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Author Notes:

Correspondence: Dr. David J. Lefer, Emory University School of Medicine, Department of Surgery, Division of Cardiothoracic Surgery, CT Surgery Research Laboratory, 550 Peachtree Street, Northeast, Atlanta, Georgia 30308; Email: dlefer@emory.edu

Acknowledgments: The authors thank Henry Li, PhD, and Julie Wangsa, PhD, from the Forest Research Institute, for their technical help.

Disclosures: Dr. Wright is an employee of Forest Research Institute, a subsidiary of Forest Laboratories.

All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Research Funding:

Forest Research Institute provided nebivolol and an Investigator-Initiated Grant for this study.

Additional funding was provided by the National Institutes of Health, National Heart, Lung, and Blood Institute (2R01HL-060849-09, 5R01HL-092141-01, and 1R01HL093579-01 to Dr. Lefer, and 5Ro1HL098481-02 to Dr. Calvert); the American Heart Association (09BGIA2250379 to Dr. Barouch); the American Diabetes Association (7-09-BS-26 to Dr. Calvert and 1-10-BS-11 to Dr. Barouch), and the Carlyle Fraser Heart Center.

Dr. Lefer has received grant support from Forest Research Labs to perform studies with nebivolol.

Keywords:

  • beta3 adrenergic receptor
  • cardiac ischemia
  • endothelial nitric oxide synthase
  • neuronal nitric oxide synthase
  • nitric oxide

Beta3-Adrenoreceptor Stimulation Ameliorates Myocardial Ischemia-Reperfusion Injury Via Endothelial Nitric Oxide Synthase and Neuronal Nitric Oxide Synthase Activation

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Journal Title:

Journal of the American College of Cardiology

Volume:

Volume 58, Number 25

Publisher:

, Pages 2683-2691

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Objectives This paper examined whether nebivolol protects the heart via nitric oxide (NO) synthase and NO-dependent signaling in an in vivo model of acute myocardial infarction. Background Beta3-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta3-AR agonists would attenuate myocardial ischemia-reperfusion (MI/R) injury via eNOS activation and increased NO bioavailability. Methods Mice were subjected to 45 min of myocardial ischemia in vivo followed by 24 h of reperfusion (R). Nebivolol (500 ng/kg), CL 316243 (1 μg/kg), BRL-37344 (1 μg/kg), or vehicle (VEH) was administered at the time of R. Myocardial area-at-risk (AAR) and infarct size (INF)/AAR was measured at 24 h of R. Cardiac tissue and plasma were collected to evaluate eNOS phosphorylation, neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase expression, and nitrite and nitrosothiol levels. Results Nebivolol (500 ng/kg) reduced INF/AAR by 37% (p < 0.001 vs. VEH) and serum troponin-I levels from 41 ± 4 ng/ml to 25 ± 4 ng/ml (p < 0.05 vs. VEH). CL 316243 and BRL-37344 reduced INF by 39% and 42%, respectively (p < 0.001 vs. VEH). Nebivolol and CL 316243 increased eNOS phosphorylation at Ser-1177 (p < 0.05 vs. VEH) and increased nitrite and total nitrosylated protein levels. Nebivolol and CL 316243 significantly increased myocardial nNOS expression. Nebivolol failed to reduce INF after MI/R in beta3-AR−/−, eNOS−/−, and in nNOS−/− mice. Conclusions Our results indicate that beta3-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta3-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.

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© 2011 by the American College of Cardiology Foundation

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported License (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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