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

We have read with great interest the recently published article by Neuman and coworkers1 in which they hypothesized that nebivolol, a selective β₁‐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, β₁‐adrenergic receptor antagonist that has vasodilatory properties both in animals and humans independent of β₁‐receptor antagonism and related to β₃‐receptor agonist effects.2, 3, 4, 5 It is a racemic mixture of D‐ and L‐enantiomers, of which D‐nebivolol is considered to be a highly selective β‐adrenergic receptor antagonist.5, 6, 7, 8 It was demonstrated that nebivolol stimulates NO release through both β₃‐receptor and adenosine triphosphate–dependent, P2Y‐receptor activation.3, 9, 10, 11, 12 In a well‐designed clinical study, Tzemos and coworkers13 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 coworkers14 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 β₁‐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 hypertension is associated with endothelial dysfunction, and with greater oxidative stress producing free oxygen radicals that contribute to the decrease in NO bioavailibility. Elevated plasma levels of malondialdehyde, a final product of lipid peroxidation and an index of oxidative stress, have been demonstrated in patients with essential hypertension.15, 16 Concordantly, our study group previously found that nebivolol, differently from metoprolol, improved oxidative stress and insulin sensitivity, decreased plasma sP‐selectin, and increased adiponectin levels in hypertensive patients.17 From that standpoint, we concluded that nebivolol may significantly improve endothelial dysfunction in hypertensive patients. However, our study population had no African American patients, unlike the patient population from the study by Neumann and coworkers.

In conclusion, nebivolol has beneficial effects on endothelial function mainly by increasing NO bioavailability. We strongly believe that although standard β‐blockers are falling out of favor nowadays, perhaps the new generation of β‐blockers such as nebivolol may “rescue” the reputation of these agents in the near future.