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The effect of fatty acids and prostaglandins on the catecholamine release from rat heart
53 86.
THE ROLE OF E N D O G E N O U S C A T E C H O L A M I N E S AND P R O S T A G L A N D I N S IN THE M A I N T E N A N C E OF C O R O N A R Y F L O W IN ISOLATED, P E R F U S E D HEARTS OF CONTROL, F A S T E D AND S T R E P T O Z O T O C I N - D I A B E T I C RATS. H. Stam, W.C. H~ismann, T h o r a x c e n t e r and D e p a r t m e n t of B i o c h e m istry I, Erasmus U n i v e r s i t y Rotterdam, The N e t h e r lands. D u r i n g r e t r o g r a d e perfusion, the c o r o n a r y flow in hearts of fasted (group I) and s t r e p t o z o t o c i n d i a b e t i c rats (group II) was s i g n i f i c a n t l y e n h a n c e d w h e n c o m p a r e d w i t h the flow in hearts from c o n t r o l rats (group III). P e r f u s i o n with i n d o m e t h a c i n (inhibitor of the p r o s t a g l a n d i n synthesis) d e c r e a s e d the flow in hearts from controls and from groups I and II. The lowest flow rates were o b s e r v e d in all groups when hearts were d e p l e t e d from e n d o g e n o u s c a t e c h o l a m i n e s by reserpin. The release of p r o s t a g l a n d i n - l i k e substances was i n c r e a s e d in hearts from groups I and II and was r e d u c e d both by i n d o m e t h a c i n and by reserpin. The results suggest that c o r o n a r y v a s o d i l a t i o n in hearts from groups I and II is med i a t e d both by e n d o g e n o u s c a t e c h o l a m i n e s and by a c a t e c h o l a m i n e - i n d u c e d r e l e a s e of p r o s t a g l a n d i n - l i k e substances. S u p p o r t e d by the Dutch Heart F o u n d a t i o n .
87.
THE E F F E C T OF FATTY ACIDS AND P R O S T A G L A N D I N S ON THE C A T E C H O L A M I N E RELEASE F R O M RAT HEART. H. Stam, W.C. H~ismann, T h o r a x c e n t e r and D e p a r t m e n t of B i o c h e m i s t r y I, Erasmus U n i v e r s i t y Rotterdam, The Netherlands. At low external Ca ++ c o n c e n t r a t i o n s l o n g - c h a i n fatty acids both increase the c o r o n a r y flow rate and the c o n t r a c t i l i t y of i s o l a t e d p e r f u s e d rat h e a r t s (comp. Basic Res. Cardiol. 71, !79, 1976). R e s e r p i n i z a t i o n of rats as well as p r e p e r f u s i o n of i s o l a t e d hearts with tyramine d e p r e s s e d the effect of fatty acids (and of fasting and diabetes - see p r e v i o u s abstract), s u g g e s t i n g a link b e t w e e n fatty acids and r e l e a s e of n o r e p i n e p h r i n e from e n d o g e n o u s stores. T h e p r e s e n t study shows that hearts p r e l o a d e d w i t h r a d i o a c t i v e n o r e p i n e p h r i n e s u d d e n l y r e l e a s e radioa c t i v i t y into the p e r f u s a t e w h e n fatty acids or p r o s t a g l a n d i n E 1 (PG) are introduced. It r e e m p h a s i z e s the p o s s i b l e i o n o p h o r i c p r o p e r t i e s of fatty acids and PG as r e s p o n s i b l e for c a t e c h o l a m i n e release, since
54 S c h a f f e r et al. (Biochem. P h a r m a c o l . 23, 1609, 1974) s h o w e d this for the i o n o p h o r e X-537A. M u t u a l f a c i l i t a t i o n of p r o s t a g l a n d i n and c a t e c h o l a m i n e r e l e a s e m i g h t lead to a m p l i f i c a t i o n of effects. 88.
