Nebivolol and Endothelial Dysfunction in Patients With Essential Hypertension: A Reputation Saver of β‐Blockers?

Abstract

We have read with great interest the recently published article by Neuman and coworkers 1 in which they hypothesized that nebivolol, a selective b 1 -antagonist that stimulates nitric oxide (NO), improves endothelial function in African Americans with hypertension when compared with metoprolol. In that well-designed study, the authors found evidence for NO bioavailability at rest during treatment with both nebivolol and metoprolol succinate in hypertensive African American patients, with a clear trend for a greater contribution of NO during nebivolol therapy. Moreover, after combined blockade of NO and endothelium-derived hyperpolarizing factor (EDHF), there was significantly greater vasoconstriction during nebivolol compared with metoprolol therapy, suggesting a greater contribution of both NO and EDHF combined to resting vasomotor tone during nebivolol treatment. Moreover, the contribution of NO to exercise-induced vasodilation was greater during treatment with nebivolol compared with metoprolol succinate.Nebivolol is a third-generation, b 1 -adrenergic receptor antagonist that has vasodilatory properties both in animals and humans independent of b 1 -receptor antagonism and related to b 3 -receptor agonist effects. 2-5It is a racemic mixture of D-and L-enantiomers, of which D-nebivolol is considered to be a highly selective b-adrenergic receptor antagonist.5-8 It was demonstrated that nebivolol stimulates NO release through both b 3 -receptor and adenosine triphosphate-dependent, P2Y-receptor activation.3,9-12 In a well-designed clinical study, Tzemos and coworkers 13 analyzed whether nebivolol could improve endothelial dysfunction in patients with essential hypertension. They showed that nebivolol/bendrofluazide increased both stimulated and basal endothelial NO release, whereas, for the same degree of blood pressure control, atenolol/bendrofluazide had no effect on NO bioactivity; therefore, they concluded that nebivolol may offer additional vascular protection in treating hypertension. 13 Moreover, Oelze and coworkers 14 demonstrated that nebivolol but not metoprolol improved endothelial function and reduced vascular oxidative stress in an experimental model of AngII-induced hypertension. These effects were associated with a normalization of the expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits Nox1, Nox2, p22phox, p47phox, p67phox, and Rac1 and an inhibition of NOS III uncoupling in a rat hypertension model. More importantly, they found that nebivolol but not metoprolol inhibited activation of vascular NADPH oxidase and were able to dissociate an already assembled and active membrane-associated NADPH oxidase complex. These observations indicate that nebivolol, in addition to its b 1 -receptor-blocking and NO-releasing effects, possesses substantial inhibitory effects on vascular oxidative stress, all of which may beneficially influence endothelial dysfunction because of oxidative stress in the setting of arterial hypertension.14 It is well-known that essential hyperten...