Imidapril treatment improves the attenuated inotropic and intracellular calcium responses to ATP in heart failure due to myocardial infarction.
1. Adenosine 5'-triphosphate (ATP) is known to augment cardiac contractile activity and cause an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) in isolated cardiomyocytes. However, no information regarding the ATP-mediated signal transduction in the myocardium in congestive heart failure (CHF) is available. 2. CHF due to myocardial infarction (MI) in rats was induced by the occlusion of the left coronary artery for 8 weeks. The positive inotropy due to ATP was depressed in failing hearts. Treatment of 3 weeks infarcted animals with imidapril (1 mg kg(-1) day(-1)) for a period of 5 weeks improved the left ventricle function and decreased the attenuation of inotropic response to ATP. 3. ATP-induced increase in [Ca(2+)](i) was significantly depressed in cardiomyocytes isolated from the failing heart and this change was partially attenuated by imidapril treatment. However, the binding characteristics of (35)S-labeled adenosine 5'-(gamma-thio) triphosphate in sarcolemma isolated from the failing heart remained unaltered. 4. ATP-induced increase in [Ca(2+)](i) was depressed by verapamil and cibacron blue in both control and failing heart cardiomyocytes; however, the ATP response in the failing hearts, unlike the control preparations, was not decreased by ryanodine. This insensitivity to ryanodine was attenuated by imidapril treatment. 5. Treatment of infarcted rats with enalapril and losartan produced effects similar to imidapril. 6. These findings indicate that the positive inotropic response to ATP and ATP-induced increase in [Ca(2+)](i) in cardiomyocytes are impaired in heart failure. Furthermore, blockade of renin angiotensin system prevented the impairment of the ATP-mediated inotropic and [Ca(2+)](i) responses in the failing heart.
Saini
Harjot K
HK
Institute of Cardiovascular Sciences, St Boniface General Hospital Research Centre, Winnipeg, MB, Canada.
Shao
Qiming
Q
Musat
Sorin
S
Takeda
Nobuakira
N
Tappia
Paramjit S
PS
Dhalla
Naranjan S
NS
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism; D048289:Imidazolidines / Q000494:pharmacology / Q000627:therapeutic use*; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D048289:Imidazolidines; D000255:Adenosine Triphosphate; C065166:imidapril