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Protective effects of a metoprolol thromboxane synthesis inhibitor combination onmyocardial damage during acute myocardial ischaemia
43 109 S A L V A G E OF R E V E R S I B L Y I S C H E M I C ~ Y O C A R D I U ~ B Y P R E V E N T I O N OF O X Y G E N P A R A D O X . E F F E C T S OF C A L E O D U L I N A N D P R O T E A S E I N H I B I T I O N S . Q U A N T I T A T I V E E V A L U A T I O N . J. Slezak, I. Gabauer, A. Z i e g e l h 8 f f e r , N. Tribulova, J. Styk. D e p a r t m e n t of M o r p h o l o g y , I n s t i t u t e of E x p e r i m e n t a l Surgery, C e n t e r of P h y s i o l o g i c a l S c i e n c e s SAS, B r a t i s l a v a , C z e c h o s l o v a k i a . R e p e r f u s i o n of m y o c a r d i u m w i t h i s c h e m i a e x c e e d i n g 40 m i n r e s u l t s i n m o r p h o l o g i c a l , p h y s i o l o g i c a l and b i o c h e m i c a l c h a n g e s i n d u c e d b y e n h a n c e d c y t o s o l i c C a ~ c o n c e n t r a t i o n and/or a c t i v a t i o n of l y s o s o m a l e n z y m e s . Left d e s c e n d i n g c o r o n a r y l i g a t i c n w a s p e r f o r m e d o n 45 dogs. C h l o r p r o m a z i n e /Spofa/, T r i f l u o p e r a z i n e / S K and P / a n d / o r T r a s y l o l / B a y e r / were a d m i n i s t e r e d 30 m i n a f t e r the l i g a t i o n as c a l m o d u l i n and p r o t e a s e s i n h i b l t o r s . Total i s c h e m i c p e r i o d of 60 m i n w a s f o l l o w e d by ]20 m i n r e p e r f u s i o n . E f f e c t of d r u g s w a s q u a n t i f i e d on t e t r a z o l i u m s t a i n e d g r o s s s e c t i o n s and e v a l u a t e d f r o m p h y s i o l o g i c a l , b i o c h e m i c a l and u l t r a s t r u c t u r a l p o i n t s of view. R e s u l t s r e v e a l that t r e a t m e n t of a n i m a l s w i t h p r o t e a s e s a n d / o r c a l m o d u l i n i n h i b i t o r s or both, c o n s i d e r a b l y i m p r o v e d the u l t r a s t r u c t u r e of m y o c y t e s i n a r e a at r i s k and a l l o w e d the r e c o v e r y of 50 per cent or more of r e v e r s i b l y i n j u r e d m y o c y t e s a f t e r r e s t o r a t i o n of r e f l o w , l ~ t r a s t r u c t u r a l f i n d i n g s t i g h t l y correlate w i t h p h y s i o l o g i c a l and b i o c h e m i c a l r e s u l t s .
