Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation.

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.

• Authors: 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
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 58 Issue 25 Pg. 2683-91 (Dec 13 2011) ISSN: 1558-3597 [Electronic] United States
• PMID: 22152956 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Adrenergic beta-1 Receptor Antagonists
• Benzopyrans
• Ethanolamines
• Receptors, Adrenergic, beta-3
• Nebivolol
• Nitric Oxide Synthase Type I
• Nitric Oxide Synthase Type III

Topics

• Adrenergic beta-1 Receptor Antagonists (pharmacology)
• Animals
• Benzopyrans (pharmacology)
• Biological Availability
• Disease Models, Animal
• Ethanolamines (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardial Reperfusion Injury (enzymology)
• Nebivolol
• Nitric Oxide Synthase Type I (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Receptors, Adrenergic, beta-3 (drug effects)