Nitric oxide mechanisms of nebivolol

β-blockers are among the most widely used drugs in the prevention and treatment of cardiovascular disease, although they are associated with increased peripheral resistance. Third-generation β-blockers avoid this adverse effect by inducing vasodilation through different mechanisms. In particular, nebivolol, a highly selective blocker of β₁-adrenergic receptors, is the only β-blocker known to induce vascular production of nitric oxide, the main endothelial vasodilator. The specific mechanism of nebivolol is particularly relevant in hypertension, where nitric oxide dysfunction occurs. Indeed, nebivolol is able to reverse endothelial dysfunction. Nebivolol induces nitric oxide production via activation of β₃-adrenergic receptors, which can explain the good metabolic profile observed after treatment with this drug. Moreover, nebivolol can also stimulate the β₃-adrenergic receptor-mediated production of nitric oxide in the heart, and this stimulation can result in a greater protection against heart failure. In conclusion, nebivolol has a unique profile among antihypertensive drugs, adding to a very high selectivity against β₁ adrenergic receptors, and an agonist action on β₃ receptors and nitric oxide (NO), which has led to clinically significant improvements in hypertensive patients.