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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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AN ANALYSIS OF THE MECHANISMS OF 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 i n the Department o f Pharmacology We accept t h i s t h e s i s as conforming to the r e q u i r e d standard THE UNIVERSITY OF BRITISH COLUMBIA October 1956 I n p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s f o r an advanced degree a t t h e U n i v e r s i t y o f B r i t i s h Columbia, I agree t h a t .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 r e f e r e n c e and s t u d y . I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d by the Head of my Department o r by h i s r e p r e s e n t a t i v e . I t i s under- st o o d t h a t c o p y i n g o r p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n . Department of The U n i v e r s i t y o f B r i t i s h Columbia, Vancouver 8, Canada. Date (\(tiJM\ " , » i i A b s t r a c t Continuous i n f u s i o n s o f b a r b i t u r a t e s i n a r t i f i c i a l l y - r e s p i r e d animals r e s u l t i n profound c a r d i o v a s c u l a r d e p r e s s i o n w i t h t e r m i n a l c a r d i a c a r r e s t . I n an attempt to e l u c i d a t e the nature o f t h i s c a r d i a c d e p r e s s i o n a t a c e l l u l a r l e v e l , t i s s u e e l e c t r o l y t e analyses were performed on mammalian h e a r t s i n f a i l u r e f o l l o w i n g i n f u s i o n o f the i n t a c t animal w i t h sodium p e n t o b a r b i t a l . The p a t t e r n s of e l e c t r o l y t e d i s t r i b u t i o n en- countered were compared to those i n animals r e c e i v i n g c o n t r o l s a l i n e i n f u s i o n s , and to those i n cats subjected to p a r t i a l m y o c ardial ischemia through l i g a t i o n o f the l e f t coronary- a r t e r y . S i g n i f i c a n t s p e c i e s d i f f e r e n c e s i n r e s i s t a n c e to the c a r d i o l e t h a l e f f e c t o f p e n t o b a r b i t a l were observed. On the b a s i s o f d i f f e r e n c e s i n e f f e c t s on e l e c t r o l y t e d i s t r i b u t i o n and p a t t e r n o f f a i l u r e , the c o n c l u s i o n was reached t h a t m y o cardial ischemia was probably not r e s p o n s i b l e f o r pento- b a r b i t a l f a i l u r e i n the c a t and the dog. I n c a t a u r i c l e s , p e n t o b a r b i t a l exerted 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 metabolism which may have been r e l a t e d to d e p r e s s i o n o f a t r i a l e l e c t r i c a l a c t i v i t y . I n a d d i t i o n , evidence was found o f a d i r e c t a c t i o n o f p e n t o b a r b i t a l on c a r d i a c c o n t r a c t i l i t y independent o f Na and K d i s t r i b u t i o n . C o n t r o l e l e c t r o l y t e v a l u e s provided support f o r the h y p o t h e s i s t h a t e l e c t r o l y t e 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 a u t o m a t i c i t y . v i ACKNOWLEDGEMENTS The author wishes to thank Dr. E.E. D a n i e l and Dr. J.G. Fou l k s f o r t h e i r encouragement and a s s i s t a n c e i n the 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 provided by the N a t i o n a l Research C o u n c i l o f Canada and the Banting Research Foundation i s a l s o g r a t e f u l l y acknowledged. i i i TABLE OF CONTENTS ABSTRACT i i LIST OF TABLES i v LIST OF FIGURES v ACKNOWLEDGEMENTS v i I . INTRODUCTION 1 I I . METHODS 3 1 I I I . RESULTS 8 IV. DISCUSSION 23 V. SUMMARY 30 V I . BIBLIOGRAPHY 31 i v LIST OF TABLES TABLE I. T i s s u e blood content o f v a r i o u s animal p r e p a r a t i o n s 6 I I . Comparison o f the a n e s t h e t i c , r e s p i r a t o r y - depressant, and c a r d i a c l e t h a l doses o f PB i n c a t s , dogs, and r a b b i t s . 10 I I I . E f f e c t s o f coronary l i g a t i o n on the c a r d i o - v a s c u l a r s t a t u s .of c a t s 13 IV. E f f e c t s o f PB i n f u s i o n and coronary l i g a t i o n on the 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 h e a r t s 15 V. Data d e r i v e d from Table IV, assuming a l l CI to be e x t r a c e l l u l a r . 16 VI. E f f e c t s o f PB i n f u s i o n s on the 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 dog h e a r t s 18 V I I . Data d e r i v e d from Table VT, assuming a l l CI to be e x t r a c e l l u l a r 19 V I I I . E f f e c t s of s a l i n e and PB i n f u s i o n s , and coronary l i g a t i o n on whole blood e l e c t r o - l y t e s i n the c a t 21 IX. 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 eoronary l i g a t i o n on plasma e l e c t r o l y t e s i n c a t s and dogs 22 V TABLE OF FIGURES FIGURE I. Comparative e f f e c t s o f PB i n f u s i o n s on the h e a r t r a t e of c a t s , dogs, and r a b b i t s 9 I I . Comparative e f f e c t s o f PB i n f u s i o n s on the blood pressure of c a t s , dogs, and r a b b i t s 9 I I I . Comparative e f f e c t s o f PB i n f u s i o n s and coronary l i g a t i o n on the h e a r t r a t e o f c a t s 12 IV. Comparative e f f e c t s o f PB i n f u s i o n s and coronary l i g a t i o n on the blood pressure of 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 direct depressant action on the contractile 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 inotropic action of PB was antagonized by infusion of sympathomimetic amines, permit- ting large amounts of the barbiturate to be administered, a t r i a l s tandst i l l and A-V block occurred. Holland (1954) nas reported that PB alters the rate of K transport i n isolated rabbit and guinea pig auricles i n concentrations which produce a 50-80$ reduction i n the amplitude of contraction. In addition, the changes encountered i n the intrace l lu lar amounts of Na and K following previous stimulation (Hajdu, 1953), and the adminis- trat ion 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 under- l i e changes i n cardiac contract i l i ty . The present investigation was undertaken i n order to discover whether or not the cardiac fa i lure induced by PB was associated with alterations i n tissue electrolytes i n the intact animal.. In the dog, no significant changes were encountered, i n keeping with the earl ier finding of l i t t l e change i n e l e c t r i c a l ac t i v i ty . In the cat, however, the response to continuous 2 i n f u s i o n s o f PB f o l l o w e d a d i f f e r e n t course, and the c a r d i a c l e t h a l dose was s i g n i f i c a n t l y g r e a t e r than i n the dog. Brady- c a r d i a was pronounced, even w i t h o u t i n f u s i o n s o f sympatho- mimetic amines, and t e r m i n a l e l e c t r o l y t e changes were marked. The evidence suggests a s e l e c t i v e a c t i o n o f PB on c a t a u r i c l e s . 