Document Detail

Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation.
MedLine Citation:
PMID:  22152956     Owner:  NLM     Status:  MEDLINE    
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.
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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  58     ISSN:  1558-3597     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-14     Completed Date:  2012-05-11     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2683-91     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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MeSH Terms
Adrenergic beta-1 Receptor Antagonists / pharmacology*
Benzopyrans / pharmacology*
Biological Availability
Disease Models, Animal
Ethanolamines / pharmacology*
Mice, Inbred C57BL
Myocardial Reperfusion Injury / enzymology*
Nitric Oxide Synthase Type I / metabolism*
Nitric Oxide Synthase Type III / metabolism*
Receptors, Adrenergic, beta-3 / drug effects*
Grant Support
1R01HL093579-01/HL/NHLBI NIH HHS; 2R01HL-060849-09/HL/NHLBI NIH HHS; 5R01HL-092141-01/HL/NHLBI NIH HHS; 5R01HL098481-02/HL/NHLBI NIH HHS; R01 HL092141/HL/NHLBI NIH HHS; R01 HL092141-03/HL/NHLBI NIH HHS; R01 HL093579/HL/NHLBI NIH HHS; R01 HL093579-03/HL/NHLBI NIH HHS; R01 HL098481/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Adrenergic beta-1 Receptor Antagonists; 0/Benzopyrans; 0/Ethanolamines; 0/Receptors, Adrenergic, beta-3; 030Y90569U/nebivolol; EC Oxide Synthase Type I; EC Oxide Synthase Type III
Comment In:
J Am Coll Cardiol. 2011 Dec 13;58(25):2692-4   [PMID:  22152957 ]

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