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The coronary microcirculation in clinical and experimental diabeticheart disease
J Mol Cell Cardiol 19 (Supplement III) (1987)
61
THE EFFECTS OF CYCLIC i[UCLEOTiDES IN T ~ HEART. Paul J. England. Department of Cellular Pharmacology, Smith Kline at. 9ranch Research, The Prythe, ~elwyn, Hefts AL6 9TX U.K. Cyclic A~P and cyclic GYP mediate their effects in tissues by activating cyclic nuclectide-dependent protein kinases /cA-PrK and cG-PrK respectively/. These enzymes catalyse the phosphorilation of serine or threonine residues in specific proteins modifying their fum.ctional properties. In the heart, substrates for cA-PrK include the voltage-dependent Ca2+ channel, and phcspholamban, a protein of the sarcoplasmic reticulum membrane. Phosphorilation of those proteins causes an increased rate of Ca2+ influx during systole, and an increase rate of removal of Ca2+ during diastole. In addition, two contractile proteins are phosphorilated, troponin-I and C-p~otein. ~nosphorilation of troponin-I increases the rate of dissociation of Ca2+ from troponin; the effect of phasphorilation of C-protein is unknov~. Cyclic nucleotides are removed by a group of phosphodiester~ses /PDE's/, which show different substrate specificities and activator requirements. Inhibition of selected insoenzymes causes different effects in the tissue, even though the increases in cyclic nucleotides may be the same. There is strong evidence for compartmentation of cyclic .~P in heart, and inotropic effects may be obtained by i ~ a ~ cyclic ~ { P ~ specific compartments by inhibition of selected PDE isoenz~mes.
62
F e n d i ] i n e i n the t r e a t m e n t o f c o r o n a r y h e a r t d i s e a s e H. Erwes, H.-U. Benn, Evangelisehes Krankenhaus, H a t t i n g e n FRG; In a d o u b l e - b l i n d study FendiLine versus N i f e d i p i n e was t e s t e d . AFter a t h r e e - d a y wash-out p e r i o d , l l p a t i e n t s (age 59,9) were t r e a t e d For two weeks w i t h 2 x 100 mg F e n d i l i n e and 7 p a t i e n t s (age 56,4) w i t h 3 x 10 mg N i f e d i p i n e . Blood p r e s s u r e and h e a r t rate in r e s t were o n l y m a r g i n a l l y i n f l u e n c e d . Mean ST-segment d e p r e s s i o n in r e s t was 0,10 mV For F e n d i l i n e and 0,11 mV f o r N i f e d i p i n e . During e x e r c i s e a f t e r 3 days t r e a t m e n t , a 22% r e d u c t i o n o f ST-segment d e p r e s s i o n For F e n d i l i n e resp. 12,5% f o r N i f e d i p i n e was proven. AFter 2 weeks t r e a t m e n t , the reduction for Fendiline and Nifedipine was similar (22~ resp. 21%). The ST-index (Kaltenbaeh/ Rosskamm) for this time was 41,3% for Fendiline and 15,5% for Nifedipine. Blood pressure and heart rate were moderately reduced during exercise in the Fendiline-treated group. The effects of Nifedipine were more pronounced. Ap-frequency and nitroglycerine consumption were markedly redU6ed (65,6~ for Fendiline resp. 85,7% for Nifedipine). The quotient PEP/LVET, an indicator for ventricular performance, was decreased (-7%) for the Fendiline and increased (+7%) for the Nifedipine group. In conclusion, Fendiline and Nifedipine reduce ST-segment depression, Ap-frequency and nitroglycerine consumption. The Nifedipine effects on blood pressure and heart rate are more pronounced.
