Cardioprotective Effect of Beta-3 Adrenergic Receptor Agonism Role of Neuronal Nitric Oxide Synthase

Objectives The aim of this study was to determine whether activation of beta 3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload. Background beta 3-AR and its downstream signaling pathways are recognized as novel modulators of heart function. Unlike beta 1-and beta 2-ARs, beta 3-ARs are stimulated at high catecholamine concentrations and induce negative inotropic effects, serving as a brake to protect the heart from catecholamine overstimulation. Methods C57BL/6J and neuronal NOS (nNOS) knockout mice were assigned to receive transverse aortic constriction (TAC), BRL37344 (beta 3 agonist, BRL 0.1 mg/kg/h), or both. Results Three weeks of BRL treatment in wild-type mice attenuated left ventricular dilation and systolic dysfunction, and partially reduced cardiac hypertrophy induced by TAC. This effect was associated with increased nitric oxide production and superoxide suppression. TAC decreased endothelial NOS (eNOS) dimerization, indicating eNOS uncoupling, which was not reversed by BRL treatment. However, nNOS protein expression was up-regulated 2-fold by BRL, and the suppressive effect of BRL on superoxide generation was abrogated by acute nNOS inhibition. Furthermore, BRL cardioprotective effects were actually detrimental in nNOS-/-mice. Conclusions These results are the first to show in vivo cardioprotective effects of beta 3-AR-specific agonism in pressure overload hypertrophy and heart failure, and support nNOS as the primary downstream NOS isoform in maintaining NO and reactive oxygen species balance in the failing heart. (J Am Coll Cardiol 2012; 59: 1979-87) (C) 2012 by the American College of Cardiology Foundation