AT1 Receptor Antagonist Restores Cardiac Ryanodine Receptor Function, Rendering Isoproterenol-Induced Failing Heart Less Susceptible to Ca2+-Leak Induced by Oxidative Stress

Abstract

The Ca(2+) regulatory proteins in the sarcoplasmic reticulum (SR) play a key role in the pathogenesis of heart failure. In the present study the effect of chronic beta-receptor-stimulation on cardiac and SR functions was assessed, with or without angiotensin-II receptor antagonist treatment recently reported to have anti-beta-adrenergic activity. Rats were treated with isoproterenol with (+) or without (-) candesartan (CAN) and then SR vesicles were isolated from the left ventricular muscle. Both Ca(2+)-uptake and the amount of SR Ca(2+)-ATPase were significantly lower in the CAN (-) group than in the shams, but those were almost normally restored in the CAN (+). Although the level of the protein kinase A (PKA)-phosphorylation of the SR Ca(2+) release channel, known as the ryanodine receptor (RyR2), was elevated in the CAN (-), no Ca(2+)-leak was detected. However, SIN-1 (O(2) (-) donor) induced Ca(2+)-leak in the CAN (-) at a 10-fold lower dose than in the sham and CAN (+). In cardiomyocytes, SIN-1 decreased cell shortening and the peak Ca(2+) transient and prolonged time from peak to 70% decline in CAN (-), again at 10-fold lower dose than in the sham and CAN (+). Chronic beta-receptor-stimulation did not induce any Ca(2+)-leak from the SR, whereas Ca(2+)-leak was easily induced when oxidative stress was applied to the PKA-phosphorylated RyR2. Candesartan not only improved Ca(2+)-uptake, but also prevented PKA-phosphorylation, rendering the SR less susceptible to Ca(2+)-leak.