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

被引：140

作者：

Aragon, Juan P. ^{[2
]}

Condit, Marah E. ^{[2
]}

Bhushan, Shashi ^{[2
]}

Predmore, Benjamin L. ^{[2
]}

Patel, Sandeep S. ^{[3
]}

Grinsfelder, D. Bennett ^{[2
]}

Gundewar, Susheel ^{[3
]}

Jha, Saurabh ^{[3
]}

Calvert, John W. ^{[2
]}

Barouch, Lili A. ^{[4
]}

Lavu, Madhav ^{[2
]}

Wright, Harold M. ^{[5
]}

Lefer, David J. ^{[1
,2
]}

机构：

[1] Emory Univ, Sch Med, Dept Surg, Div Cardiothorac Surg,CT Surg Res Lab, Atlanta, GA 30308 USA

[2] Emory Univ, Crawford Long Hosp, Carlyle Fraser Heart Ctr, Atlanta, GA 30365 USA

[3] Albert Einstein Coll Med, Dept Med, Div Cardiol, Bronx, NY 10467 USA

[4] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA

[5] Forest Labs Inc, Forest Res Inst, Dept Pharmacol, Jersey City, NJ USA

来源：

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY | 2011年 / 58卷 / 25期

基金：

美国国家卫生研究院;

关键词：

beta(3) adrenergic receptor; cardiac ischemia; endothelial nitric oxide synthase; neuronal nitric oxide synthase; nitric oxide; HUMAN BETA-3-ADRENERGIC RECEPTOR; 3RD-GENERATION BETA-BLOCKER; HUMAN HEART; MOLECULAR CHARACTERIZATION; CARDIOVASCULAR-SYSTEM; DEFICIENT MICE; NEBIVOLOL; RAT; MECHANISMS; AGONIST;

D O I：

10.1016/j.jacc.2011.09.033

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

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 Beta(3)-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bio-availability. We hypothesized that specific beta(3)-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 mu g/kg), BRL-37344 (1 mu g/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 beta(3)-AR(-/-), eNOS(-/-), and in nNOS(-/-) mice. Conclusions Our results indicate that beta(3)-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta(3)-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability. (J Am Coll Cardiol 2011;58:2683-91) (C) 2011 by the American College of Cardiology Foundation

引用

页码：2683 / 2691

页数：9

共 51 条

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