Mechanism of vasodilating action of Nebivolol

Nebivolol (N), a racemic mixture of (SRRR) and (RSSS) enantiomers, is a β1-selective adrenoceptor antagonist. However, its haemodynamic effects, including increased cardiac outpu and stroke volume in anaesthetised dogs (Janssens et al. Drug Invest 1991; 3 (suppl. 1): 13-24), differ from those of classical β-adrenoceptor antagonists as a result of a vasodilating action. This contribution reviews evidence that this involves activation of the L-arginine (L-arg)/nitric oxide (NO) pathway via a non β-adrenoceptor initiated mechanism. N relaxes precontracted strips of canine coronary and carotid artery only if the endothelium is intact, and such relaxation is antagonised by inhibition of NO synthase (Gao et al. J Cardiovasc Pharmacol 1991; 7:964-969). Bowman et al. (Br J Clin Pharmac 1994; 38: 199-204) infused N and atenolol (A) into phenylephrine preconstricted dorsal hand veins of 11 healthy men. N caused venodilation, which was antagonised by NG-monomethyl-L-arg (LNMMA), whereas A did not. β2-adrenoceptor stimulation increases forearm blood flow (FBF) by activating the L-arg/NO pathway, but this does not explain the vasodilating effect of N in this vascular bed. Cockcroftet al . (J Pharmacol Exp Therap 1995; 274: 1067-1071) measured FBF plethysmographically in healthy men during brachial artery infusions of racemic N and its enantiomers, A, carbachol (C), nitroprusside (P) and LNMMA. N (354 μg/min) increased FBF by 91 ± 18% (mean ± SE, n = 8, P<0.01) whereas an equimolar dose of A had no significant effect. LNMMA inhibited responses to N and C to a significantly greater extent than it reduced responses to P. Antagonism of N by LNMMA was abolished by L-arg (SRRR) and (RSSS) enantiomers caused similar increases of FBF. Endothelial dysfunction is an early event in several cardiovascular disorders. If the acute effects of N in healthy subjects also occur during chronic treatment of patients with hypertension or heart failure, its effect on the L-arg/NO pathway could contribute to improved organ perfusion and a reduced incidence of cardiovascular disease.