TY - JOUR
T1 - Beta 3-adrenoreceptor stimulation ameliorates myocardial ischemia-reperfusion injury via endothelial nitric oxide synthase and neuronal nitric oxide synthase activation
AU - Aragón, Juan P.
AU - Condit, Marah E.
AU - Bhushan, Shashi
AU - Predmore, Benjamin L.
AU - Patel, Sandeep S.
AU - Grinsfelder, D. Bennett
AU - Gundewar, Susheel
AU - Jha, Saurabh
AU - Calvert, John W.
AU - Barouch, Lili A.
AU - Lavu, Madhav
AU - Wright, Harold M.
AU - Lefer, David J.
N1 - Funding Information:
Forest Research Institute provided nebivolol and an Investigator-Initiated Grant for this study. Additional funding was provided by the National Institutes of Health, National Heart, Lung, and Blood Institute ( 2R01HL-060849-09 , 5R01HL-092141-01 , and 1R01HL093579-01 to Dr. Lefer, and 5Ro1HL098481-02 to Dr. Calvert); the American Heart Association ( 09BGIA2250379 to Dr. Barouch); the American Diabetes Association ( 7-09-BS-26 to Dr. Calvert and 1-10-BS-11 to Dr. Barouch), and the Carlyle Fraser Heart Center. Dr. Wright is an employee of Forest Research Institute, a subsidiary of Forest Laboratories. Dr. Lefer has received grant support from Forest Research Labs to perform studies with nebivolol. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
PY - 2011/12/13
Y1 - 2011/12/13
N2 - 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.
AB - 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.
KW - beta adrenergic receptor
KW - cardiac ischemia
KW - endothelial nitric oxide synthase
KW - neuronal nitric oxide synthase
KW - nitric oxide
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U2 - 10.1016/j.jacc.2011.09.033
DO - 10.1016/j.jacc.2011.09.033
M3 - Article
C2 - 22152956
AN - SCOPUS:82955217769
VL - 58
SP - 2683
EP - 2691
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
SN - 0735-1097
IS - 25
ER -