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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Left ventricular pressure-volume data in WT and β3–/– mice. A combined m...
Left ventricular pressure-volume data in WT and β3–/– mice. A combined micromanometer-conductance catheter was inserted into the LV through the apex. Transient occlusion of the descending aorta was used to generate the end-systolic pressure-volume relationship (loops not shown). Depicted are (a) example steady-state loops and their respective ESPVR (from which Ees is determined) at base line after receiving isoproterenol (5 ng/kg/min) and after receiving isoproterenol and L-NMMA (10 mg/kg/h). Also shown is (b) pooled data of the augmentation of isoproterenol-stimulated inotropy by L-NMMA in WT (n = 8) and β3–/– (n = 10) mice. Isoproterenol-induced increases in Ees were augmented by NOS inhibition in WT, but not in β3–/–, mice. Data are reported as mean ± SEM. AP < 0.05 vs. base line by paired t test; BP < 0.05 vs. WT by unpaired t test.