Effects of long‐term treatment with trandolapril on sarcoplasmic reticulum function of cardiac muscle in rats with chronic heart failure following myocardial infarction

Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction. CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end‐diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned 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 caffeine (45–93%). The [3H]‐ryanodine‐binding activity in SR‐enriched fractions 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 rate of SR Ca2+ uptake and a downregulation of the SR Ca2+‐release channel. Rats were treated orally with 3 mg kg−1 day−1 trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end‐diastolic pressure, and improved the developed force transients of the skinned fibre 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. It is concluded that long‐term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel. British Journal of Pharmacology (1998) 123, 326–334; doi:10.1038/sj.bjp.0701592