  when v e n t r i c u l a r c o n t r a c t i o n was s u p p o r t e d norepinephrine,  l a r g e amounts o f PB c o u l d  cardiac failure  occurred  offailure  such  a p p e a r s t o be s u s c e p t i b l e t o  expounded b y G r e e n e t aJL  independently  that  concentration  o f PB o n c a t v e n t r i c u l a r e l e c t r o l y t e s , bility  contradictionto  The l a c k o f e l e c t r o l y t e a l t e r a t i o n s  The d o g h e a r t  of c o n t r a c t i l i t y .  o f K i n the presence  I t w o u l d be o f i n t e r e s t t o  may be d e p e n d e n t u p o n t h e a b s o l u t e in  evidence  media, which he r e p o r t s i n r e s p o n s e  through l o s s o f i n t r a c e l l u l a r  Dog  i s no  o f the drug i n the  i s i napparent  know w h e t h e r o r n o t t h e d e c r e a s e d beating  probably  basis.  findings o f Holland  auricles  there  absence o f an accumulation  o f PB i n d u c e d the  This action  (Daniel e t a l ,  preparations,  by i n f u s i o n s o f be i n f u s e d  1956).  o f a n t a g o n i s m , a s e r i e s o f EGG e v e n t s  before  A t the point characterized  28 by  auricular standstill,  tricular not  bradycardia  i n heart-lung  A-V b l o c k  were o b s e r v e d .  I n i n t a c t dogs,  t o that reported  following intravenous  author  states that, while  latter  due  t o the increased L i concentration,  secondary t o a decrease i n the r a t i o K.  I t w o u l d be o f c o n s i d e r a b l e  not  changes i n t h e i n t r a -  vestigate  these they  interest  The  c h a n g e s c o u l d be could  a l s o be  to extracellular  t o know w h e t h e r o r  toextracellular  ratio  o fK occur  o f norepinephrine  I t w o u l d be e q u a l l y i n f o r m a t i v e  t h e ECG c h a n g e s a t PB f a i l u r e ,  norepinephrine  occurred.  by MeKusiek  ofintra-  a t the point o f f a i l u r e  a n t a g o n i s m t o PB.  although  infusion ofL i salts.  The  i n dog a u r i c l e s  idioven-  experiments, hyperkalemia a l s o  T h i s ECG p a t t e r n i s s i m i l a r  (195^) t o o c c u r  and t e r m i n a l  toi n -  and t h e e f f e c t s o f  infusion i n cats.  effect  o f PB o n t h e e l e c t r i c a l  excitability of  n e r v o u s t i s s u e h a s been a p o i n t o f c o n s i d e r a b l e  interest  ( G r u b e r e t a l , 1938, E c c l e s , 19^6 and B r o o k s and E c c l e s , 19^7.) I n v i e w o f t h e c h a n g e s e n c o u n t e r e d I n Na a n d w a t e r in  cat auricles,  regarding in  The  this  microelectrode  an e f f e c t  metabolism  s t u d i e s might provide  evidence  o f PB o n membrane and a c t i o n p o t e n t i a l s  tissue.  R e l a t i o n o f T i s s u e E l e c t r o l y t e s i n D i f f e r e n t Chambers o f  the Heart t o F u n c t i o n . Control values i n general  agreement w i t h  f o r cardiac electrolytes, those  reported  which a r e  b y R o b e r t s o n and  P e y s e r , d951)'and M a n e r y (195*0 a r e o f c o n s i d e r a b l e  interest.  29 In the a u r i c l e s ,  CIspace  whereas, i n the l e f t larger.  