beta(3)-adrenoceptor deficiency blocks nitric oxide-dependent inhibition of myocardial contractility.
Journal Article
The cardiac beta-adrenergic pathway potently stimulates myocardial performance, 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 feedback mechanism. Recently, in vitro studies suggest that stimulation of the beta(3)-adrenoceptor results in a negative inotropic effect through NO signaling. In this study, using mice with homozygous beta(3)-adrenoceptor deletion mutations, we tested the hypothesis that the beta(3)-adrenoceptor is responsible for beta-adrenergic activation of NO. Although resting indices of myocardial contraction were similar, beta-adrenergic-stimulated inotropy was increased in beta(3)(-/-) 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 beta(3)(-/-) mice. Moreover, isoproterenol increased myocardial cGMP in WT, but not beta(3)(-/-), mice. NOS3 protein abundance was not changed in beta(3)(-/-) mice, and cardiac beta(3)-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.
Full Text
Duke Authors
Cited Authors
- Varghese, P; Harrison, RW; Lofthouse, RA; Georgakopoulos, D; Berkowitz, DE; Hare, JM
Published Date
- September 2000
Published In
Volume / Issue
- 106 / 5
Start / End Page
- 697 - 703
PubMed ID
- 10974023
Pubmed Central ID
- 10974023
International Standard Serial Number (ISSN)
- 0021-9738
Digital Object Identifier (DOI)
- 10.1172/JCI9323
Language
- eng
Conference Location
- United States