PERFOR~NCE AND COMPETITION FOR OXIDATION B E T W E E N FFAs A N D C A R B O H Y D R A T E S IN C A R D I A C MUSCLE. K. S~sskand, M. Siess, D e p a r t m e n t of P h a r m a cology, U n i v e r s i t y of T u e b i n g e n , W e s t Germany. In g u i n e a pig a t r i a the o x i d a t i o n of long and s h o r t - c h a i n fatty acids (FFAs) as s u b s t r a t e s lowers the e f f i c i e n c y of c a r d i a c w o r k c o m b i n e d w i t h negative i n o t r o p i c effects. An i n c r e a s e in the heart rate is f o l l o w e d by a shift to c a r b o h y d r a t e o x i d a tion; in c o n t r a s t FFAs are p r e f e r e n t i a l l y o x i d i z e d w h e n r e s t i n g atria are i n c u b a t e d s i m u l t a n e o u s l y w i t h 15 m M g l u c o s e and 0.5 m M p a l m i t i c acid (GI.5 fold K m values). L o n g - c h a i n FFAs are not s u f f i c i e n t as sole s u b s t r a t e s to m e e t the i n c r e a s e d d e m a n d for e n e r g y at h i g h h e a r t rates, and are not o x i d i z e d to the r e q u i r e d extent. The r e a s o n must be a l i m i t a t i o n of the o x i d a t i o n rate of l o n g - c h a i n FFAs. P a l m i t i c a c i d p e n e t r a t e s the m i t o c h o n d r i a l m e m b r a n e t h r o u g h the a g e n c y of the a c y l - t r a n s f e r a s e system, in contrast to C 4 - C I 0 FFAs, w h i c h are o x i d i z e d directly. T h i s could be the l i m i t i n g step. T h e k i n e t i c s show c l e a r l y that glucose, w i t h a K m v a l u e of I0 mM and a Vma x of 6.4 ~Mol 0 2 / h . 1 0 0 mg w.w., and h e x a n o a t e (C 6 FFA) w i t h a K m of 0.58 m M and a V m a x of 6.03 ~Mol 02 b o t h h a v e a h i g h e r o x i d a t i o n rate than palm i t i c acid w i t h a K m of 0.34 m M and a Vma x of only 2.55 ~Mol 0 2 / h - i 0 0 mg. The p r o b l e m s a s s o c i a t e d w i t h Ca ++ b i n d i n g by F F A s in the c a r d i a c c y t o p l a s m after i n h i b i t i o n of their o x i d a t i o n will be discussed. W i t h s u p p o r t of the D e u t s c h e F o r s c h u n g s g e m e i n s c h a f t . 89.
THE E F F E C T S A N D T E M P O R A L L I M I T S OF A C U T E R E D U C T I O N S IN C O R O N A R Y SUPPLY. G.C. Taichman, Y. A k y u r e k l i , W.J. Keon, B. Korecky, U n i v e r s i t y of O t t a w a C a r d i a c Unit, Ottawa, Canada. In o u r initial s t u d y (Can. J. Surg. 19, 531, 1976) on in situ w o r k i n g dog h e a r t s on total c o r o n a r y b y p a s s we w e r e able to d e m o n s t r a t e that p r e d e t e r m i ned levels of c a r d i a c p u m p f u n c t i o n c o u l d be r e p e a t e d l y a c h i e v e d by i n d e p e n d e n t l y m a n i p u l a t i n g coronary p e r f u s i n g p r e s s u r e . S u b s e q u e n t e x p e r i m e n t s en-
THE ROLE OF E N D O G E N O U S C A T E C H O L A M I N E S AND P R O S T A G L A N D I N S IN THE M A I N T E N A N C E OF C O R O N A R Y F L O W IN ISOLATED, P E R F U S E D HEARTS OF CONTROL, F A S T E D AND S T R E P T O Z O T O C I N - D I A B E T I C RATS. H. Stam, W.C. H~ismann, T h o r a x c e n t e r and D e p a r t m e n t of B i o c h e m istry I, Erasmus U n i v e r s i t y Rotterdam, The N e t h e r lands. D u r i n g r e t r o g r a d e perfusion, the c o r o n a r y flow in hearts of fasted (group I) and s t r e p t o z o t o c i n d i a b e t i c rats (group II) was s i g n i f i c a n t l y e n h a n c e d w h e n c o m p a r e d w i t h the flow in hearts from c o n t r o l rats (group III). P e r f u s i o n with i n d o m e t h a c i n (inhibitor of the p r o s t a g l a n d i n synthesis) d e c r e a s e d the flow in hearts from controls and from groups I and II. The lowest flow rates were o b s e r v e d in all groups when hearts were d e p l e t e d from e n d o g e n o u s c a t e c h o l a m i n e s by reserpin. The release of p r o s t a g l a n d i n - l i k e substances was i n c r e a s e d in hearts from groups I and II and was r e d u c e d both by i n d o m e t h a c i n and by reserpin. The results suggest that c o r o n a r y v a s o d i l a t i o n in hearts from groups I and II is med i a t e d both by e n d o g e n o u s c a t e c h o l a m i n e s and by a c a t e c h o l a m i n e - i n d u c e d r e l e a s e of p r o s t a g l a n d i n - l i k e substances. S u p p o r t e d by the Dutch Heart F o u n d a t i o n .
87.
