Beta 3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation

Juan P. Aragón, Marah E. Condit, Shashi Bhushan, Benjamin L. Predmore, Sandeep S. Patel, D. Bennett Grinsfelder, Susheel Gundewar, Saurabh Jha, John W. Calvert, Lili A. Barouch, Madhav Lavu, Harold M. Wright, David J. Lefer

Research output: Contribution to journalArticlepeer-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: Beta 3-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. 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 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 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.

Original languageEnglish (US)
Pages (from-to)2683-2691
Number of pages9
JournalJournal of the American College of Cardiology
Volume58
Issue number25
DOIs
StatePublished - Dec 13 2011

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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