The Involvement of ATP-Sensitive Potassium Channels in the Nebivolol-Induced Relaxation of Endothelium-Intact Aorta Isolated from Rats

Abstract

Objective: Nebivolol is a highly selective beta-1 adrenergic receptor blocker with additional vasorelaxant properties. The vasorelaxant effect of nebivolol has been mainly attributed to endothelium-dependent mechanisms including beta-adrenergic receptors. However, the involvement of ATP-sensitive potassium (KATP) channels, another potential mechanism for vasorelaxant effect, in the vasorelaxant response to nebivolol remains unclear. Therefore, this study was aimed to investigate the role of KATP channels in the nebivolol-induced vasorelaxation in the isolated rat aorta Methods: The rat thoracic aortic rings isolated from Sprague-Dawley rats were mounted in organ bath chambers containing Krebs-Henseleit solution at 37 o C continuously bubbled with 95% O2 and 5% CO2. After an equilibration period, the presence of endothelium was confirmed by the response (more than 50%) to acetylcholine (10 μM) in aortic rings precontracted with phenylephrine (1 μM). After washout, in control group, the endothelium-intact aortic rings were contracted by potassium chloride (30 mM) before the cumulative addition of nebivolol (0.0001-100 μM). In some experiments, the relaxant response to nebivolol (0.0001-100 μM) was also obtained in the presence of glibenclamide (KATP channel blocker, 10 μM) or Nω-Nitro-L-arginine methyl ester (L-NAME: eNOS inhibitor, 100 μM) in the endothelium-intact aortic rings precontracted with potassium chloride (30 mM). Data were presented as means±SEM. Multiple comparisons of groups were performed by using ANOVA followed by post-hoc Bonferroni test. Results: Nebivolol elicited a concentration dependent vasorelaxant effect in the endothelium-intact aortic rings. Relaxant response to nebivolol was significantly inhibited by the presence of glibenclamide or L-NAME (p< 0.05). Although Emax values were not found significantly different among groups, pD2 values of nebivolol were reduced in the endothelium-intact aortic rings incubated with glibenclamide or L-NAME. Conclusion: These results demonstrate for the first time the involvement of KATP channels in the nebivololinduced vasorelaxation in the endothelium-intact aorta precontracted with potassium chloride.

Multitargeting in cardioprotection: An example of biaromatic compounds

“…However, the analysis of direct blocking activity in relation to this channel was not carried out. [ 239 ]…”

Elastogenesis Stimulation by Minoxidil or Nebivolol Reduces Premature Aging of the Aortic Wall in Diabetic Mice

“…Many antihypertensive drugs targeting, for example, angiotensin, also exert a signi cant metabolic in uence [28][29][30]. This is why we prioritized beta-blocking molecules and tested nebivolol, which would have negligible metabolic effects [31,32] while also potentially impacting potassium channels [33][34][35]. Furthermore, nebivolol has been described as a cardiac brosis inhibitor, thus demonstrating a signi cant impact on the ECM of the heart and suggesting potentially, a role on vascular ECM remodeling [32,36,37] .…”