THE E F F E C T OF FATTY ACIDS AND P R O S T A G L A N D I N S ON THE C A T E C H O L A M I N E RELEASE F R O M RAT HEART. H. Stam, W.C. H~ismann, T h o r a x c e n t e r and D e p a r t m e n t of B i o c h e m i s t r y I, Erasmus U n i v e r s i t y Rotterdam, The Netherlands. At low external Ca ++ c o n c e n t r a t i o n s l o n g - c h a i n fatty acids both increase the c o r o n a r y flow rate and the c o n t r a c t i l i t y of i s o l a t e d p e r f u s e d rat h e a r t s (comp. Basic Res. Cardiol. 71, !79, 1976). R e s e r p i n i z a t i o n of rats as well as p r e p e r f u s i o n of i s o l a t e d hearts with tyramine d e p r e s s e d the effect of fatty acids (and of fasting and diabetes - see p r e v i o u s abstract), s u g g e s t i n g a link b e t w e e n fatty acids and r e l e a s e of n o r e p i n e p h r i n e from e n d o g e n o u s stores. T h e p r e s e n t study shows that hearts p r e l o a d e d w i t h r a d i o a c t i v e n o r e p i n e p h r i n e s u d d e n l y r e l e a s e radioa c t i v i t y into the p e r f u s a t e w h e n fatty acids or p r o s t a g l a n d i n E 1 (PG) are introduced. It r e e m p h a s i z e s the p o s s i b l e i o n o p h o r i c p r o p e r t i e s of fatty acids and PG as r e s p o n s i b l e for c a t e c h o l a m i n e release, since
54 S c h a f f e r et al. (Biochem. P h a r m a c o l . 23, 1609, 1974) s h o w e d this for the i o n o p h o r e X-537A. M u t u a l f a c i l i t a t i o n of p r o s t a g l a n d i n and c a t e c h o l a m i n e r e l e a s e m i g h t lead to a m p l i f i c a t i o n of effects. 88.
PERFOR~NCE AND COMPETITION FOR OXIDATION B E T W E E N FFAs A N D C A R B O H Y D R A T E S IN C A R D I A C MUSCLE. K. S~sskand, M. Siess, D e p a r t m e n t of P h a r m a cology, U n i v e r s i t y of T u e b i n g e n , W e s t Germany. In g u i n e a pig a t r i a the o x i d a t i o n of long and s h o r t - c h a i n fatty acids (FFAs) as s u b s t r a t e s lowers the e f f i c i e n c y of c a r d i a c w o r k c o m b i n e d w i t h negative i n o t r o p i c effects. An i n c r e a s e in the heart rate is f o l l o w e d by a shift to c a r b o h y d r a t e o x i d a tion; in c o n t r a s t FFAs are p r e f e r e n t i a l l y o x i d i z e d w h e n r e s t i n g atria are i n c u b a t e d s i m u l t a n e o u s l y w i t h 15 m M g l u c o s e and 0.5 m M p a l m i t i c acid (GI.5 fold K m values). L o n g - c h a i n FFAs are not s u f f i c i e n t as sole s u b s t r a t e s to m e e t the i n c r e a s e d d e m a n d for e n e r g y at h i g h h e a r t rates, and are not o x i d i z e d to the r e q u i r e d extent. The r e a s o n must be a l i m i t a t i o n of the o x i d a t i o n rate of l o n g - c h a i n FFAs. P a l m i t i c a c i d p e n e t r a t e s the m i t o c h o n d r i a l m e m b r a n e t h r o u g h the a g e n c y of the a c y l - t r a n s f e r a s e system, in contrast to C 4 - C I 0 FFAs, w h i c h are o x i d i z e d directly. T h i s could be the l i m i t i n g step. T h e k i n e t i c s show c l e a r l y that glucose, w i t h a K m v a l u e of I0 mM and a Vma x of 6.4 ~Mol 0 2 / h . 1 0 0 mg w.w., and h e x a n o a t e (C 6 FFA) w i t h a K m of 0.58 m M and a V m a x of 6.03 ~Mol 02 b o t h h a v e a h i g h e r o x i d a t i o n rate than palm i t i c acid w i t h a K m of 0.34 m M and a Vma x of only 2.55 ~Mol 0 2 / h - i 0 0 mg. The p r o b l e m s a s s o c i a t e d w i t h Ca ++ b i n d i n g by F F A s in the c a r d i a c c y t o p l a s m after i n h i b i t i o n of their o x i d a t i o n will be discussed. W i t h s u p p o r t of the D e u t s c h e F o r s c h u n g s g e m e i n s c h a f t . 89.
THE E F F E C T S A N D T E M P O R A L L I M I T S OF A C U T E R E D U C T I O N S IN C O R O N A R Y SUPPLY. G.C. Taichman, Y. A k y u r e k l i , W.J. Keon, B. Korecky, U n i v e r s i t y of O t t a w a C a r d i a c Unit, Ottawa, Canada. In o u r initial s t u d y (Can. J. Surg. 19, 531, 1976) on in situ w o r k i n g dog h e a r t s on total c o r o n a r y b y p a s s we w e r e able to d e m o n s t r a t e that p r e d e t e r m i ned levels of c a r d i a c p u m p f u n c t i o n c o u l d be r e p e a t e d l y a c h i e v e d by i n d e p e n d e n t l y m a n i p u l a t i n g coronary p e r f u s i n g p r e s s u r e . S u b s e q u e n t e x p e r i m e n t s en-