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.
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: K E Loke; S K Laycock; S Mital; M S Wolin; R Bernstein; M Oz; L Addonizio; G Kaley; T H Hintze Journal: Circulation Date: 1999-09-21 Impact factor: 29.690
Authors: Mark R Duranski; James J M Greer; Andre Dejam; Sathya Jaganmohan; Neil Hogg; William Langston; Rakesh P Patel; Shaw-Fang Yet; Xunde Wang; Christopher G Kevil; Mark T Gladwin; David J Lefer Journal: J Clin Invest Date: 2005-04-14 Impact factor: 14.808
Authors: M R Candelore; L Deng; L Tota; X M Guan; A Amend; Y Liu; R Newbold; M A Cascieri; A E Weber Journal: J Pharmacol Exp Ther Date: 1999-08 Impact factor: 4.030
Authors: Marcus D Flather; Marcelo C Shibata; Andrew J S Coats; Dirk J Van Veldhuisen; Aleksandr Parkhomenko; Joszef Borbola; Alain Cohen-Solal; Dan Dumitrascu; Roberto Ferrari; Philippe Lechat; Jordi Soler-Soler; Luigi Tavazzi; Lenka Spinarova; Jiri Toman; Michael Böhm; Stefan D Anker; Simon G Thompson; Philip A Poole-Wilson Journal: Eur Heart J Date: 2005-01-09 Impact factor: 29.983
Authors: Klara Brixius; Wilhelm Bloch; Christian Pott; Andreas Napp; Andreas Krahwinkel; Christoph Ziskoven; Marco Koriller; Uwe Mehlhorn; J Hescheler; Bernd Fleischmann; Robert H G Schwinger Journal: Br J Pharmacol Date: 2004-10-04 Impact factor: 8.739
Authors: C Gauthier; V Leblais; L Kobzik; J N Trochu; N Khandoudi; A Bril; J L Balligand; H Le Marec Journal: J Clin Invest Date: 1998-10-01 Impact factor: 14.808
Authors: Xiaolin Niu; Vabren L Watts; Oscar H Cingolani; Vidhya Sivakumaran; Jordan S Leyton-Mange; Carla L Ellis; Karen L Miller; Konrad Vandegaer; Djahida Bedja; Kathleen L Gabrielson; Nazareno Paolocci; David A Kass; Lili A Barouch Journal: J Am Coll Cardiol Date: 2012-05-29 Impact factor: 24.094
Authors: Danielle M Trappanese; Yuchuan Liu; Ryan C McCormick; Alessandro Cannavo; Gayani Nanayakkara; Marina M Baskharoun; Harish Jarrett; Felix J Woitek; D Michael Tillson; A Ray Dillon; Fabio A Recchia; Jean-Luc Balligand; Steven R Houser; Walter J Koch; Louis J Dell'Italia; Emily J Tsai Journal: Basic Res Cardiol Date: 2014-12-06 Impact factor: 17.165
Authors: Xavier Rossello; Antonio Piñero; Rodrigo Fernández-Jiménez; Javier Sánchez-González; Gonzalo Pizarro; Carlos Galán-Arriola; Manuel Lobo-Gonzalez; Jean Paul Vilchez; Jaime García-Prieto; Jose Manuel García-Ruiz; Ana García-Álvarez; David Sanz-Rosa; Borja Ibanez Journal: J Cardiovasc Transl Res Date: 2018-08-02 Impact factor: 4.132
Authors: Rukhsana Gul; Vincent G Demarco; James R Sowers; Adam Whaley-Connell; Lakshmi Pulakat Journal: Cardiorenal Med Date: 2012-07-24 Impact factor: 2.041