3 I I . METHODS Cats PB I n f u s i o n . Cats weighing 1-3.5 Kgm. were anes- t h e t i z e d , 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 30-^5 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 Drug Houses, 60 mgm./ml. i n 10$ e t h y l a l c o h o l ) . The tr a c h e a and the l e f t c a r o t i d a r t e r y were cannulated, and a mercury manom- e t e r was arranged to measure a r t e r i a l blood p r e s s u r e . A con- t r o l blood sample was withdrawn from the c a r o t i d a r t e r y . I n - f u s i o n s were made i n t o the femoral v e i n by means o f an a d j u s t - able r a t e pump. PB was g i v e n a t the r a t e of 3 mgm./Kgm./min. i n 0.95$ NaCl ( 0 . 5 ml./min.). C o n t r o l animals r e c e i v e d 0 .5 ml./min. o f 0.95$ NaCl and supplemental a n e s t h e t i c doses o f PB i n a l c o h o l . Heart r a t e , blood p r e s s u r e , and r e s p i r a t o r y r a t e were recorded every 5-10 minutes. A f t e r r e s p i r a t o r y f a i l u r e , a r t i f i c i a l r e s p i r a t i o n was p r o v i d e d a t the r a t e o f 16 resp./min. i n animals i n f u s e d w i t h PB. When the b l o o d pressure f e l l below 15 mm. o f Hg (or immediately before t e r - m i n a t i o n o f the experiment i n c o n t r o l s ) , 1000 Iv U», Heparin (Connaught 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 . A t e r m i n a l b l o o d sample was taken by h e a r t puncture and the chest was opened. I n c o n t r o l animals, the h e a r t was removed a t once. In PB i n f u s e d animals, i t was memoved when there was no l o n g e r a v i s i b l e h e a r t b e a t . Coronary L i g a t i o n . I n one group o f c a t s , prepared 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 ischemia was produced by i n t e r f e r e n c e w i t h the coronary blood supply. The chest and 4 per 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 a r r e s t , and the l e f t coronary a r t e r y was d i s s e c t e d out abovce the l e v e l o f i t s f i r s t major brances. When f i f t e e n minutes had elapsed s i n c e r e s p i r a - t o r y f a i l u r e 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 , the l e f t c oronary was l i g a t e d , the PB i n f u s i o n was d i s c o n t i n u e d , and the per i c a r d i u m and chest were c l o s e d . I n one animal (Cat #13) the experiment was allowed to proceed to complete c a r d i a c f a i l u r e . I n the remaining animals, the h e a r t was removed when the l e f t v e n t r i c l e f a i l e d . Dogs PB I n f u s i o n . Dogs weighing 7-16 Kgm. were anesthe- t i z e d w i t h 2$-h0 mgm./Kgm. PB i n a l c o h o l and prepared and i n f u s e d i n the same manner as the c a t s . I n both c o n t r o l and experimental animals, a r t i f i c i a l r e s p i r a t i o n was s t a r t e d a t the same time as the intravenous i n f u s i o n s which were g i v e n a t a r a t e o f 1.5 ml./min. At t e r m i n a t i o n o f the experiment, on l y the r i g h t a u r i c u l a r appendage and the apex o f the l e f t v e n t r i c l e were removed. R a b b i t s PB I n f u s i o n . R a b b i t s whose h e a r t s were to be used f o r t i s s u e blood content e s t i m a t i o n s were prepared i n the same manner as PB i n f u s e d c a t s . The a n e s t h e t i c dose r e q u i r e d was 35-55 mg$./Kgm. PB, and the r a t e o f the i n f u s i o n s v a r i e d from 0.5-1.56 ml./min. I s o l a t e d H earts . An attempt was made to study the e f f e c t s o f PB p e r f u s i o n 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 L a n g e n d o r f f procedure. Owing t o l a r g e l o s s e s o f K and h e a r t f a i l u r e i n c o n t r o l p r e p a r a t i o n s , the r e l i a b i l i t y o f the technique employed was questioned.. T h e r e f o r e , t h i s phase o f the 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 s t u d i e s i n i n t a c t animals* A n a l y t i c a l Methods T i s s u e Blood Content.. T i s s u e b l o o d content was e s - timated by a m o d i f i c a t i o n o f the method o f Lowry and H a s t i n g s (194-2) • Readings o f hemoglobin c o n c e n t r a t i o n were made on the Beckman DU Spectrophotometer. S i n c e no attempt was made t o d i s t i n g u i s h between b l o o d hemoglobin and t i s s u e myoglobin, th e c o n c e n t r a t i o n s r e p o r t e d are pr o b a b l y h i g h e r than those a c t u a l l y p r e s e n t . The average bl o o d content o f the a u r i c l e s and l e f t v e n t r i c l e s o f v a r i o u s animal p r e p a r a t i o n s a r e l i s t e d i n T a b l e I (see f o l l o w i n g page) . The maximum change i n c o n c e n t r a t i o n o f any t i s s u e e l e c t r o l y t e which c o u l d be produced by the observed v a r i a t i o n s i n b l o o d content would be l e s s t h a n 3$. The c o n t r i b u t i o n o f bl o o d e l e c t r o l y t e s to t o t a l t i s s u e c o n c e n t r a t i o n s was con- s i d e r e d n e g l i g i b l e , and c o r r e c t i o n s were not a p p l i e d . T i s s u e E l e c t r o l y t e s . T i s s u e s were d i s s e c t e d f r e e from g r o s s d e p o s i t s o f f a t and conne c t i v e t i s s u e , b l o t t e d l i g h t l y , and minced w i t h s c i s s o r s i n t o s m a l l weighed v e s s e l s . T i s s u e water and e l e c t r o l y t e s were determined by the t e c h - niques d e s c r i b e d by D a n i e l and Boyes (1956). F a t content was determined by the method o f Lowry and H a s t i n g s (194-2) * TABLE I TISSUE BLOOD CONTENT OF VARIOUS ANIMAL PREPARATIONS Animal P r e p a r a t i o n R a b b i t R a b b i t Cat Cat C o n t r o l PB f a i l u r e C o n t r o l PB f a i l u r e ?f o f t e s t s —» 5 5 l Ml. b l o o d per Kgm. A u r i c l e s 19.7 t 2.4 14.8 r 1,5 22.3 t 2.1 45.3 t i s s u e (wet wt.) L e f t V e n t r i c l e 32.5^ 1.6 29.7T 4.9 23.0 • 2.4 20.4 Combined Average 14 20.7 ! 