Different Pharmacological Properties of Two Enantiomers in a Unique β ‐Blocker, Nebivolol

Nebivolol is a racemic combination of d‐nebivolol (+SRRR nebivolol) and l‐nebivolol (–RSSS nebivolol) that differs chemically from other β‐blockers, with an absolutely symmetrical configuration developing from a central nitrogen atom. D‐nebivolol and l‐nebivolol divaricate pharmacologically and therapeutically, with a noticeably different profile from that of conventional β‐blockers; for instance, the selective blocking of β 1 ‐adrenoceptors is determined almost exclusively by d‐nebivolol. Both enantiomers act synergistically with respect to blood pressure reduction: the effect of nebivolol on heart rate is exclusively exerted by d‐nebivolol, with these hypotensive effects enhanced by the addition of the l‐enantiomer, which in itself does not influence systolic and diastolic blood pressure. Furthermore, this pronounced and lasting blood pressure reduction is roughly equal to the effect of conventional β‐blockers in high doses. In certain vascular districts, nebivolol stimulates endothelial nitric oxide (NO) synthesis, thereby increasing the availability of NO in the endothelium, smooth muscle, and platelets and, consequently, producing a sustained vasodilation, with decreases in peripheral resistance and blood pressure. These effects are not shared by other β‐adrenoceptor blockers used as references and mainly rely on the l‐enantiomer. L‐nebivolol also increases NO availability under conditions of oxidative stress by the inhibition of endothelial NO synthase (eNOS) uncoupling, thereby reducing NO inactivation. Furthermore, neither nebivolol nor its enantiomers show any intrinsic sympathomimetic activity and undesirable β‐blocker effects, such as a decrease in cardiac output, which do not occur or are less pronounced with the combination of d‐nebivolol and l‐nebivolol. In conclusion, the independent pharmacologic and clinical effects of d‐nebivolol and l‐nebivolol act synergistically to produce a cardiovascular profile that differs noticeably from that of conventional β‐blockers.