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

Abstract

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca 2+ 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. 2 CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic¯ow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. 3 The developed force transients of cardiac skinned ®bres of the rats with CHF were decreased when the skinned ®bre was preloaded for 0.25 ± 1 min with 10 75 M Ca 2+ (48 ± 88%) and when preloaded with 10 76 M Ca 2+ and then exposed to 0.1 ± 1 mM ca eine (45 ± 93%). 4 The [ 3 H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca 2+ released from SR is decreased due to a reduced rate of SR Ca 2+ uptake and a downregulation of the SR Ca 2+ -release channel. 5 Rats were treated orally with 3 mg kg 71 day 71 trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic¯ow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned ®bre 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 underlying this e ect is, at least in part, attributed to prevention of downregulation of Ca 2+ release channel.

Sarcoplasmic reticulum Ca2+ transport and gene expression in congestive heart failure are modified by imidapril treatment

“…These findings are in agreement with previous reports on the MI model of CHF (1,2,34,40,41). The depression in SR Ca 2ϩ uptake appears to be related to the SR Ca 2ϩ pump mechanism, because SR Ca 2ϩ -stimulated ATPase activity was also decreased in MI-induced heart failure.…”

“…A similar magnitude of depression (ϳ50%) in the SR Ca 2ϩ release channel in the failing heart was apparent when it was monitored by two different techniques: Ca 2ϩ -induced Ca 2ϩ release and ryanodine receptor binding assay. Our results for Ca 2ϩ release and Ca 2ϩ uptake activities obtained by employing isolated SR preparations are similar to those of other investigators (40,41) who assessed the SR Ca 2ϩ transport activities in the infarcted hearts by employing skinned fiber preparations. Because SR Ca 2ϩ release and Ca 2ϩ uptake are intimately involved in the processes of cardiac contraction and relaxation, respectively, the observed depression in SR Ca 2ϩ release and Ca 2ϩ uptake activities may explain the reduction in cardiac ϩdP/dt and ϪdP/dt in the failing heart.…”

“…Imidapril has also been shown to prevent changes in myofibrillar ATPase, myosin protein content, and gene expression for myosin isozymes (37). Because other ACE inhibitors such as captopril, enalapril, trandolapril, and cilazapril have also been reported to attenuate SR function or SR gene expression in hearts failing as a result of MI (14,16,34,41,42), it appears that ACE inhibitors may improve cardiac function by preventing alterations in SR gene expression. In view of the observations that imidapril prevented changes in PKC isozymes in the infarcted heart, it is possible that imidapril may produce beneficial effects on subcellular organelles through this mechanism in heart failure due to MI.…”

“…Although some investigators (3,32) were unable to detect changes in mRNA levels for SERCA2 and phospholamban, others (7,14,24,40) showed decreases in SR Ca 2ϩ uptake, Ca 2ϩ release, Ca 2ϩ pump ATPase, and mRNA levels for SR proteins in hearts failing due to MI. Furthermore, alterations in MI-induced SR Ca 2ϩ transport and heart function were prevented by some angiotensin-converting enzyme (ACE) inhibitors, such as captopril and trandolapril (14,34,41). Other ACE inhibitors, enalapril and cilazapril, and an angiotensin II receptor type 1 (AT 1 R) antagonist, losartan, were shown to attenuate MI-induced changes in SR gene expression (16,42); however, no report concerning these agents on MI-induced alterations in SR Ca 2ϩ transport is available.…”

Effects of Zofenopril on Cardiac Sarcoplasmic Reticulum Calcium Handling

“…11,12 There is indirect evidence that ACE inhibitors can affect SR function because it has been reported that several ACE inhibitors antagonize the changes in SR calcium uptake or release observed in different experimental models of heart failure. [13][14][15][16][17][18][19] It is however uncertain whether these observations reflect a direct effect on SR proteins or are rather a nonspecific consequence of the improved cardiac function. Therefore, it seemed interesting to investigate whether zofenopril may modulate SR function.…”