2.3 27.3 - 2.2 7 Blood and Plasma Electrolytes . Whole blood samples were measured, weighed and dried for water and electrolyte analysis by the same methods as tissues. Plasma C l was de- termined by the method of Asper, Schales, and Schales (1947)• Ha and K were determined by internal standard flame analysis on diluted plasma with the Janice flame spectrophotometer (Hald, 1951). Calculations A l l tissue electrolyte concentrations are reported i n terms of fat free weights. Formulae for the derivation of i n t r a - and extracellular water and electrolytes were taken from Manery (1954) • I t nas been reported that the absolute values of extracellular volume derived from plasma and tissue electrolyte concentrations are unreliable for cardiac muscle (Robertson and Peyser, 1956). Therefore, conclusions arising from the data to be presented are based on comparisons of the relat ive sizes of the chloride and sodium spaces, and are subject to quantitative revis ion 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 probabil ity of a higher value of t of less than 0.05 (P =<0.05) i s con- sidered to be significant i n the comparison of any two groups. 8 I I I . RESULTS C a r d i o v a s c u l a r Depressant E f f e c t s ; o f PB I n f u s i o n s . The comparative doses o f PB r e q u i r e d to produce a n e s t h e s i a , 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 f a i l u r e i n c a t s , dogs, and r a b b i t s are l i s t e d i n Table I I . (see f o l l o w i n g page) The c a r d i a c l e t h a l dose o f PB i n the dog, which compares to t h a t r e p o r t e d by D a n i e l e t a l (1956) when c a l - c u l a t e d on the b a s i s o f the f r e e base, i s s i g n i f i c a n t l y lower than i n the c a t or the r a b b i t . The r a t i o o f r e s p i r a t o r y a r r e s t dose to a n e s t h e t i c dose was l e s s i n the r a b b i t , but was s i m i l a r i n a l l s p e c i e s . The r a t i o s o f c a r d i a c l e t h a l doses to a n e s t h e t i c doses were markedly d i f f e r e n t , being h i g h e s t i n the r a b b i t and lowest i n the dog. The p a t t e r n o f d e p r e s s i o n o f h e a r t r a t e and blood pressure a l s o d i f f e r e d a c c o r d i n g to the s p e c i e s . F i g u r e s I and I I on the f o l l o w i n g page show the h e a r t r a t e and blood p r e s s u r e , expressed as percentage o f the c o n t r o l v a l u e s , p l o t t e d a g a i n s t the mgm./Kgm. of PB i n f u s e d . In the c a t , h e a r t r a t e decreased s t e a d i l y throughout the course o f the i n f u s i o n and reached a minimum of 32% of normal j u s t before c a r d i a c a r r e s t . In the dog and the r a b b i t , the decrease occurred a t a slower r a t e , and the h e a r t was bea t i n g a t 65$ of the c o n t r o l r a t e i n the dog, and hQ% i n the r a b b i t when a r r e s t o c c u r r e d . In a l l s p e c i e s , the blood pressure f e l l r a p i d l y t o 20-30$ of normal w i t h the f i r s t 100 mgm./Kgm. o f PB. I n the c a t and the r a b b i t , the r a t e o f f a l l then decreased markedly and the animal s u r v i v e d u n t i l a c o n s i d e r a b l y l a r g e r dose o f PB had been i n f u s e d . 9 MGM./ KGM.PB F i g u r e I . Comparative e f f e c t s o f PB i n f u s i o n s on the h e a r t r a t e o f c a t s , dogs, and r a b b i t s . (Rate o f i n f u s i o n , 3.jngm.PB/Kem. /min.) MGM./KGM. PB F i g u r e I I . Comparative e f f e c t s o f PB i n f u s i o n s on the blood pressure of c a t s , dogs, and r a b b i t s . ( Rate of 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 IN CATS, DOGS, AND RABBITS Animal # o f D u r a t i o n Anesth. Resp. Depressant t e s t s min. Dose Dose mgm./Kgm, mgm./Kgm. R a t i o n t o Anesth. Dose C a r d i a c L e t h a l Dose mgm./Kgm. R a t i o t o Anesth. Dose Cat 6 94 .9 19 .9 43.4 t l . 2 74.4 *5.9 1.72 326.1 129.5 7.52 Dog R a b b i t 43 .9 14 .1 118.3 129.9 30.0 r o . O 4 2 . 9 :5.6 (55.0)' 53.3 t8.5 (1 .84) 1 .24 170.6 113.7 403.7 J82.6 5.69 9.42 a From D a n i e l e t a l (1956) Rate o f i n f u s i o n , 3 mgm. PB/Kgm./min. .11 In the dog, the blood pressure continued i t s r a p i d descent and the animal succumbed w i t h i n a s h o r t time. E f f e c t o f Reduced Coronary Flow i n Cats. The observed d i f f e r e n c e between c a t s and dogs i n t h e i r response to PB i n f u s i o n s i n d i c a t e d the p o s s i b i l i t y t h a t the g r e a t e r r e s i s t a n c e o f the former might be due to the a b i l i t y o f the c a t h e a r t to withstand prolonged p e r i o d s of reduced coronary flow attendant upon the extreme hypotension. With c i r c u l a t i o n o b v i o u s l y impaired, the c o n c e n t r a t i o n o f PB reac h i n g the h e a r t from the femoral i n f u s i o n s i t e might be c o n s i d e r a b l y reduced or n o n - e x i s t e n t , and e v e n t u a l c a r d i a c f a i l u r e might be due to myocardial anoxia alone. I n order to d i s c o v e r whether or not reduced coronary f l o w c o u l d produce the e f f e c t s observed i n PB i n f u s e d c a t s , a s e r i e s of animals were gi v e n s u f f i c i e n t PB to depress the blood pressure to the p l a t e