title: Beta3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation.
abstract: OBJECTIVE
  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.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, Emory University School of Medicine, Atlanta, Georgia 30308, USA.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Aragón
authors.forename: Marah E
authors.initials: ME
authors.lastname: Condit
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Predmore
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Patel
authors.forename: D Bennett
authors.initials: DB
authors.lastname: Grinsfelder
authors.forename: Susheel
authors.initials: S
authors.lastname: Gundewar
authors.forename: Saurabh
authors.initials: S
authors.lastname: Jha
authors.forename: John W
authors.initials: JW
authors.lastname: Calvert
authors.forename: Lili A
authors.initials: LA
authors.lastname: Barouch
authors.forename: Madhav
authors.initials: M
authors.lastname: Lavu
authors.forename: Harold M
authors.initials: HM
authors.lastname: Wright
authors.forename: David J
authors.initials: DJ
authors.lastname: Lefer
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D001682:Biological Availability; D004195:Disease Models, Animal; D004983:Ethanolamines / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015428:Myocardial Reperfusion Injury / Q000201:enzymology*; D000068577:Nebivolol; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D001578:Benzopyrans; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; D000068577:Nebivolol; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III