Nebivolol: Endothelium-Mediated Vasodilating Effect

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Abstract
Nebivolol, a racemic mixture of (S,R,R,R) and (R,S,S,S) enantiomers, is the most β1-selective adrenoceptor antagonist currently available for clinical use. However, its haemodynamic effects differ from those of classical β-adrenoceptor antagonists as a result of a vasodilating action. Nebivolol is devoid of α-adrenergic antagonist actions, and the detailed mechanism of its vasodilator action is unknown. Nebivolol relaxes precontracted strips of canine coronary and carotid artery only if the endothelium is intact, and such relaxation is antagonized by inhibition of nitric oxide (NO) synthase, implicating the endothelial L-arginine/NO mechanism. Nebivolol and atenolol have been compared in phenylephrine preconstricted dorsal hand veins of 11 healthy men. Nebivolol caused venodilation, which was antagonized by NG-monomethyl-L-arginine (LNMMA), whereas atenolol did not, suggesting that such a mechanism could also operate in human veins. Venodilation could be functionally important in reducing cardiac pre-load. β2-Adrenoceptor stimulation increases forearm blood flow (FBF) by activating the L-arginine/NO pathway but nebivolol lacks direct β2-adrenoceptor agonist activity. Resistance vessel function has been studied by measuring FBF by venous occlusion plethysmography in healthy men during brachial artery infusions of racemic nebivolol and its enantiomers, atenolol, carbachol (a stable analogue of acetylcholine that vasodilates this vas- cular bed, in part by activating the L-arginine/NO pathway), nitroprusside (a NO donor that causes non-endothelium-dependent vasodilation through the same effector mechanism as endothelium-dependent agonists) and LNMMA. Nebivolol (354 μg/min) increased FBF by 91 ± 18% (mean ± SE, n = 8; p S