t o be l a r g e r  ventricle,  t h e Na  t h a n Na  space  space,  i s always  the  T h i s i s an i n d i c a t i o n o f a g r e a t e r p r o p o r t i o n  Cl-containing tration, similar fundus  tends  cells,  or a higher i n t r a c e l l u l a r  i n the a u r i c l e s ,  D a n i e l and  evidence o f the i n t r a c e l l u l a r  Boyes  CI  concen-  (1956) f o u n d  p o s i t i o n o f CI i n t h e  o f t h e u t e r u s , w h i c h i s t h e pacemaker a r e a o f  organ.  The  apparent p r o p o r t i o n of i n t r a c e l l u l a r  i n v e r s e l y w i t h the d i s t a n c e appears maticity  that  intracellular  i n excitable  from C I may  tissues.  CI  t h e pacemaker a r e a . be  of  associated with  that varied It auto-  30 V.  1.  A species  SUMMARY  difference i n resistance  t o the c a r d i o v a s c u l a r  d e p r e s s a n t e f f e c t s o f c o n t i n u o u s PB i n f u s i o n s h a s b e e n The  cardiac lethal  d o s e f o r dogs was 1 7 1 , f o r c a t s  for  r a b b i t s h-Oh mgm./Kgm. o f NaPB.  2.  Myocardial  i s c h e m i a r e s u l t i n g from  found.  326,  the hypotensive  and  effects  o f PB i s p r o b a b l y n o t t h e c a u s e o f c a r d i a c a r r e s t i n PB i n toxicated  c a t s and d o g s .  3.  E l e c t r o l y t e studies  the  control of intracellular  cat  auricle.  k.  The p o s s i b l e  to  some o t h e r  discussed. that  5.  Na and w a t e r c o n c e n t r a t i o n s  r e l a t i o n o f PB i n d u c e d  in  e l e c t r o l y t e changes  d i r e c t a c t i o n o f PB o n t h e m y o c a r d i u m i s  Evidence  i s produced  changes i n c a r d i a c  ently  i n d i c a t e a s e l e c t i v e a c t i o n o f PB o n  i n support o f the hypothesis  c o n t r a c t i l i t y may o c c u r  o f changes i n Na and K  independ-  distribution.  The d i s t r i b u t i o n o f e l e c t r o l y t e s i n d i f f e r e n t c a r d i a c  tissues  indicates that  tissues with greater  automaticity,  s u c h a s t h e a u r i c l e s , may c o n t a i n more i n t r a c e l l u l a r C I .  31 V  BIBLIOGRAPHY  A s p e r , S.P., J r . , S c h a l e s , 0 . , and S c h a l e s , S.S., I m p o r t a n c e o f c o n t r o l l i n g pH i n t h e S c h a l e s a n d S c h a l e s method o f c h l o r i d e d e t e r m i n a t i o n . J . B i o l . Chem., 1 6 8 : 779-780,1947. B r o o k s , C. M c C , a n d E c c l e s , J . C , A s t u d y o f t h e e f f e c t s : o f a n a e s t h e s i a and a s p h y x i a on the monosynaptic pathway t h r o u g h t h e s p i n a l c o r d . J . H e u r o p h y s i o l . ,  10:  3^9-360, 1947.  Conn, H.L., J r . , E f f e c t s o f d i g i t a l i s a n d h y p o x i a o n potassium t r a n s f e r and d i s t r i b u t i o n i n the dog h e a r t . Am. J . P h y s i o l . , 184:548-552. 1956. D a n i e l , E . E . , and B o y e s , D.A., The e l e c t r o l y t e s o f human u t e r u s and t h e i r p o s s i b l e r e l a t i o n t o f u n c t i o n a l a c t i v i t y . Am. J . O b s t e t . , 1956. ( I n p r e s s ) D a n i e l , E . E . , F u l t o n , J.B., H i d d l e s t o n , M., M a r t i n , W., a n d F o u l k s , |r.G., A n a n a l y s i s o f t h e mechanism o f b a r b i t u r a t e induced c a r d i o v a s c u l a r d e p r e s s i o n and i t s antagonism by sympathomimetic amines. A r c h . I n t e r n a t . pharmacodyn. e t e x p e r . t h e r a p . , 1956. ( I n p r e s s ) Eccles,  J.C.,  Synaptic potentials  p h y s i o l . , 2* 87-120, 1946.  