TY - JOUR
T1 - β3-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility
AU - Varghese, Paul
AU - Harrison, Robert W.
AU - Lofthouse, Robert A.
AU - Georgakopoulos, Dimitrios
AU - Berkowitz, Dan E.
AU - Hare, Joshua M.
PY - 2000/9
Y1 - 2000/9
N2 - 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 hyperresponsiveness 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.
AB - 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 hyperresponsiveness 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.
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U2 - 10.1172/JCI9323
DO - 10.1172/JCI9323
M3 - Article
C2 - 10974023
AN - SCOPUS:0033823132
SN - 0021-9738
VL - 106
SP - 697
EP - 703
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 5
ER -