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1 Department of Physiology, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, University of Manitoba, Winnipeg, MB, Canada
2 Department of Internal Medicine, Aoto Hospital, Jikei University, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: nsdhalla{at}sbrc.ca.
This study was designed to test the hypothesis that blockade of the reninangiotensin system (RAS) improves cardiac function in congestive heart failure (CHF) by preventing changes in gene expression of the sarcoplasmic reticulum (SR) proteins. We employed rats with myocardial infarction (MI) to examine the effects of an angiotensin converting enzyme (ACE) inhibitor, imidapril, on the SR Ca2+-transport, protein content and gene expression. Imidapril (1 mg/kg/day) was given for a 4 week period starting at 3 weeks after occluding the coronary artery. Infarcted rats exhibited a 4-fold increase in left ventricular end diastolic pressure whereas rates of pressure development and pressure decay were decreased by 60 and 55%, respectively. The SR Ca2+-uptake and Ca2+-pump ATPase as well as Ca2+-release and ryanodine receptor binding activities were depressed in the failing hearts; both protein content and mRNA levels for Ca2+-pump ATPase, phospholamban and ryanodine receptor were also decreased by about 55 to 65%. Imidapril treatment of the infarcted animals improved cardiac performance and attenuated the alterations in SR Ca2+-pump and Ca2+-release activities. The changes in protein content and mRNA levels for SR Ca2+-pump ATPase, phospholamban and ryanodine receptor were also prevented by imidapril treatment. The beneficial effects of imidapril on cardiac function and SR Ca2+-transport were not only seen at different intervals of MI but were also simulated by another ACE inhibitor, enalapril, and an angiotensin II receptor antagonist, losartan. These results suggest that the blockade of RAS may increase the abundance of mRNA for SR proteins and thus may prevent the depression in SR Ca2+-transport and improve cardiac function in CHFdue to MI.
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