a u l e v e l and were then subjected to l i g a t i o n o f the l e f t coronary. The r e s u l t s are summarized i n Table I I I . (see page 13). I n a l l cases, the animals s u b j e c t e d to coronary l i g a t i o n s u r v i v e d l o n g e r than those i n f u s e d w i t h PB d e s p i t e the f a c t t h a t they maintained a s i m i l a r degree of hypotension. Although the l e f t v e n t r i c l e had f a i l e d , the h e a r t was s t i l l b e a t i n g s t r o n g l y enough to produce f l u c t u a t i o n s i n blood p r e s s u r e . F i g u r e s I I I and IV on page 12 present g r a p h i c a l l y the d i f f e r e n c e 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 . Comparative e f f e c t s o f PB i n f u s i o n and coronary l i g a t i o n on the h e a r t r a t e o f c a t s . M I N U T E S F i g u r e IV. Comparative e f f e c t s of PB i n f u s i o n and coronary l i g a t i o n on the blood pressure of c a t s . •TABLE III EFFECTS OF CORONARY LIGATION ON THE : CARDIOVASCULAR STATUS OF CATS Animal # o f t e s t s C o n t r o l Heart Rate beats/min. C o n t r o l Blood Press, mm. Hg. Term i n a l Heart Rate beats/min. Te r m i n a l Blood P r e s s . mm. Hg, S u r v i v a l A Time min. PB i n f u s e d 6 c a t s Coronary 6 l i g a t e d c a t s 165 - 4 165 * 6 110 .* 4 0 110 t 12 89 * 20 69.5 I 8.8 111.9 t 21 . 5 H Cat #13 180 107 0 248.0 A S u r v i v a l time a f t e r l i g a t i o n o f the coronary, or from 15 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 a f t e r coronary l i g a t i o n f o l l o w e d the same course as i n PB f a i l u r e , but the p l a t e a u p o r t i o n o f the curve was c o n s i d e r a b l y extended. The h e a r t d i d not e x h i b i t the gradual slowing 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 , but was maintained above 60% o f the c o n t r o l v a l u e . The r e s u l t s , as w e l l as the e l e c t r o l y t e analyses r e p o r t e d below, i n d i c a t e d t h a t myocardial ischemia d i d not d u p l i c a t e the e f f e c t s o f PB i n f u s i o n . E f f e c t s of PB I n f u s i o n and Coronary L i g a t i o n on T i s s u e E l e c t r o l y t e s . R e s u l t s of e l e c t r o l y t e analyses are l i s t e d i n Tables IV (pagel5) and VI (pagel8) Data d e r i v i n g from the assumption t h a t CI i s co n f i n e d to the e x t r a c e l l u l a r space are r e p o r t e d i n Tables V (pagel6) and VII (page 19). The most important o b s e r v a t i o n s a r e summarized below. Cat. In c a t a u r i c l e s , PB f a i l u r e was accompanied by s i g n i f i c a n t i n c r e a s e s i n the Na and CI c o n c e n t r a t i o n s , together w i t h a s l i g h t decrease i n t o t a l t i s s u e water, but no change i n the K content. The sum of the c a t i o n s was markedly i n c r e a s e d . Na space was i n c r e a s e d , as was CI space to a l e s s e r e x t e n t . The content o f i n t r a c e l l u l a r water was lower and the i n t r a c e l l u l a r c a t i o n s appeared to have i n - creased i n c o n c e n t r a t i o n . The i n c r e a s e i n t o t a l t i s s u e Na occur r e d i n excess o f the i n c r e a s e i n CI. In c a t v e n t r i c l e s . PB f a i l u r e was a s s o c i a t e d w i t h s i m i l a r , but s t a t i s t i c a l l y i n s i g n i f i c a n t , changes o f a l e s s e r magnitude..However, t o t a l t i s s u e water i n the r i g h t v e n t r i c l e TABLE IV EFFECTS OF PB INFUSION AND CORONARY LIGATION ( C L . ) ON THE ELECTROLYTE DISTRIBUTION IN CAT HEARTS T i s s u e # of T o t a l t e s t s H 20 Gm./Kgm. wot wt. C o n t r o l A u r i c l e s 5 819 ? 4 PB 6 811 i 6 C L . 6 783 i 21 C o n t r o l PB C L . C o n t r o l PB C L . R i g h t V e n t r i c l e L e f t V e n t r i c l e 5 799-2 6 804*4 6 797 i 3 6 6 794 - 1 778 t 23 796 • 3 C l Na mSq./Kgm. mEq./Kgm. wet wt. d r y wt. 63.6: 3.3 370 2 14 76.41 473 • 33* 52.11 1.2*'ft384+ 12* 42.8! 1.9 2391 10 50.7: 1.9* 275* 13 41. 5! 0.7ft 234 t 6* 33.4- 1.6 203: 9 40. 5 * 1.3** 2171 10 31.4 * 1.2ff 199 i 7 Na K mEq./Kgm. raEq./Kgra. . wet wt. d r y wt. 66.8 t 3.2 89.I • 6,4* 70.3 * 1.9* 351*12 345133 335 i 12 48 .2 * 2.4 3381 9 53.7 r 2.3 390! 5 47.5 * l . l * 373 i 9 41.8*1.6 45.8• 3.2 40.6 1.2 383 t 7 397 t 4 3712 11t K mEq./Kgm, wet wt. 63.4 13.2 65.2 * 6,4 61.2 * 2.4 78.1i 2.3 76. 5 *- 2.3 75.6 s 1.9 78.9 * 1.4 79.6 1.8 75.5- 2.4 *• S i g n i f i c a n t change (P=0.01-o.05) w i t h r e s p e c t to 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 to c o n t r o l v a l u e T, ft S i g n i f i c a n c e of changes w i t h r e s p e c t t o PB i n f u s i o n v a l u e s . TABLE V C o n t r o l PB C.L. C o n t r o l PB C.L. C o n t r o l PB C.L. DATA DERIVED FROM TABLE IV, ASSUMING ALL CI TO BE EXTRACELLULAR T i s s u e ' c i space Na space Gm. EC H 2 0 Gm. EC H 2 0 A u r i c l e s R i g h t V e n t r i c l e L e f t V e n t r i c l e h?6 t 25 5kh t 27 389 ! 7-M t t * 320 : 12 362 I 15* 311* - 8 tt 2h9 1 11 289 • 11** 23^ 1 9 ft* ifl 6 : 21 555 t 3k*** M+3 t l i t * 301 t 16 33^ - 12 295 * 6 *+ 261 t 10 285 t 19 2h9 t 7 'IC H 2 0 Gm./Kgm. wet wt. 1+03 t 2h 282 t 23*** ^07 1 l 8*t* 501 - 15 ^70 ! 13 502 ; 6 t 5h6 i 10 1+99 + 29 562 • 6 t IC Na Gm./Kgm. IC H 2 0 IC K Gm./Kgm, IC HpO a 29.6 t 21.0 13.0 - 7.0 156 228 150 i -+ 15 t 2h ** 19 tT H ON 15k t 161 t ll+8 ! 