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The effects of a new calcium entry blocker “Anipamil” on rabbit myocardium and aortic smooth muscle
63 169 THE EFFECTS OF A NEW CALCIUM ENTRY BLOCKER "ANIPAMIL" ON RABBIT MYOCARDIUM AND AORTIC SMOOTH MUSCLE. R. Ferrari, R. R a d d i n o , C. B i g o l i , S. C u r e l l o , O. V i s i o l i and A. Alber'tini*. C h a i r of C a r d i o l o g y a n d * I n s t i t u t e of C h e m i s t r y , U n i v e r s i t y of B r e s c i a , I t a l y . We s t u d i e d the effects of a new compound, a n i p a m i l (A) on h e a r t c o n t r a c t i l i ty and on r a b b i t a o r t i c s t r i p s s t i m o l a t e d by Kcl and metoxarnine (M). I t ' s p r o p e r ties have been compared w i t h t h a t of v e r a p a m i l (V). We o b t a i n e d these r e s u l t s : l ) A showed a dose dependent (10 -8 -10-5M) n e g a t i v e i n o t r o p i c effect s i m i l a r to that of V -2) The n e g a t i v e i n o t r o p i c effect of A is i n d i p e n d e n t from b e t a - r e c e p t o r b l o c kade and it is a n t a g o n i z e d b y small doses of isoproterenol ( 1 0 - 5 Q u g / m l ) . -3) The n e g a t i v e i n o t r o p i c effect of A is a n t a g o n i z e d , in a dose dependent manner, by i n c r e a s i n 9 calcium content of the p e r f u s a t e : lmM and 4mM c a l c i u m r e s t o r e d , in the case of A, 13~0 and 75% of c o n t r a c t i o n , w h i l s t , in the case of V 50~0 and the 1OO~0 r e s p e c t i v e l y . -4) The n e g a t i v e i n o t r o p i c effect of A is long l a s t i n g : it is s t i l l present a f t e r 12 hours of w a s h i n g w h i l s t the effect of V is r e v e r s e d a f t e r 3 hours -6) A d i d not a n t a g o n i z e the v a s o c o s t r i c t i o n of Kcl and M on a o r t i c s t r i p s w h i l s t V a b o l i s h e d i t . T h e d a t a suggest that A is s p e c i f i c for the m y o c a r d i a l c e l l .
170 CALCIUM LEVELS IN NON-INFARCTED AREAS OF RAT HEARTS WITH CHRONICAL OCCLUSION OF THE LEFT MAIN CORONARYARTERY AS SHOWN BY ATOMIC~ABSORPTION SPECTROSCOPY. S.Rotevatn, H.Jodalen, T.Smtersdal. I n s t i t u t e o~Anatomy U n i v e r s i t y of Bergen, Norway. Myocardial i n f a r c t i o n was produced in female Wistar r a t s by l e f t coronary a r t e r y l i g a t i o n . A f t e r i n t e r v a l s of I and 2 weeks, r e s p e c t i v e l y , the heart was e x c i s ed, i n f a r c t e d t i s s u e and a t r i a q u i c k l y removed and the r e s t of the v e n t r i c l e s submerged in the incubation medium. Whole t i s s u e samples and the m i t o c h o n d r i a l f r a c t i o n s were analysed f o r calcium by atomic absorption spectroscopy. Protein contents were determined by the Bio Rad Assay procedure. Myocardial i n f a r c t i o n was f o l l o w e d by a s i g n i f i c a n t increase of the calcium l e v e l in whole t i s s u e samp]es and in i s o l a t e d mitochondria, obtained from t i s s u e o u t s i d e the i n f a r c t e d area. This increase was about 6o % in the m i t o c h o n d r i a l f r a c t i o n s and about Joo % in the whole t i s s u e samp l e s . These r e s u l t s i n d i c a t e t h a t chronic calcium overload takes place in the noni n f a r c t e d parts of the myocardium. Recent studies by Dr. E . F e l l e n i u s et aI(1983) suggest t h a t the s u r v i v i n g myocardium f o l l o w i n g experimental i ~ a r c t i o n has a reduced f u n c t i o n a l c a p a c i t y . In such areas they found a reduced Ca - s e n s i t i v i t y and increased v u l n e r a b i l i t y f o r g l o b a l ischemia. We suggest t h a t increased calcium l e v e l s might be of s i g n i f i c a n c e in the development of mal-functJon of the n o n - i n f a r c t e d p a r t s of the heart. 171 IS P R O G R E S S I V E C A L C I N O S I S OF SENESCENT A R T E R I E S R E S P O N S I V E TO CALCIUM A N T A G O N I S T S ? A. Fleckenstein, M. Frey, G. Fleckenstein-Grfin. Physiological Institute, U n i v e r s i t y of Freiburg / Germany (Fed. Rep.). One of the most important effects of the new p h a r m a c o l o g i c a l family of Ca a n t a g o n i s t i c drugs is to prevent d e l e t e r i o u s m y o c a r d i a l Ca overload which is the decisive etiological factor in the p r o d u c t i o n of cardiac necroses by overdoses of 9 ~ - a d r e n e r g i c catecholamines, vitamin Do + ++ dihydrotachysterol, or following a l i m e n t a r y K - or Mg -deficiency well as genetic defects (hereditary c a r d i o m y o p a t h y of Syrian hamsters). However, at an advanced age, also in the human arterial walls, cytotoxic degrees of Ca overload are reached, which are probably a decisive factor in the p a t h o g e n e s i s of a r t e r i o s c l e r o t i c lesions. I n t e r e s t i n g l y in rats, the Ca a n t a g o n i s t s v e r a p a m i l and d i l t i a z e m not only prevented arterial calcinosis due to overdoses of vitamin D{ and J i h y d r o t a c h y sterol, but also c o u n t e r a c t e d a g e - d e p e n d e n t Ca accumulation, if given orally over a period of s e v e r a l months. Our findings nourish the hope that suitable Ca a n t a g o n i s t s can possibly interfere with arterial calcinosis also in humans, thus bearing a new v a s o p r o t e c t i v e indication. *See the monograph: A.Fleckenstein: Calcium Antagonism in Heart and Smooth/Muscle Experimental Facts and Therapeutic Prospects. J.Wiley & Sons, New York, 1983.
