β3-adrenoceptor deficiency blocks nitric oxide–dependent inhibition of myocardial contractility
Paul Varghese, Robert W. Harrison, Robert A. Lofthouse, Dimitrios Georgakopoulos, Dan E. Berkowitz, Joshua M. Hare
Paul Varghese, Robert W. Harrison, Robert A. Lofthouse, Dimitrios Georgakopoulos, Dan E. Berkowitz, Joshua M. Hare
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β3-adrenoceptor deficiency blocks nitric oxide–dependent inhibition of myocardial contractility

Abstract

The cardiac β-adrenergic pathway potently stimulates myocardial performance, thereby providing a mechanism for myocardial contractile reserve. β-Adrenergic activation also increases cardiac nitric oxide (NO) production, which attenuates positive inotropy, suggesting a possible negative feedback mechanism. Recently, in vitro studies suggest that stimulation of the β3-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous β3-adrenoceptor deletion mutations, we tested the hypothesis that the β3-adrenoceptor is responsible for β-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, β-adrenergic–stimulated inotropy was increased in β3–/– mice, and similar hyper-responsiveness was seen in mice lacking endothelial NO synthase (NOS3). NOS inhibition augmented isoproterenol-stimulated inotropy in wild-type (WT), but not in β3–/– mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not β3–/–, mice. NOS3 protein abundance was not changed in β3–/– mice, and cardiac β3-adrenoceptor mRNA was detected in both NOS3–/– and WT mice. These findings indicate that the β3-adrenergic subtype participates in NO-mediated negative feedback over β-adrenergic stimulation.

Authors

Paul Varghese, Robert W. Harrison, Robert A. Lofthouse, Dimitrios Georgakopoulos, Dan E. Berkowitz, Joshua M. Hare

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(a) Contractile effects of isoproterenol and L-NMMA in WT, β3–/–, and NO...
(a) Contractile effects of isoproterenol and L-NMMA in WT, β3–/–, and NOS3–/– mice. Isoproterenol was administered intravenously at a rate of 5 ng/kg/min for 4 minutes, followed by a co-infusion with L-NMMA at 10 mg/kg/h for 5 minutes. Contractility was indexed by dP/dt-IP and is shown as a percentage of change from base line. The β3–/– mice (n = 10) had greater responses to isoproterenol than did the WT mice (n = 8), but did not show any further augmentation after NOS inhibition with L-NMMA. Similarly, NOS3–/– mice (n = 15) were hyper-responsive to isoproterenol. L-NMMA augmented the isoproterenol response in WT mice to the level observed in β3–/– mice. (b) The effect of an additional NOS inhibitor, L-NAME. L-NAME had an effect similar to L-NMMA, augmenting the response to isoproterenol in WT, but not β3–/–, mice. Data are reported as mean ± SEM. AP < 0.05 vs. respective base line; BP < 0.01 vs. respective base line; CP < 0.05 vs. WT isoproterenol response by one-way ANOVA.