Endothelial β ₃ -Adrenoreceptors Mediate Nitric Oxide–Dependent Vasorelaxation of Coronary Microvessels in Response to the Third-Generation β-Blocker Nebivolol

Abstract

Background-The therapeutic effects of nonspecific ␤-blockers are limited by vasoconstriction, thus justifying the interest in molecules with ancillary vasodilating properties. Nebivolol is a selective ␤ 1 -adrenoreceptor antagonist that releases nitric oxide (NO) through incompletely characterized mechanisms. We identified endothelial ␤ 3 -adrenoreceptors in human coronary microarteries that mediate endothelium-and NO-dependent relaxation and hypothesized that nebivolol activates these ␤ 3 -adrenoreceptors. Methods and Results-Nebivolol dose-dependently relaxed rodent coronary resistance microarteries studied by videomicroscopy (10 mol/L, Ϫ86Ϯ6% of prostaglandin F2␣ contraction); this was sensitive to NO synthase (NOS) inhibition, unaffected by the ␤ 1-2 -blocker nadolol, and prevented by the ␤ 1-2-3 -blocker bupranolol (PϽ0.05; nϭ3 to 8). Importantly, nebivolol failed to relax microarteries from ␤ 3 -adrenoreceptor-deficient mice. Nebivolol (10 mol/L) also relaxed human coronary microvessels (Ϫ71Ϯ5% of KCl contraction); this was dependent on a functional endothelium and NO synthase but insensitive to ␤ 1-2 -blockade (all PϽ0.05). In a mouse aortic ring assay of neoangiogenesis, nebivolol induced neocapillary tube formation in rings from wild-type but not ␤ 3 -adrenoreceptor-or endothelial NOS-deficient mice. In cultured endothelial cells, 10 mol/L nebivolol increased NO release by 200% as measured by electron paramagnetic spin trapping, which was also reversed by NOS inhibition. In parallel, endothelial NOS was dephosphorylated on threonine 495 , and fura-2 calcium fluorescence increased by 91.8Ϯ23.7%; this effect was unaffected by ␤ 1-2 -blockade but abrogated by ␤ 1-2-3 -blockade (all PϽ0.05). Conclusions-Nebivolol dilates human and rodent coronary resistance microarteries through an agonist effect on endothelial ␤ 3 -adrenoreceptors to release NO and promote neoangiogenesis. These properties may prove particularly beneficial for the treatment of ischemic and cardiac failure diseases through preservation of coronary reserve.

Effect of the long-term administration of nebivolol on clinical symptoms, exercise capacity and left ventricular function in patients with heart failure and preserved left ventricular ejection fraction: background, aims and design of the ELANDD study

“…Nebivolol is a beta-blocker characterised by a high degree of selectivity for the beta-1 adrenergic receptors (ARs), compared to beta-2 ARs, with associated vasodilatory properties mediated by nitric oxide release [17] and probably by beta-3 ARs stimulation of endothelial cells [18]. Nitric oxide release at the level of the myocardium has favourable lusitropic effects with a downward shift of the LV pressure-volume relation in the diastolic phase and lower LV filling pressures [19].…”

β 2 -Adrenoceptor Antagonist ICI 118,551 Decreases Pulmonary Vascular Tone in Mice via a G i/o Protein/Nitric Oxide-Coupled Pathway

“…6 In systemic arteries, it has been demonstrated that thirdgeneration ␤-blockers can directly induce vasodilation via NO release from the endothelium 7 and thereby positively affect the afterload. The aim of our study was to identify pulmonary specific vasorelaxants, and we have, therefore, investigated the impact of different ␤-adrenergic mediators on vascular tone in the pulmonary and systemic circulations of mouse.…”

Efficacy and Safety of Vasoactive Beta-Blockers in Acute Pharmacological Test in Hypertensive Patients of Different Ages

“…При этом меха-низмы влияния на тонус периферических сосудов у пре-паратов принципиально различаются. Карведилол обладает Δ-адреноблокирующей активностью [14], а не-биволол приводит к высвобождению эндотелиально-го фактора релаксации (оксида азота) сосудистой стенкой и замедляет его распад [15]. Гипотензивный эф-фект стартовой дозы карведилола был отмечен и ранее [16][17][18].…”