63
THE CORONARY MICROCIRCULATION IN C L I N I C A L A N D E X P E R I M E N T A L DIABETIC HEART DISEASE. S,M.Factor, F.Fein, S.Cho, D e p a r t m e n t s of P a t h o l o g y and M e d i c i n e , A l b e r t E i n s t e i n C o l l e g e of M e d i c i n e , B r o n x , N e w Y o r k We s t u d i e d t h e m i c r o c i r c u l a t i o n ( M C ) of d i a b e t i c ( D ) h u m a n h e a r t s at a u t o p s y by i n f u s i n g s i l i c o n e r u b b e r ( S R ) i n t o t h e c o r o n a r y a r t e r i e s . We observed discrete microaneurysms(MA) in c a p i l l a r i e s , a r t e r i o l e s , and v e n u l e s ; we a l s o s a w a r e a s of a b r u p t v e s s e l c o n s t r i c t i o n s u g g e s t i v e of spasm. T h e m e c a r d i a c MA w e r e i d e n t i c a l to t h o s e s e e n in d i a b e t i c r e t i n o p a t h y . To f u r t h e r study t h e D m i c r o v a s c u l a t u r e , we a n a l y z e d r a t s made diabetic(D) with etreptozotocin and hypertensive(H) with renal artery clipping. T h i s c o m b i n a t i o n of HD p r o d u c e s a s e v e r e c a r d i o m y o p a t h y ( C M ) s i m i l a r to h u m a n d i s e a s e , w i t h s i g n i f i c a n t m o r t a l i t y at 67 months. The MC of HD a n i m a l s had m u l t i p l e MA a n d n u m e r o u s a r e a s of s p a s m ~ t h e D or H a n i m a l s a l s o h a d l e s i o n s , b u t w i t h r e d u c e d f r e q u e n c y c o m p a r e d to HD. S i n c e the p a t h o l o g y of HD i n c l u d e s f o c a l m y o c a r d i a l n e c r o s i s and scarring, a b n o r m a l i t i e s of t h e MC m a y m e d i a t e t h e m e changes. R e c e n t e v i d e n c e s u g g e s t s p o s i t i v e e f f e c t s os c a l c i u m c h a n n e l b l o c k e r s in p r e v e n t i n g c h a n g e s of HD CM, e v e n w i t h o u t d e c r e a s i n g b l o o d pressure. T h e a n t i s p a s m e f f e c t s of t h e c a l c i u m b l o c k e r s m a y be b e n e f i c i a l in t h i s d i s e a s e , es t h e y e r e in o t h e r e x p e r l m e n t e l CMs.
S.21
61
THE EFFECTS OF CYCLIC i[UCLEOTiDES IN T ~ HEART. Paul J. England. Department of Cellular Pharmacology, Smith Kline at. 9ranch Research, The Prythe, ~elwyn, Hefts AL6 9TX U.K. Cyclic A~P and cyclic GYP mediate their effects in tissues by activating cyclic nuclectide-dependent protein kinases /cA-PrK and cG-PrK respectively/. These enzymes catalyse the phosphorilation of serine or threonine residues in specific proteins modifying their fum.ctional properties. In the heart, substrates for cA-PrK include the voltage-dependent Ca2+ channel, and phcspholamban, a protein of the sarcoplasmic reticulum membrane. Phosphorilation of those proteins causes an increased rate of Ca2+ influx during systole, and an increase rate of removal of Ca2+ during diastole. In addition, two contractile proteins are phosphorilated, troponin-I and C-p~otein. ~nosphorilation of troponin-I increases the rate of dissociation of Ca2+ from troponin; the effect of phasphorilation of C-protein is unknov~. Cyclic nucleotides are removed by a group of phosphodiester~ses /PDE's/, which show different substrate specificities and activator requirements. Inhibition of selected insoenzymes causes different effects in the tissue, even though the increases in cyclic nucleotides may be the same. There is strong evidence for compartmentation of cyclic .~P in heart, and inotropic effects may be obtained by i ~ a ~ cyclic ~ { P ~ specific compartments by inhibition of selected PDE isoenz~mes.