110 PROTECTIVE EFFECTS OF A METOPROLOL THROMBOXANE SYNTHESIS INHIBITOR COMBINATION ON
MYOCARDIAL DAY'AGE DURING ACUTE MYOCARDIAL ISCHAEMIAo C.Lo W a i n w r i g h t , JoRo P a r r a t t , I . L e p r a n T, L. S z e k e r e s t & G.R. B u l l o c k o D e p a r t m e n t o f P h y s i o l o g y and P h a r m a c o l o g y , University of Strathclyde, Glasgow, Scotland; Institute of Pharmacology, University M e d i c a l S c h o o l o f S z e g e d , S z e g ~ d , Hungary t and C i b a G e i g y P h a r m a c e u t i c a l s D i v i s i o n , Horsham, West S u s s e x , E n g l a n d . -1 The e f f e c t s o f p r e t r e a t m e n t w i t h m e t o p r o l o l (2mg kg i.vo), the thromboxane s y n t h e t a s e i n h i b i t o r d a z m e g r e l (UK38,485; 5mg kg - 1 i ~ and a c o m b i n a t i o n o f t h e two were investigated on m y o c a r d i a l damage o c c u r r i n g d u r i n g a c u t e m y o c a r d i a l i s c h a e m i a o C o r o n a r y a r t e r y l i g a t i o n was p e r f o r m e d on a n a e s t h e t i s e d and c o n s c i o u s r a t s , i n o r d e r t o a s s e s s t h e e x t e n t o f m y o c a r d i a l damage a f t e r 4 h o u r s and 48 h o u r s o f i s c h a e m i a respectively, by h i s t o l o g i c a l and h i s t o e h e m i e a l techniques. Histological d e t e r m i n a t i o n o f m y o c a r d i a l damage showed a s i g n i f i c a n t r e d u c t i o n from 1701% o f l e f t ventricular v o l u m e i n c o n t r o l r a t s a t 4 h o u r s t o 8~ in rats pretreated with metoprolol, and from 34~1% i n c o n t r o l r a t s a t 48 h o u r s t o 21% i n r a t s p r e t r e a t e d w i t h the combination. Histoehemieal analysis indicated a significant r e d u c t i o n from 34.8% i n c o n t r o l a n i m a l s , a t 48 h o u r s , t o 17.1% and 22.1% i n m e t o p r o l o l and c o m b i n a t i o n pretreated animals respectively. The c o m b i n a t i o n , b u t n o t e i t h e r d r u g a l o n e , significantly increased survival in a more severe conscious rat model.
111 REDUCTION OF ISCHEMIA-INDUCED MITOCHONDRIAL INJURY BY LB 32841, A NEW CARDIOPROTECTIVE AGENT. P. Nokin, L. Jungbluth and A. Ben Mohamed. Sanofi Research-Labaz, Brussels, Belgium. LB 32841 is a new indolizine derivative having some pharmacological properties in cormnon with amiodarone. The effect of LB 32841 on ischemia-induced mitochondrial dysfunction was evaluated in Langendorff perfused rat hearts made globally ischemic. Rats received a single intravenous injection of LB 32841 (20 mg/kg) or saline 30 min before sacrifice. After a 15 min perfusien period with Krebs-Henseleit solution at 37~ hearts were either further perfused for 30 min, made totally ischemic for 30 min or made ischemic for 30 min then reperfused for 15 min. Respiratory parameters of heart mitochondria and myocardial high energy phosphate contents were measured. LB 32841 did not affect any of these parameters in perfused hearts. State 3 respiration (natom0/min x mg prot.) and P/0 ratio were severely depressed by ischemia in control hearts F194 + 10 to 101 ~ 23 (P < .001) and 2.48 + 0.03 to 1.98 + 0.39 respectively ] but maintained at much higher levels in LB 328~I pretreated h~arts D76 + 21 (P <.001 vs ischemic controls) and 2.41 + 0.04 (P <.05 vs ischemic controls) ]. Residual ATPlevels were significantly higher in--LB 32841 pretreated hearts than in control hearts after is~hemia. After 15 min reperfusion, [ATP] and ~Creatin phosphate] return to 59 % and 11~ % of their pre-ischemic values in LB 32841 pretreated hearts but only to 3 1 % and 77 % of pre-ischemic values in control hearts. The results indicate that LB 32841 can protect cardiac mitochondria against ischemia-indueed injury.
