Role of myocardial inducible nitric oxide synthase in contractile dysfunction and β-adrenergic hyporesponsiveness in rats with experimental volume-overload heart failure

Background-Whereas nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF), the significance and functional role of different NO synthase (NOS) isoforms in this pathology are controversial. Our aim was to study in the myocardium of rats with volume-overload-induced HF the expression, activity, and localization of endothelial (eNOS) and inducible (iNOS) isoforms and the involvement of iNOS in depressed cardiac contractile properties, intracellular Ca2+ ([Ca2+](i)) transients, and beta-adrenergic hyporesponsiveness. Methods and Results-HF was induced by aortocaval fistula (ACF). Compensated and decompensated subgroups of HF were selected on the basis of daily sodium excretion. ACF induced cardiac hypertrophy in rats with compensated (36%) and decompensated (76%) HF. Whereas in HF rats, cardiac eNOS expression and activity were unchanged, iNOS expression and activity increased approximate to2-fold. iNOS immunostaining was observed in ventricular myocytes of compensated and decompensated HF rats but not in controls. Isoproterenol-positive inotropic and lusitropic effects were markedly attenuated in papillary muscle of HF rats, more pronouncedly in decompensated than in compensated rats. Isoproterenol-induced increases in the rates of [Ca2+](i) activation and relaxation were also depressed in ACF rats. Selective iNOS blockade by N-(3-(aminomethyl)benzylacetamidine improved the attenuated beta-adrenergic responsiveness in HF rats. Conclusions-Our findings indicate that myocardial iNOS is activated in rats with volume-overload HF and suggest that increased iNOS activity contributes to depressed myocardial contractility and beta-adrenergic hyporesponsiveness.