|Ph.D Student||Gealekman Olga|
|Subject||Mechanical, Electrophysiological and Paracrine Profile|
of Cardiac Myocytes in Rats with Compensated
and Decompensated Heart Failure
|Department||Department of Medicine||Supervisors||Professor Emeritus Joseph Winaver|
|Professor Emeritus Ofer Binah|
Whereas Nitric Oxide (NO) has been implicated in pathophysiology of heart failure (HF), the significance and functional role of different NO synthase 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 involvement of iNOS in depressed cardiac contractile properties, intracellular Ca2+ ([Ca2+]i) transients, and ß-adrenergic hyporesponsiveness. HF was induced by surgical creation of Aorto-Caval fistula (ACF). Compensated and decompensated subgroups of HF were selected based on 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 were increased ≈2 fold. iNOS immunostaining was observed in ventricular myocytes of compensated and decompensated rats, but not in controls. Isoproterenol-positive inotropic and lusitropic effects were markedly attenuated in HF rats, more pronouncedly in decompensated than in compensated stage. Isoproterenol-induced increases in the rates of [Ca2+]i activation and relaxation were also depressed in HF rats. Selective iNOS blockade by N - (3-(aminomethyl) benzyl) acetamidine (1400W) improved the attenuated ß-adrenergic responsiveness in HF rats. 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 ß-adrenergic hyporesponsiveness.