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

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Background The Ca²⁺ 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 β-receptor-stimulation on cardiac and SR functions was assessed, with or without angiotensin-II receptor antagonist treatment recently reported to have anti-β-adrenergic activity. Methods and Results Rats were treated with isoproterenol with (+) or without (-) candesartan (CAN) and then SR vesicles were isolated from the left ventricular muscle. Both Ca²⁺-uptake and the amount of SR Ca²⁺-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 Ca²⁺ release channel, known as the ryanodine receptor (RyR2), was elevated in the CAN (-), no Ca²⁺-leak was detected. However, SIN-1 (O₂ ^- donor) induced Ca²⁺-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 Ca²⁺ transient and prolonged time from peak to 70% decline in CAN (-), again at 10-fold lower dose than in the sham and CAN (+). Conclusion Chronic β-receptor-stimulation did not induce any Ca²⁺-leak from the SR, whereas Ca²⁺-leak was easily induced when oxidative stress was applied to the PKA-phosphorylated RyR2. Candesartan not only improved Ca²⁺-uptake, but also prevented PKA-phosphorylation, rendering the SR less susceptible to Ca²⁺-leak. (Circ J 2006; 70: 777 - 786)