7 5 5.08 t 1.55 1̂ 3 - k 5.95 * ^.10 161 t ih if.95 i 1.13 133 t 6 a Absence o f a value f o r i n t r a c e l l u l a r Na i n d i c a t e s t h a t a n e g a t i v e v a l u e 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-0.05-0.1) w i t h r e s p e c t to 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 to 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 to c o n t r o l v a l u e . t f ff f 4 t f S i g n i f i c a n c e o f changes w i t h r e s p e c t to PB i n f u s i o n v a l u e s . !7 was s l i g h t l y i n c r e a s e d , and CI space i n c r e a s e d more than Na space In both v e n t r i c l e s , so t h a t there was no apparent i n c r e a s e 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 . The onl y s i g - n i f i c a n t changes from c o n t r o l v a l u e s were i n the i n c r e a s e d t i s s u e CI i n both v e n t r i c l e s , and i n c r e a s e d CI space i n the l e f t v e n t r i c l e . The i n c r e a s e d CI space i n the r i g h t v e n t r i c l e was of b o r d e r l i n e s i g n i f i c a n c e . With coronary l i g a t i o n ^ c a t h e a r t s showed v e r y few e l e c t r o l y t e a l t e r a t i o n s from the c o n t r o l s , but agai n these were most pronounced i n the a u r i c l e s . T i s s u e CI was s i g n i f i c a n t l y decreased, and minor decreases oc c u r r e d i n t o t a l water and K. Na c o n c e n t r a t i o n was s l i g h t l y i n c r e a s e d . The CI space was s i g n i f i c a n t l y s m a l l e r w h i l e Na space expanded s l i g h t l y . In the v e n t r i c l e s . the changes o c c u r r i n g f o l l o w i n g coronary l i g a t i o n were minor. When the e l e c t r o l y t e s i n anoxic h e a r t s , were com- pared to those i n PB f a i l e d h e a r t s , s i g n i f i c a n t l y lower c o n c e n t r a t i o n s o f CI and Na were found i n anoxic a u r i c l e s and r i g h t v e n t r i c l e s , and lower c o n c e n t r a t i o n s o f CI and K i n l e f t v e n t r i c l e s . T o t a l water content tended to be l e s s i n a l l but the l e f t v e n t r i c l e , and K c o n c e n t r a t i o n was a l s o decreased. Na space was s m a l l e r i n a l l t i s s u e s , s i g n i f i c a n t l y so i n the a u r i c l e and r i g h t v e n t r i c l e . An even g r e a t e r decrease i n CI space was observed, which was s i g n i f i c a n t l y TABLE VI EFFECTS OF PB INFUSIONS ON THE ELECTROLYTE DISTRIBUTION IN DOG HEARTS T i s s u e # o f t e s t s C o n t r o l A u r i c l e s 5 PB 5 T o t a l C l Na Na K K HpO mEq,/Kgm. mEq./Kgm, mEq./Kgm, mEq./Kgm, mEn./Kgm. Gm./Kgm. wet wt. d r y wt. 'wet wt. dry wt. wet wt. wet wt. 8 1 9 - 6 54.9 - 0.9 369 -* 15 66.311.4 374 1 7 67.6^2.7 818 - 6 53.9 ! 2.0 400 1 27 72.0 1 2.1* .362 1 12 65.7 - 2.7 H 00 L e f t C o n t r o l V e n t r i c l e 5 PB 5 786 1 4 30.9 - 2 .5 196*15 41.9* 2.9 420 1 27 89.71 5.5 786 * 2 . 33.2 1 2.6 202 110 43.1 11.9 419 1 13 89.6 12.7 A 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* 0.05-0.1) w i t h r e s p e c t to the c o n t r o l v a l u e . TABLE V I I DATA DERIVED FROM TABLE VI, ASSUMING ALL CI TO BE EXTRACELLULAR T i s s u e C o n t r o l PB A u r i c l e s CI space Gm.EC H 2 0 per Kgm. wet wt. hi? r 10 hZO t 16 Na space Gm. EC H 2 0 per Kgm. wet wt. 1+27 - 1*+ 1+58 • 13 IC H 20 Gm./Kgm. wet wt. **13 t 11 398 ! 11 IC Na mEq./Kgm. IC H 2 0 IC K mEq./Kgm. IC K 20 10.6 Z 6.1 159 t 8 16.1+ * 2.0 161 * 5 C o n t r o l PB L e f t V e n t r i c l e 23*+ - 20 259 t 21 269 * 19 27!+ Z 11 552 t 18 53^ ! 16 10.2 t h.6 163 - 15 11.1 I 2.0 167 t 8 20 l e s s i n a l l t i s s u e s . A s i g n i f i c a n t i n c r e a s e i n i n t r a c e l l u l a r water and decrease i n i n t r a c e l l u l a r K occurred i n the a u r i c l e s o f anoxic h e a r t s , and t h i s p a t t e r n was repeated to a l e s s e r degree i n the other t i s s u e s . Dog. I n dog a u r i c l e s , the on l y change i n PB f a i l u r e was 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 unaccompanied by i n c r e a s e s i n water or C l . Dog v e n t r i c l e s showed o n l y minor changes f o l l o w i n g PB f a i l u r e . 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 Coronary L i g a t i o n on Plasma and Blood E l e c t r o l y t e s . A n a l y t i c a l r e s u l t s are r e p o r t e d i n Tables V I I I (page 21) and IX (page 22). I n the c a t , t e r m i n a l blood and plasma samples showed an i n c r e a s e i n water and C l and, a f t e r PB i n f u s i o n , an i n c r e a s e i n Na c o n c e n t r a t i o n over the i n i t i a l samples. There was l i t t l e change i n K c o n c e n t r a t i o n . PB i n f u s i o n s were accompanied by s i g n i f i c a n t l y i n c r e a s e d blood water and C l and plasma C l as compared to the c o n t r o l s a l i n e i n f u s i o n s . F o l l o w i n g coronary l i g a t i o n , the t e r m i n a l changes were s m a l l i n magnitude and tended to be o p p o s i t e i n d i r e c t i o n to those o c c u r r i n g i n PB i n f u s i o n . I n the dog, the o n l y important change was an i n c r e a s e i n water content o f the t e r m i n a l plasma samples f o l l o w i n g PB i n f u s i o n . TABLE V I I I EFFECTS OF SALINE AND PB INFUSIONS* AND CORONARY LIGATION (CL) ON WHOLE BLOOD ELECTROLYTES IN THE CAT I n f u s i o n Sample H 20 CI Na Na K K or Gm./Kgm. mEq./Kgm. mEq./Kgm. mEq./Kgm. mEq./Kgm. mEq./Kgm. Procedure wet wt. -wet wt. d r y wt. wet wt. d r y wt. wet wt. None I n i t i a l 8281 h 93 .8! 1.8 760*26 129 2 25.5 - 0.8 *+.35-0.10 S a l i n e T erminal 8*f9 ! 9 '** 97.5 - 2.5 905+b%+* 133 + 32.2 i 1 . 8 »+.82 i 0.37 * PB Terminal 877 J6*****" 111 + 2 *•*«*• 1180 - 9 0 • lh24-h++* 3*+.2 J1.8»*« *f . 08 !0 .12 t CL Terminal 833 i 8 H f 9^.9 - i M i i 777 i & W • 128+-3 ^ 27 .0 ! 2.8? l . ^ - + 0 . 3 8 tv> * 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 (Pr 0.05-0.1) with r e s p e c t to i n i t i a l c o n t r o l sample (no i n f u s i o n ) . * * S i g n i f i c a n t change (PrO.01-0.05) with r e s p e c t to i n i t i a l sample (no i n f u s i o n ) . * * + 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 to i n i t i a l sample (no i n f u s i o n ) . * *T ^ t t S i g n i f i c a n c e o f changes wi t h r e s p e c t to c o n t r o l s a l i n e i n f u s i o n . l . f f S i g n i f i c a n c e o f changes wi t h r e s p e c t to PB i n f u s i o n . TABLE IX EFFECTS OF SALINE AND PB INFUSIOFS AND CORONARY LIGATION (CL) PON PLASMA ELECTROLYTES IN CATS AND DOG'S Animal I n f u s i o n Sample H 2 0 C l Na K or Gm./Kgm. 