o f motoneurones. J . Heuro-  G r e e n , J . P . , G i a r m a n , N . J . , and S a l t e r , W.T., Combined e f f e c t s ; o f c a l c i u m and potassium o n c o n t r a c t i l i t y and e x c i t a b i l i t y o f t h e mammalian m y o c a r d i u m . Am. J . P h y s i o l . , 1 7 1 * 1 7 4 - 1 7 7 »  1952.  G r u b e r , C M . , H a u r y , V.G., a n d G r u b e r , C M . , J r . , The p o i n t o f a c t i o n o f the b a r b i t u r a t e s i n depressing the c a r d i a c vagus n e r v e s . J . P h a r m a c o l . & E x p e r . T h e r a p . , 63.: 239-252",  1938.  H a j d u , S., Mechanism o f s t a i r c a s e a n d c o n t r a c t u r e i n v e n t r i c u l a r m u s c l e . £m. J . P h y s i o l . , 1 7 4 ; 371-380, 1953. Hald,  P.M., D e t e r m i n a t i o n s  w i t h flame  Med. Res., 4: 79-105, 1951.  photometer, Meth.  i n  H a r r i s , A.S., B i s t e n i , A., R u s s e l i y R.A., Brigham, J . C , and F i r e s t o n e , J.E., E x c i t a t o r y f a c t o r s i n v e n t r i c u l a r tachyc a r d i a r e s u l t i n g from m y o c a r d i a l i s c h e m i a . Potassium a m a j o r e x c i t a n t . S c i e n c e , 112:200-203, 1954.  32  H o f f m a n . B.F., B i n d l e r , E . , and S u c k l i n g , E.E., Postextrasystolic potentiation o f contraction i n cardiac muscle. Am. J . P h y s i o l . , 185: 95-102, 1956. H o l l a n d , W.C., The a c t i o n o f a n e s t h e t i c a g e n t s o n t h e l o s s o f p o t a s s i u m from i s o l a t e d g u i n e a p i g a u r i c l e s . J . P h a r m a c o l . & E x p e r . T h e r a p . , I l l : 1-8, 195^. Lowry, O.H., a n d H a s t i n g s , A.B., H i s t o c h e m i c a l c h a n g e s a s s o c i a t e d w i t h a g i n g . I . Methods and c a l c u l a t i o n s . J . B i o l . Chem., l V i : 257-269, 19^2. Manery, J . F . , W a t e r and e l e c t r o l y t e m e t a b o l i s m . Rev., 3it: 3 3 ^ 1 7 , 195^.  Physiol.  M c K u s i c k , V.A., The e f f e c t o f l i t h i u m o n t h e e l e c t r o c a r d i o g r a m o f a n i m a l s and r e l a t i o n o f t h i s e f f e c t t o t h e r a t i o o f i n t r a c e l l u l a r and e x t r a c e l l u l a r c o n c e n t r a t i o n s of potassium. J . C l i n . Invest., 589-610, 1951*-.  33:  R o b e r t s o n , W. v . B., and P e y s e r , P., Changes i n w a t e r a n d e l e c t r o l y t e s o f c a r d i a c muscle f o l l o w i n g e p i n e p h r i n e . Am. J . P h y s i o l . , 166: 277-283, 1951. R o b e r t s o n , W. v . B., and P e y s e r , P., E s t i m a t e s o f e x t r a c e l l u l a r f l u i d volume o f myocardium. Am. J . P h y s i o l . , 18^+: 171 -17^,  1956.  S n e d e c o r , G.W., S t a t i s t i c a l methods a p p l i e d t o e x p e r i m e n t s i n a g r i c u l t u r e and b i o l o g y . *+th ed., Iowa s t a t e p r e s s ,  Ames, 19 +6, pp. 5*+-88. 1  S z e n t - G y o r g y i , A.. C h e m i c a l p h y s i o l o g y o f c o n t r a c t i o n i n body and h e a r t m u s c l e . A c a d e m i c p r e s s , New Y o r k , 1953» pt. I I .  

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