EFFECTS OF LONG-TERM TREATMENT WITH TRANDOLAPRIL ON SARCOPLASMIC-RETICULUM FUNCTION OF CARDIAC-MUSCLE IN RATS WITH CHRONIC HEART-FAILURE FOLLOWING MYOCARDIAL-INFARCTION

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulu m (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The prese nt study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic r eticular function in animals with CHF following myocardial infarction. 2 CHF was induced by left coronary artery ligation in rats, which res ulted in an infarction of approximately 45% of the left ventricle. Aor tic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, sug gesting the development of CHF. 3 The developed force transients of ca rdiac skinned fibres of the rats with CHF were decreased when the skin ned fibre was preloaded for 0.25-1 min with 10(-5) M Ca2+ (48-88%) and when preloaded with 10(-6) M Ca2+ and then exposed to 0.1-1 mM caffei ne (45-93%). 4 The [H-3]-ryanodine-binding activity in SR-enriched fra ctions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rat e of SR Ca2+ uptake and a downregulation of the SR Ca2+-release channe l. 5 Rats were treated orally with 3 mg kg(-1) day(-1) trandolapril fr om the 2nd to the 8th week after the coronary artery ligation. Treatme nt with trandolapril attenuated the reduction in aortic flow and cardi ac output index and the increase in left ventricular end-diastolic pre ssure, and improved the developed force transients of the skinned fibr e of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF. 6 It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underly ing this effect is, at least in part, attributed to prevention of down regulation of Ca2+ release channel.