'mEq.A. mEq;/L. mEq./L. Procedure wet wt. Cat None I n i t i a l 921 • 1 121 * 1 159 t 1 3.67 • 0.12 S a l i n e Terminal 935 * 3 *• 122 * 1 160 * 1 3.83 0.40 PB Terminal 942 * 3 ** 130 * 2 *+ t 162 • w 1 * 3.70 • 0.12 CL Terminal 930 - * 2** % 122 • 2 % 161 4 3 3.98 + 0.86 Dog None I n i t i a l 925 * 2 116 * • 2 157 f 1 4*35 * 0.17 S a l i n e Terminal 930 * 3 120 + 2 153 * 2 * • 0.23 PB Terminal 934 4 2 * 118 4 1 156 4 1 4.08 0.31 * S i g n i f i c a n t change (P*0.01-0.05) w i t h 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 ) *-* H i g h l y s i g n i f i c a n t change (P**0.Q1) w i t h r e s p e c t to i n i t i a l c o n t r o l sample (no i n f u s i o n ) T 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 s a l i n e i n f u s i o n . £ S i g n i f i c a n t 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 . 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 o f PB. The 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 to con- c e n t r a t i o n s o f PB g r e a t e r than those r e q u i r e d to produce a r r e s t i n dog h e a r t s might be due i n p a r t t o the a b i l i t y o f the former to s u r v i v e i n the presence o f reduced b l o o d p r e s s u r e . T h i s a b i l i t y c ould r e s u l t from b e t t e r coronary flow a t low a r t e r i a l b l o o d p r e s s u r e s , or from a s m a l l e r demand f o r the m e t a b o l i t e s or oxygen s u p p l i e d by the c i r c u l a t i o n . I n dogs, v e n t r i c u l a r t a c h y c a r d i a has been r e p o r t e d to f o l l o w severe myocardial ischemia, w i t h ven- t r i c u l a r f i b r i l l a t i o n ensuing i n a h i g h percentage o f cases ( H a r r i s , e t al.,1951*-). V e n t r i c u l a r t a c h y c a r d i a and f i b r i l l a - t i o n were not'encountered d u r i n g PB i n f u s i o n . T h i s f a c t , together w i t h t h e e l e c t r o l y t e data d i s c u s s e d below, are taken as an i n d i c a t i o n t h a t decreased coronary flow d i d not occur to any s i g n i f i c a n t degree i n dogs. D i r e c t evidence i n favour o f the p o s s i b i l i t y t h a t c a t h e a r t s r e q u i r e l e s s coronary blood supply i s presented by a comparison o f the t e r m i n a l t i s s u e e l e c t r o l y t e s i n the r i g h t and l e f t v e n t r i c l e s o f c a t s subjected to l e f t , coronary l i g a t i o n t o c o n t r o l s and to one another. The v a l u e s f o r both v e n t r i c l e s n©re s i m i l a r to those i n c o n t r o l s , and the l e f t v e n t r i c l e , which was presumably s e v e r e l y i s c h e m i c , showed v a l u e s s i m i l a r to those i n the r i g h t v e n t r i c l e , w i t h the e x c e p t i o n of an i n s i g n i f i c a n t decrease i n d r y weight.K. T h e r e f o r e , i n c o n t r a s t to the dog 2h h e a r t , the metabolism of these t i s s u e s , i n s o f a r as i t i s r e f l e c t e d by e l e c t r o l y t e c o n c e n t r a t i o n , appears to be l i t t l e i n f l u e n c e d by the degree o f t i s s u e anoxia. Even the severe anoxia which was present i n the l e f t v e n t r i c l e d i d not r e s u l t i n s i g n i f i c a n t a l t e r a t i o n s from c o n t r o l e l e c t r o l y t e v a l u e s . These e l e c t r o l y t e data, combined wi t h the f a c t t h a t b r a d y c a r d i a was much more pronounced d u r i n g PB i n f u s i o n , are evidence that PB i n f u s i o n s acted d i f f e r e n t l y from ischemia i n producing c a r d i a c d e p r e s s i o n i n the c a t h e a r t . I n r a b b i t s , where the h e a r t r a t e was w e l l maintained, as i t was i n ca t s w i t h coronary l i g a t i o n , the p o s s i b i l i t y t h a t anoxia was a major f a c t o r i n producing c a r d i a c a r r e s t by a l t e r i n g the mechanisms concerned i n e l e c t r o l y t e d i s t r i b u t i o n cannot be excluded s i n c e e l e c t r o l y t e s were ,not analyzed. I n dog h e a r t s , myocardial ischemia i s probably unimportant i n PB d e p r e s s i o n s i n c e v e n t r i c u l a r t a c h y c a r d i a d i d not occur, and s i n c e the t e r m i n a l decrease i n i n t r a c e l l u l a r K which has been r e p o r t e d i n the presence o f reduced v e n t r i c u l a r pO^ (Conn, 1956) was not encountered. T h e r e f o r e i t seems probable t h a t the d i f f e r e n c e i n s p e c i e s r e s i s t a n c e to PB 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 i s due to some d i r e c t a c t i o n or a c t i o n s o f the drug on h e a r t t i s s u e . The s p e c i e s d i f f e r e n c e s observed here are cause f o r s p e c u l a t i o n as to the s u s c e p t i b i l i t y o f the human h e a r t . 2? PB and C a r d i a c E l e c t r o l y t e s . Cat Heart. The changes accompanying PB f a i l u r e were most marked i n the cat a u r i c l e . The net e f f e c t was an uptake o f Na and C l by the t i s s u e and a l o s s o f water from the c e l l s i n t o the i n t e r s t i t i a l f l u i d and plasma. Since t i s s u e K was u n a l t e r e d , and water was s l i g h t l y de- creased, the r e s u l t s must be due to an uptake of i o n s without water. The q u e s t i o n a r i s e s as to whether or not these changes could be due to an expansion o f the e x t r a - c e l l u l a r space w i t h an osmotic s h i f t of water caused by the h y p e r t o n i c i n f u s i o n f l u i d , The most extreme assumption which could be made i s t h a t the i n f u s i o n f l u i d ( c o n t a i n i n g hl8 m i l l i o s m o l s per l i t e r ) accumulated behind the r i g h t a u r i c l e i n the f a i l i n g h e a r t and r e p l a c e d the i n t e r s t i t i a l f l u i d , thus forming a h y p e r t o n i c e x t r a c e l l u l a r f l u i d o f t h e o r e t i c a l l y i n f i n i t e volume surrounding the c e l l s of the r i g h t a u r i c l e . Even t h i s extreme c o n d i t i o n would account f o r 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 