Overexpression myocardial inducible nitric oxide synthase exacerbates cardiac dysfunction and beta-adrenergic desensitization in experimental hypothyroidism

Background: Altered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cardiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca2+](i) transient ([Ca2+](iT)), and beta-adrenergic hyporesponsiveness. Methods and results: Wesimultaneously evaluated LV functional performance and compared myocyte three NOS, beta-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca2+](iT) responses to beta-AR stimulation with and without pretreatment of iNOS inhibitor (1400 W, 10(-5) mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (similar to 30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T-3 and T-4 were significantly reduced followed by significantly decreased LV contractility (E-ES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dt(max)), relaxation (dR/dt(max)), and [Ca2+](iT). In hypothyroidism, isoproterenol (10(-8) M) produced significantly smaller increases in dL/dt(max), dR/dt(max) and [Ca2+](iT). These changes were associated with decreased beta(1)-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca2+](iT). Conclusions: Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with beta-AR desensitization. Up-regulation of cardiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism. (C) 2015 Elsevier Ireland Ltd. All rights reserved.