110 PROTECTIVE EFFECTS OF A METOPROLOL THROMBOXANE SYNTHESIS INHIBITOR COMBINATION ON
MYOCARDIAL DAY'AGE DURING ACUTE MYOCARDIAL ISCHAEMIAo C.Lo W a i n w r i g h t , JoRo P a r r a t t , I . L e p r a n T, L. S z e k e r e s t & G.R. B u l l o c k o D e p a r t m e n t o f P h y s i o l o g y and P h a r m a c o l o g y , University of Strathclyde, Glasgow, Scotland; Institute of Pharmacology, University M e d i c a l S c h o o l o f S z e g e d , S z e g ~ d , Hungary t and C i b a G e i g y P h a r m a c e u t i c a l s D i v i s i o n , Horsham, West S u s s e x , E n g l a n d . -1 The e f f e c t s o f p r e t r e a t m e n t w i t h m e t o p r o l o l (2mg kg i.vo), the thromboxane s y n t h e t a s e i n h i b i t o r d a z m e g r e l (UK38,485; 5mg kg - 1 i ~ and a c o m b i n a t i o n o f t h e two were investigated on m y o c a r d i a l damage o c c u r r i n g d u r i n g a c u t e m y o c a r d i a l i s c h a e m i a o C o r o n a r y a r t e r y l i g a t i o n was p e r f o r m e d on a n a e s t h e t i s e d and c o n s c i o u s r a t s , i n o r d e r t o a s s e s s t h e e x t e n t o f m y o c a r d i a l damage a f t e r 4 h o u r s and 48 h o u r s o f i s c h a e m i a respectively, by h i s t o l o g i c a l and h i s t o e h e m i e a l techniques. Histological d e t e r m i n a t i o n o f m y o c a r d i a l damage showed a s i g n i f i c a n t r e d u c t i o n from 1701% o f l e f t ventricular v o l u m e i n c o n t r o l r a t s a t 4 h o u r s t o 8~ in rats pretreated with metoprolol, and from 34~1% i n c o n t r o l r a t s a t 48 h o u r s t o 21% i n r a t s p r e t r e a t e d w i t h the combination. Histoehemieal analysis indicated a significant r e d u c t i o n from 34.8% i n c o n t r o l a n i m a l s , a t 48 h o u r s , t o 17.1% and 22.1% i n m e t o p r o l o l and c o m b i n a t i o n pretreated animals respectively. The c o m b i n a t i o n , b u t n o t e i t h e r d r u g a l o n e , significantly increased survival in a more severe conscious rat model.
111 REDUCTION OF ISCHEMIA-INDUCED MITOCHONDRIAL INJURY BY LB 32841, A NEW CARDIOPROTECTIVE AGENT. P. Nokin, L. Jungbluth and A. Ben Mohamed. Sanofi Research-Labaz, Brussels, Belgium. LB 32841 is a new indolizine derivative having some pharmacological properties in cormnon with amiodarone. The effect of LB 32841 on ischemia-induced mitochondrial dysfunction was evaluated in Langendorff perfused rat hearts made globally ischemic. Rats received a single intravenous injection of LB 32841 (20 mg/kg) or saline 30 min before sacrifice. After a 15 min perfusien period with Krebs-Henseleit solution at 37~ hearts were either further perfused for 30 min, made totally ischemic for 30 min or made ischemic for 30 min then reperfused for 15 min. Respiratory parameters of heart mitochondria and myocardial high energy phosphate contents were measured. LB 32841 did not affect any of these parameters in perfused hearts. State 3 respiration (natom0/min x mg prot.) and P/0 ratio were severely depressed by ischemia in control hearts F194 + 10 to 101 ~ 23 (P < .001) and 2.48 + 0.03 to 1.98 + 0.39 respectively ] but maintained at much higher levels in LB 328~I pretreated h~arts D76 + 21 (P <.001 vs ischemic controls) and 2.41 + 0.04 (P <.05 vs ischemic controls) ]. Residual ATPlevels were significantly higher in--LB 32841 pretreated hearts than in control hearts after is~hemia. After 15 min reperfusion, [ATP] and ~Creatin phosphate] return to 59 % and 11~ % of their pre-ischemic values in LB 32841 pretreated hearts but only to 3 1 % and 77 % of pre-ischemic values in control hearts. The results indicate that LB 32841 can protect cardiac mitochondria against ischemia-indueed injury.