water which o c c u r r e d . The extreme nature o f the assumption i s i l l u s t r a t e d by (1) the f a c t t h a t terminal plasma samples, taken by h e a r t puncture, d i d not e x h i b i t any g r e a t i n c r e a s e i n Na c o n c e n t r a t i o n , (2) the f a c t t h a t t i s s u e analyses were performed on the combined r i g h t and l e f t a u r i c l e s , and (3) the f a c t t h a t K d i d not move out o f c e l l s as i s u s u a l l y the case i n osmotic d e h y d r a t i o n . T h e r e f o r e i t can be concluded t h a t , although the e x t r a c e l l u l a r space probahly expanded a t the 26 expense o f i n t r a c e l l u l a r water i n response to the hyper- t o n i c i t y o f the i n f u s i o n , PB exerted some other a c t i o n d i r e c t l y on the mechanisms c o n t r o l l i n g the maintenance o f i n t r a c e l l u l a r water content. An 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 to t h a t d i s - cussed above a l s o o c c u r r e d . I t must be borne i n mind t h a t the absolute v a l u e s f o r Na and CI space d i s c u s s e d here may be s u b j e c t 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 Robertson and Peyser (1956), however, there i s l i t t l e r eason to b e l i e v e t h a t such a r e v i s i o n would l e a d t o marked changes i n the r e l a t i v e volumes of d i s t r i b u t i o n o f these two i o n s . The c a l c u l a t e d Na space expanded more than the CI space, i n - d i c a t i n g t h a t Na was p e n e t r a t i n g some compartment from which CI was excluded, probably the c e l l s . Normally, when Na e n t e r s c e l l s , due to some d e f e c t i n the t r a n s p o r t system which exchanges Na f o r K, the l a t t e r i o n i s l o s t . However, s i n c e t i s s u e K remained unchanged, and e x t r a c e l l u l a r K was not in c r e a s e d , one of two p o s s i b i l i t i e s must have o c c u r r e d . E i t h e r some anion other than CI entered the c e l l w i t h Na, or a c a t i o n other than K was l o s t . E i t h e r p o s s i b i l i t y would 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 c o n c e n t r a t i o n o f CI which was encountered, but there i s i n s u f f i c i e n t evidence at p r e s e n t t o determine the nature o f the io n s i n v o l v e d . The f a c t s w h i c h can be concluded from t h i s study are t h a t PB ex e r t s a s e l e c t i v e and d i r e c t a c t i o n on the systems which r e g u l a t e the i n t r a - to e x t r a c e l l u l a r r a t i o s 27 o f Na and water i n the cat a u r i c l e . T h i s a c t i o n probably causes u l t i m a t e c a r d i a c a r r e s t , although there i s no evidence t h a t the negative i n o t r o p i c e f f e c t o f the drug i n the v e n t r i c l e s has a s i m i l a r b a s i s . The absence o f an accumulation o f K i n the presence o f PB induced h e a r t f a i l u r e i s i n apparent c o n t r a d i c t i o n t o the f i n d i n g s o f Holland (1954). I t would be o f i n t e r e s t to know whether or not the decreased r a t e o f l o s s o f K from a u r i c l e s b e a t i n g i n K - f r e e media, which he r e p o r t s i n response to PB, could be due to a d i l u t i o n o f the e x t e r n a l medium through l o s s o f i n t r a c e l l u l a r water. Dog Heart. 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 found i n dog h e a r t r a i s e s the p o s s i b i l i t y t h a t such changes may be dependent upon the absolute c o n c e n t r a t i o n o f PB present i n the t i s s u e . The dog h e a r t appears to be s u s c e p t i b l e to some other form o f s u p r e s s i o n by PB, probably an impairment o f c o n t r a c t i l i t y . T h i s f a c t , combined w i t h the l a c k o f e f f e c t o f PB on 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 , emphasizes the proba- b i l i t y expounded by Green e t aJL (1952) and Hoffman e t a l (1956) t h a t changes i n the c o n t r a c t i l i t y o f mammalian h e a r t may occur independently of changes i n Na and K d i s t r i b u t i o n * In i n t a c t dogs and i s o l a t e d h e a r t - l u n g p r e p a r a t i o n s , when v e n t r i c u l a r c o n t r a c t i o n was supported by i n f u s i o n s o f nore p i n e p h r i n e , l a r g e amounts o f PB could be i n f u s e d before c a r d i a c f a i l u r e o c c u r r e d ( D a n i e l e t a l , 1956). A t the p o i n t o f f a i l u r e o f antagonism, a s e r i e s o f EGG events c h a r a c t e r i z e d 28 by a u r i c u l a r s t a n d s t i l l , A-V bl o c k and t e r m i n a l i d i o v e n - t r i c u l a r b r a d y c a r d i a were observed. I n i n t a c t dogs, although not i n h e a r t - l u n g experiments, hyperkalemia a l s o o c c u r r e d . T h i s ECG p a t t e r n i s s i m i l a r t o t h a t r e p o r t e d by MeKusiek (195^) to occur f o l l o w i n g i n t r a v e n o u s i n f u s i o n o f L i s a l t s . The l a t t e r author s t a t e s t h a t , w h i l e these changes c o u l d be due to the i n c r e a s e d L i c o n c e n t r a t i o n , they c o u l d a l s o be secondary to a decrease i n the r a t i o o f i n t r a - to e x t r a c e l l u l a r K. I t would be o f c o n s i d e r a b l e i n t e r e s t to know whether or not changes i n the i n t r a - t o e x t r a c e l l u l a r r a t i o o f K occur i n dog a u r i c l e s a t the p o i n t o f f a i l u r e o f no r e p i n e p h r i n e antagonism to PB. I t would be e q u a l l y i n f o r m a t i v e to i n - v e s t i g a t e the ECG changes a t PB f a i l u r e , and the e f f e c t s o f nore p i n e p h r i n e i n f u s i o n i n c a t s . The e f f e c t o f PB on the e l e c t r i c a l e x c i t a b i l i t y o f nervous t i s s u e has been a p o i n t o f c o n s i d e r a b l e i n t e r e s t (Gruber e t a l , 1938, E c c l e s , 19^6 and Brooks and E c c l e s , 19^7.) I n view o f the changes encountered I n Na and water metabolism i n c a t a u r i c l e s , m i c r o e l e c t r o d e s t u d i e s might provide evidence r e g a r d i n g an e f f e c t o f PB on membrane and a c t i o n p o t e n t i a l s i n t h i s t i s s u e . The 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 to F u n c t i o n . C o n t r o l v a l u e s f o r c a r d i a c e l e c t r o l y t e s , which are i n g e n e r a l agreement w i t h those r e p o r t e d by Robertson and Peyser, d951)'and Manery (195*0 are o f c o n s i d e r a b l e i n t e r e s t . 