62
F e n d i ] i n e i n the t r e a t m e n t o f c o r o n a r y h e a r t d i s e a s e H. Erwes, H.-U. Benn, Evangelisehes Krankenhaus, H a t t i n g e n FRG; In a d o u b l e - b l i n d study FendiLine versus N i f e d i p i n e was t e s t e d . AFter a t h r e e - d a y wash-out p e r i o d , l l p a t i e n t s (age 59,9) were t r e a t e d For two weeks w i t h 2 x 100 mg F e n d i l i n e and 7 p a t i e n t s (age 56,4) w i t h 3 x 10 mg N i f e d i p i n e . Blood p r e s s u r e and h e a r t rate in r e s t were o n l y m a r g i n a l l y i n f l u e n c e d . Mean ST-segment d e p r e s s i o n in r e s t was 0,10 mV For F e n d i l i n e and 0,11 mV f o r N i f e d i p i n e . During e x e r c i s e a f t e r 3 days t r e a t m e n t , a 22% r e d u c t i o n o f ST-segment d e p r e s s i o n For F e n d i l i n e resp. 12,5% f o r N i f e d i p i n e was proven. AFter 2 weeks t r e a t m e n t , the reduction for Fendiline and Nifedipine was similar (22~ resp. 21%). The ST-index (Kaltenbaeh/ Rosskamm) for this time was 41,3% for Fendiline and 15,5% for Nifedipine. Blood pressure and heart rate were moderately reduced during exercise in the Fendiline-treated group. The effects of Nifedipine were more pronounced. Ap-frequency and nitroglycerine consumption were markedly redU6ed (65,6~ for Fendiline resp. 85,7% for Nifedipine). The quotient PEP/LVET, an indicator for ventricular performance, was decreased (-7%) for the Fendiline and increased (+7%) for the Nifedipine group. In conclusion, Fendiline and Nifedipine reduce ST-segment depression, Ap-frequency and nitroglycerine consumption. The Nifedipine effects on blood pressure and heart rate are more pronounced.
63
THE CORONARY MICROCIRCULATION IN C L I N I C A L A N D E X P E R I M E N T A L DIABETIC HEART DISEASE. S,M.Factor, F.Fein, S.Cho, D e p a r t m e n t s of P a t h o l o g y and M e d i c i n e , A l b e r t E i n s t e i n C o l l e g e of M e d i c i n e , B r o n x , N e w Y o r k We s t u d i e d t h e m i c r o c i r c u l a t i o n ( M C ) of d i a b e t i c ( D ) h u m a n h e a r t s at a u t o p s y by i n f u s i n g s i l i c o n e r u b b e r ( S R ) i n t o t h e c o r o n a r y a r t e r i e s . We observed discrete microaneurysms(MA) in c a p i l l a r i e s , a r t e r i o l e s , and v e n u l e s ; we a l s o s a w a r e a s of a b r u p t v e s s e l c o n s t r i c t i o n s u g g e s t i v e of spasm. T h e m e c a r d i a c MA w e r e i d e n t i c a l to t h o s e s e e n in d i a b e t i c r e t i n o p a t h y . To f u r t h e r study t h e D m i c r o v a s c u l a t u r e , we a n a l y z e d r a t s made diabetic(D) with etreptozotocin and hypertensive(H) with renal artery clipping. T h i s c o m b i n a t i o n of HD p r o d u c e s a s e v e r e c a r d i o m y o p a t h y ( C M ) s i m i l a r to h u m a n d i s e a s e , w i t h s i g n i f i c a n t m o r t a l i t y at 67 months. The MC of HD a n i m a l s had m u l t i p l e MA a n d n u m e r o u s a r e a s of s p a s m ~ t h e D or H a n i m a l s a l s o h a d l e s i o n s , b u t w i t h r e d u c e d f r e q u e n c y c o m p a r e d to HD. S i n c e the p a t h o l o g y of HD i n c l u d e s f o c a l m y o c a r d i a l n e c r o s i s and scarring, a b n o r m a l i t i e s of t h e MC m a y m e d i a t e t h e m e changes. R e c e n t e v i d e n c e s u g g e s t s p o s i t i v e e f f e c t s os c a l c i u m c h a n n e l b l o c k e r s in p r e v e n t i n g c h a n g e s of HD CM, e v e n w i t h o u t d e c r e a s i n g b l o o d pressure. T h e a n t i s p a s m e f f e c t s of t h e c a l c i u m b l o c k e r s m a y be b e n e f i c i a l in t h i s d i s e a s e , es t h e y e r e in o t h e r e x p e r l m e n t e l CMs.
S.21