Sarcoplasmic reticulum Ca2+ transport and gene expression in congestive heart failure are modified by imidapril treatment.
This study was designed to test the hypothesis that blockade of the renin-angiotensin system improves cardiac function in congestive heart failure by preventing changes in gene expression of sarcoplasmic reticulum (SR) proteins. We employed rats with myocardial infarction (MI) to examine effects of an angiotensin-converting enzyme inhibitor, imidapril, on SR Ca(2+) transport, protein content, and gene expression. Imidapril (1 mg.kg(-1).day(-1)) was given for 4 wk starting 3 wk after coronary artery occlusion. Infarcted rats exhibited a fourfold increase in left ventricular end-diastolic pressure, whereas rates of pressure development and decay were decreased by 60 and 55%, respectively. SR Ca(2+) uptake and Ca(2+) pump ATPase, as well as Ca(2+) release and ryanodine receptor binding activities, were depressed in the failing hearts; protein content and mRNA levels for Ca(2+) pump ATPase, phospholamban, and ryanodine receptor were also decreased by approximately 55-65%. Imidapril treatment of infarcted animals improved cardiac performance and attenuated alterations in SR Ca(2+) pump and Ca(2+) release activities. Changes in protein content and mRNA levels for SR Ca(2+) pump ATPase, phospholamban, and ryanodine receptor were also prevented by imidapril treatment. Beneficial effects of imidapril on cardiac function and SR Ca(2+) transport were not only seen at different intervals of MI but were also simulated by another angiotensin-converting enzyme inhibitor, enalapril, and an ANG II receptor antagonist, losartan. These results suggest that blockade of the renin-angiotensin system may increase the abundance of mRNA for SR proteins and, thus, may prevent the depression in SR Ca(2+) transport and improve cardiac function in congestive heart failure due to MI.
Shao
Qiming
Q
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Tache Ave., Winnipeg, Manitoba, Canada R2H 2A6.
Ren
Bin
B
Saini
Harjot K
HK
Netticadan
Thomas
T
Takeda
Nobuakira
N
Dhalla
Naranjan S
NS
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000493:pharmacokinetics*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D004656:Enalapril / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D048289:Imidazolidines / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014316:Tritium; D017725:Ventricular Pressure / Q000187:drug effects
D000959:Antihypertensive Agents; D048289:Imidazolidines; D019837:Ryanodine Receptor Calcium Release Channel; D014316:Tritium; D004656:Enalapril; C065166:imidapril; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D019808:Losartan; D002118:Calcium