29 In the a u r i c l e s , CIspace tends to be l a r g e r than Na space, whereas, i n the l e f t v e n t r i c l e , the Na space i s always the l a r g e r . T h i s i s an i n d i c a t i o n of a g r e a t e r p r o p o r t i o n o f C l - c o n t a i n i n g c e l l s , or a h i g h e r i n t r a c e l l u l a r CI concen- t r a t i o n , i n the a u r i c l e s , D a n i e l and Boyes (1956) found s i m i l a r evidence o f the i n t r a c e l l u l a r p o s i t i o n of CI i n the fundus of the u t e r u s , which i s the pacemaker area o f t h a t organ. The apparent p r o p o r t i o n o f i n t r a c e l l u l a r CI v a r i e d i n v e r s e l y with the d i s t a n c e from the pacemaker a r e a . I t appears t h a t i n t r a c e l l u l a r CI may be a s s o c i a t e d w i t h auto- m a t i c i t y i n e x c i t a b l e t i s s u e s . 30 V. SUMMARY 1. A s p e c i e s d i f f e r e n c e i n r e s i s t a n c e to the c a r d i o v a s c u l a r depressant e f f e c t s o f continuous PB i n f u s i o n s has been found. The c a r d i a c l e t h a l dose f o r dogs was 171, f o r ca t s 326, and f o r r a b b i t s h-Oh mgm./Kgm. o f NaPB. 2. M y o c a r d i a l ischemia r e s u l t i n g from the hypotensive e f f e c t s o f PB i s probably not the cause of c a r d i a c a r r e s t i n PB i n - t o x i c a t e d c a t s and dogs. 3. E l e c t r o l y t e s t u d i e s 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 on the c o n t r o l o f i n t r a c e l l u l a r Na and water c o n c e n t r a t i o n s i n c a t a u r i c l e . k. The p o s s i b l e r e l a t i o n o f PB induced e l e c t r o l y t e changes to some other d i r e c t a c t i o n of PB on the myocardium i s d i s c u s s e d . Evidence i s produced i n support o f the hypothesis t h a t changes i n c a r d i a c c o n t r a c t i l i t y may occur independ- e n t l y o f changes i n Na and K d i s t r i b u t i o n . 5. 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 t i s s u e s i n d i c a t e s t h a t t i s s u e s w i t h g r e a t e r a u t o m a t i c i t y , such as the 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 CI. 31 V BIBLIOGRAPHY Asper, S.P., J r . , S c h a l e s , 0. , and Sch a l e s , S.S., Importance o f c o n t r o l l i n g pH i n the Schales and Schales 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., 168: 779-780,1947. Brooks, C. M c C , and E c c l e s , J . C , A study o f the e f f e c t s : o f a n a e s t h e s i a and asphyxia on the monosynaptic pathway through the s p i n a l c o r d . J . He 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 and hypoxia on 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 Boyes, D.A., The e l e c t r o l y t e s o f human uter u s and t h e i r p o s s i b l e r e l a t i o n to f u n c t i o n a l a c t i v i t y . Am. J . Obstet., 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., and Fou l k s , |r.G., An a n a l y s i s o f the 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. Arch. I n t e r n a t . pharmacodyn. e t exper. therap., 1956. ( I n p r e s s ) E c c l e s , J.C., S y n a p t i c p o t e n t i a l s o f motoneurones. J . Heuro- p h y s i o l . , 2* 87-120, 1946. Green, J.P., Giarman, N.J., and S a l t e r , W.T., Combined e f f e c t s ; o f calcium and potassium on 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 the mammalian myocardium. Am. J . P h y s i o l . , 171*174-177» 1952. Gruber, CM., Haury, V.G., and Gruber, CM., 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 d e p r e s s i n g the c a r d i a c vagus nerves. J . Pharmacol. & Exper. Therap., 63.: 239-252", 1938. Hajdu, S., Mechanism o f s t a i r c a s e and c o n t r a c t u r e i n v e n t r i c u - l a r muscle. £m. J . P h y s i o l . , 174; 371-380, 1953. Hald, P.M., Determinations w i t h flame photometer, Meth. i n Med. Res., 4: 79-105, 1951. 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 tachy- c a r d i a r e s u l t i n g from myocardial i s c h e m i a . Potassium a major e x c i t a n t . S c i e n c e , 112:200-203, 1954. 32 Hoffman. B.F., B i n d l e r , E., and S u c k l i n g , E.E., P o s t e x t r a s y s t o l i c p o t e n t i a t i o n o f c o n t r a c t i o n i n c a r d i a c 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 agents on the l o s s o f potassium from i s o l a t e d guinea p i g a u r i c l e s . J . Pharmacol. & Exper. Therap., I l l : 1-8, 195^. Lowry, O.H., and Has t i n g s , A.B., H i s t o c h e m i c a l changes 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., Water and e l e c t r o l y t e metabolism. P h y s i o l . Rev., 3it: 3 3 ^ 1 7 , 195^. McKusick, V.A., The e f f e c t o f l i t h i u m on the e l e c t r o - cardiogram o f animals and r e l a t i o n o f t h i s e f f e c t to the 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 . I n v e s t . , 33: 589-610, 1951*-. Robertson, W. v. B., and Peyser, P., Changes i n water and 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. Robertson, W. v. B., and Peyser, P., Estim 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 . , 18̂ +: 171 -17^, 1956. Snedecor, G.W., S t a t i s t i c a l methods a p p l i e d t o experiments 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, 191+6, pp. 5*+-88. Szent-Gyorgyi, A.. Chemical 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 muscle. Academic p r e s s , New York, 1953» p t . I I .

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