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 Beta3-adrenergic receptor (AR) activation promotes endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. We hypothesized that specific beta3-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 beta3-AR−/−, eNOS−/−, and in nNOS−/− mice. Conclusions Our results indicate that beta3-AR agonists protect against MI/R injury. Furthermore, the cardioprotective effects of beta3-AR agonists are mediated by rapid eNOS and nNOS activation and increased NO bioavailability.

Nebivolol Induces Distinct Changes in Profibrosis MicroRNA Expression Compared With Atenolol, in Salt-Sensitive Hypertensive Rats

“…20 Myocardial Sp1 levels are increased in rats with aortic banding and in neonatal cardiomyocytes exposed to phenylephrine. 21 Our data confirm a previous report that HS diet increases myocardial Sp1 levels in Dahl salt-sensitive hypertensive rats. 22 However, previous studies have not demonstrated that Sp1 inhibition affects cardiac hypertrophy or fibrosis.…”

Enhanced Expression of β3-Adrenoceptors in Cardiac Myocytes Attenuates Neurohormone-Induced Hypertrophic Remodeling Through Nitric Oxide Synthase

“…Therefore, under harsh stress producing increased oxidant stress, inhibition of nNOS with LVNIO abrogates this protection, resulting in eNOS uncoupling with more oxidant radicals production and worse hypertrophic remodeling. This does not happen with L-NAME because this nonspecific inhibitor also interrupts uncoupled eNOS activity, thereby paradoxically reducing oxidant stress.35 Accordingly, nNOS-deficient mice exhibited worse remodeling after infarction, 36 and more recent studies have suggested the involvement of both constitutive NOS downstream β3-AR in exercise-induced protection or ischemia-reperfusion injury 37,38 ; also, the protective effect of BRL37344, a preferential β3-AR agonist, in TAC-induced remodeling was lost in mice with nNOS deletion and even resulted in worse hypertrophy.15 This is consistent with our demonstration of the colocalization of β3-AR with both NOS isoforms by PLA, as well as our observation of increased mortality of PE-treated cardiac myocytes after nNOS inhibition with LVNIO ( Figure VI in the online-only Data Supplement). Therefore, myocyte nNOS can be viewed as a guardian of eNOS-mediated NO signaling downstream β3-AR.…”

“…35 Accordingly, nNOS-deficient mice exhibited worse remodeling after infarction, 36 and more recent studies have suggested the involvement of both constitutive NOS downstream β3-AR in exercise-induced protection or ischemia-reperfusion injury 37,38 ; also, the protective effect of BRL37344, a preferential β3-AR agonist, in TAC-induced remodeling was lost in mice with nNOS deletion and even resulted in worse hypertrophy.…”

Trials, tribulations and speculation! Report from the 7th Biennial Hatter Cardiovascular Institute Workshop

“…During the discussion, it was noted that similar results have also been seen using nebivolol [8], which recruits nitric oxide synthesis through 3 receptor activation. Curiously both the data presented and the nebivolol study appear in contrast to earlier data using various beta blockers (summarised by Hearse, Yellon and Downey [9]), and the reason for the anomaly remains unclear.…”