Nebivolol: A Highly Selective β₁‐Adrenergic Receptor Blocker That Causes Vasodilation by Increasing Nitric Oxide

Abstract

Nebivolol (Bystolic R ) is a cardioselective beta 1 (β 1 )-adrenergic receptor blocker with endothelium-dependent vasodilating properties. The endothelium-dependent relaxation induced by nebivolol is blocked by inhibitors of nitric oxide synthase (NOS) and guanylate cyclase. Nebivolol also increases in vitro and in vivo nitric oxide (NO), which is an essential signaling molecule involved in the maintenance of cardiovascular homeostasis. This review summarizes the data involving nebivolol and NO bioavailability. Endothelium-dependent relaxation of blood vessels, which is impaired in hypertensive animals and humans, is reversed by nebivolol treatment. Animals exhibiting endothelial dysfunction also show an improvement in NOcyclic guanosine monophosphate (cGMP) signaling and an increase in NO bioavailability when treated with nebivolol. When blood vessel and cultured endothelial cells from hypertensive animals are treated with nebivolol, there is a decrease in superoxide production and an increase in the expression and activity of endothelial NOS (eNOS). As a result of the increased bioavailability of NO, nebivolol also increases in vivo arterial distensibility, glomerular filtration rate, and renal plasma flow. In normotensive volunteers, nebivolol infusion increases the forearm blood flow, an effect that is blocked by inhibitors of NOS and restored by the NOS substrate, L-arginine. In hypertensive patients, chronic treatment with nebivolol improves endothelium-dependent vasodilation induced by acetylcholine and shear stress and reverses endotheliumdependent vasoconstriction. Furthermore, nebivolol displays distinct hemodynamic properties in patients that include improvements in stroke volume and a decrease in peripheral vascular resistance. These studies demonstrate that nebivolol produces endothelium-dependent vasodilation by increasing NO release, decreasing oxidative stress to increase NO bioavailability, or both. The NO-dependent vasodilatory action of nebivolol, coupled with its high β 1 -adrenergic receptor selectivity, is unique among the clinically available β-blockers and contributes to its efficacy and improved tolerability (e.g., less fatigue and sexual dysfunction) as an antihypertensive agent.

Lipid Peroxidation and Antioxidants in Arterial Hypertension

“…In addition, nebivolol also increases . NO release from the endothelium, thus attenuating oxidative stress effects on endothelium-dependent vasodilation [309,310]. The calcium channel blocker lacidipine has also been demonstrated…”

The effect of nebivolol on the production of nitric oxide induced by bacterial lipopolysaccharide and peptidoglycan in mice

“…It is unique among all β1-adrenoceptor blockers in that it possesses a vasodilatory property attributed to synthesis of NO [21,22] as well as to increasing NO bioavailability by decreasing the oxidative stress [23][24][25][26][27]. The observation that nebivolol increases the concentration of nitrite in 7 out of 10 as-says using different doses and at different time intervals, reflecting an increase in the NO levels, is confirmatory to observations reported by others [31][32][33].…”

“…It is unique among all β1-adrenoceptor blockers in that it possesses a vasodilatory property attributed to synthesis of NO [20,21] as well as to increasing NO bioavailability by decreasing the oxidative stress [22][23][24][25][26]. In addition, Ladage et al [27] reported that the endothelium-dependent increase in NO induced by nebivolol was due to stimulation of β 3 -adrenoceptors and estrogen receptors.…”

Synthesis and Characterization of New 3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl 4-Propoxybenzoates and Their Hydrochloride Salts

“…The latest generation of β-blockers commonly possesses some additional beneficial features that can improve their therapeutic profile and reduce their sometimes serious side effects. These features are mainly antioxidant properties (e.g., carvedilol [3]), vasodilatory activity (e.g., carvedilol, nebivolol [3,4]) and ultra-short effect (e.g., esmolol, landiolol [5,6]). …”

“…The cardiovascular activity of the discussed compounds is provided by the presence of the arylcarbonyloxyaminopropanol pharmacophore (β-adrenolytic activity; the ester moiety ensures ultra-short effect) and the phenylpiperazine fragment (α 1 -adrenolytic activity) [2,8]. The arylcarbonyloxyaminopropanol scaffold is formed by the benzene ring (as a part of 4-hydroxybenzoic acid) substituted at the C (4) position with a propoxy chain. The phenylpiperazine segment, the basic part of the molecule, is either unsubstituted or substituted with a methoxy or a fluoro moiety in the C (2) 1 or C (4) 1 position.…”