Imidapril treatment improves the attenuated inotropic and intracellular calcium responses to ATP in heart failure due to myocardial infarction

Abstract

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.

Figure 1

Positive inotropic and chronotropic responses to ATP (1 μmol kg⁻¹) in animals with CHF with or without imidapril (IMP) treatment (1 mg kg⁻¹ day⁻¹). Values are mean±s.e.m. of six animals in each group. Sham: operated but not ligated; MI: myocardial infarcted with coronary artery ligated; imidapril (IMP) was given orally (1 mg kg⁻¹ day⁻¹). ^*P<0.05 compared with sham group; ^†P<0.05 compared with MI.

Figure 2

Representative tracings of [Ca²⁺]_i alteration in cardiomyocytes isolated from left ventricles of animals with CHF after stimulation with exogenous ATP (50 μM) and KCl (30 mM). Sham: operated but not ligated; MI: myocardial infarcted with coronary artery ligated; imidapril (IMP) was given orally (1 mg kg⁻¹ day⁻¹).