170 CALCIUM LEVELS IN NON-INFARCTED AREAS OF RAT HEARTS WITH CHRONICAL OCCLUSION OF THE LEFT MAIN CORONARYARTERY AS SHOWN BY ATOMIC~ABSORPTION SPECTROSCOPY. S.Rotevatn, H.Jodalen, T.Smtersdal. I n s t i t u t e o~Anatomy U n i v e r s i t y of Bergen, Norway. Myocardial i n f a r c t i o n was produced in female Wistar r a t s by l e f t coronary a r t e r y l i g a t i o n . A f t e r i n t e r v a l s of I and 2 weeks, r e s p e c t i v e l y , the heart was e x c i s ed, i n f a r c t e d t i s s u e and a t r i a q u i c k l y removed and the r e s t of the v e n t r i c l e s submerged in the incubation medium. Whole t i s s u e samples and the m i t o c h o n d r i a l f r a c t i o n s were analysed f o r calcium by atomic absorption spectroscopy. Protein contents were determined by the Bio Rad Assay procedure. Myocardial i n f a r c t i o n was f o l l o w e d by a s i g n i f i c a n t increase of the calcium l e v e l in whole t i s s u e samp]es and in i s o l a t e d mitochondria, obtained from t i s s u e o u t s i d e the i n f a r c t e d area. This increase was about 6o % in the m i t o c h o n d r i a l f r a c t i o n s and about Joo % in the whole t i s s u e samp l e s . These r e s u l t s i n d i c a t e t h a t chronic calcium overload takes place in the noni n f a r c t e d parts of the myocardium. Recent studies by Dr. E . F e l l e n i u s et aI(1983) suggest t h a t the s u r v i v i n g myocardium f o l l o w i n g experimental i ~ a r c t i o n has a reduced f u n c t i o n a l c a p a c i t y . In such areas they found a reduced Ca - s e n s i t i v i t y and increased v u l n e r a b i l i t y f o r g l o b a l ischemia. We suggest t h a t increased calcium l e v e l s might be of s i g n i f i c a n c e in the development of mal-functJon of the n o n - i n f a r c t e d p a r t s of the heart. 171 IS P R O G R E S S I V E C A L C I N O S I S OF SENESCENT A R T E R I E S R E S P O N S I V E TO CALCIUM A N T A G O N I S T S ? A. Fleckenstein, M. Frey, G. Fleckenstein-Grfin. Physiological Institute, U n i v e r s i t y of Freiburg / Germany (Fed. Rep.). One of the most important effects of the new p h a r m a c o l o g i c a l family of Ca a n t a g o n i s t i c drugs is to prevent d e l e t e r i o u s m y o c a r d i a l Ca overload which is the decisive etiological factor in the p r o d u c t i o n of cardiac necroses by overdoses of 9 ~ - a d r e n e r g i c catecholamines, vitamin Do + ++ dihydrotachysterol, or following a l i m e n t a r y K - or Mg -deficiency well as genetic defects (hereditary c a r d i o m y o p a t h y of Syrian hamsters). However, at an advanced age, also in the human arterial walls, cytotoxic degrees of Ca overload are reached, which are probably a decisive factor in the p a t h o g e n e s i s of a r t e r i o s c l e r o t i c lesions. I n t e r e s t i n g l y in rats, the Ca a n t a g o n i s t s v e r a p a m i l and d i l t i a z e m not only prevented arterial calcinosis due to overdoses of vitamin D{ and J i h y d r o t a c h y sterol, but also c o u n t e r a c t e d a g e - d e p e n d e n t Ca accumulation, if given orally over a period of s e v e r a l months. Our findings nourish the hope that suitable Ca a n t a g o n i s t s can possibly interfere with arterial calcinosis also in humans, thus bearing a new v a s o p r o t e c t i v e indication. *See the monograph: A.Fleckenstein: Calcium Antagonism in Heart and Smooth/Muscle Experimental Facts and Therapeutic Prospects. J.Wiley & Sons, New York, 1983.