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

• Authors: Juan Pablo Aragon, Emory University; Marah E. Condit, Emory University; Shashi Bhushan, Emory University; Benjamin L. Predmore, Emory University; Sandeep S. Patel, Albert Einstein College; D. Bennett Grinsfelder, Emory University; Susheel Gundewar, Albert Einstein College; Saurabh Jha, Albert Einstein College; John W Calvert, Emory University; Lili A. Barouch, Johns Hopkins; Madhav Lavu, Emory University; Harold M. Wright, Forest Research Institute; David J. Lefer, Emory University
• Journal Title: Journal of the American College of Cardiology
• Volume: Volume 58, Number 25
• Publisher: Elsevier: 12 months | 2011-12-13, Pages 2683-2691
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1016/j.jacc.2011.09.033
• Subjects: Health Sciences, Medicine and Surgery
• Keywords: beta3 adrenergic receptor; cardiac ischemia; endothelial nitric oxide synthase; neuronal nitric oxide synthase; nitric oxide

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.