beta(3)-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility

The cardiac beta-adrenergic pathway potently stimulates myocardial performa nce, thereby providing a mechanism for myocardial contractile reserve. beta -Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedbac k mechanism. Recently, in vitro studies suggest that stimulation of the bet a(3)-adrenoceptor results in a negative inotropic effect through NO signali ng. In this study, using mice with homozygous beta(3)-adrenoceptor deletion mutations, we tested the hypothesis that the beta(3)-adrenoceptor is respo nsible for beta-adrenergic activation of NO. Although resting indices of my ocardial contraction were similar, beta-adrenergic-stimulated inotropy was increased in beta(3)(-/-) mice, and similar hyperresponsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isop roterenol-stimulated inotropy in wild-type (WT), but not in beta(3)(-/-) mi ce, Moreover, isoproterenol increased myocardial cGMP in WT, but not beta(3 )(-/-), mice. NOS3 protein abundance was not changed in beta(3)(-/-) mice, and cardiac Pa-adrenoceptor mRNA was detected in both NOS3(-/-) and WT mice . These findings indicate that the beta(3)-adrenergic subtype participates in NO-mediated negative feedback over beta-adrenergic stimulation.