Abstract 11340: Overexpression Myocardial Inducible Nitric Oxide Synthase (iNOS) Exacerbates Cardiac Dysfunction and Beta-Adrenergic Desensitization in Rats with Experimental Hypothyroidism
Background. Nitric oxide (NO) has been implicated in the pathophysiology of heart failure (HF). The significance and functional role of different NO synthase isoforms in this pathology are controversial. Recent reports have shown that in failing myocardium, increased inducible nitric oxide synthase (iNOS) contributes to the attenuation of β-adrenergic receptor (AR)-mediated inotropic effect. However, the alteration and functional effect of cardiac iNOS in hypothyroidism (Hypo) are unknown. We tested the hypothesis that Hypo increases cadiomyocyte iNOS expression. Overexpression of iNOS plays an important role in Hypo-induced depression of cardiomyocyte contractile properties, [Ca2+]i transient ([Ca2+]iT), and β-adrenergic hyporesponsiveness.
Methods. We compared myocyte iNOS and β1-AR expression and assessed cardiomyocyte contractile and ([Ca2+]iT) responses to β-AR stimulation by superfusion of isoproterenol (ISO) with and without pretreatment of a selective iNOS inhibitor, 1400W (10-5 M), in 11 normal control and 13 Hypo rats induced by methimazole (∼30 mg/kg/day for 8 weeks in the drinking water).
Results. Compared to control myocytes (C), β1-AR expression decreased about 36% (0.48 vs 0.75), but iNOS increased 56% (0.28 vs 0.18) in Hypo myocytes. These alterations in Hypo rats were associated with significant depression in myocyte contraction and relaxation indicated by 60% decreases in dL/dtmax (Hypo: 60.8±3.1 vs C: 152.8±5.2 μm/s) and dR/dtmax (49.1±6.4 vs 121.5±5.7 μm/s) with reduced [Ca2+]iT (-29%, 0.17 vs 0.24). There were attenuated responses to β-AR stimulation. ISO (10-8 M) produced significantly less increases in dL/dtmax (31% vs 85%) and [Ca2+]iT (17% vs 37%) in Hypo myocytes compared to normal. Moreover, only in Hypo myocytes, pretreatment with 1400 W markedly improved myocyte basal contraction (dL/dtmax, 87.8 μm/s) and relaxation (dR/dtmax, 81.6 μm/s). The ISO-induced increase in dL/dtmax (77.6%) and [Ca2+]iT (28.9%) were also significantly augmented.
Conclusions. Our findings indicate that myocardial iNOS is activated in rats with hypothyroidism and suggest that increased iNOS expression contributes to depressed myocardial contractility, impaired [Ca2+]i regulation and β-adrenergic hyporesponsiveness.
- © 2012 by American Heart Association, Inc.