Involvement of nitric oxide in both central and peripheral haemodynamic effect of d/l-nebivolol and its enantiomers in rats

The cardiovascular profile of the racemate d/l-nebivolol and its enantiomers administered by intravenous (i.v.) or by intracerebroventricular (i.c.v.) route was investigated in anaesthetized normotensive rats. d/l-Nebivolol (0.1-0.5 mg/kg) induced a dose-related reduction in blood pressure when administered by i.c.v. route. These hypotensive effects were more marked as compared to those achieved by peripheral administration of d/l-nebivolol (0.1-1 mg/kg i.v.). Both enantiomers contributed to the hypotensive effect of d/l-nebivolol by i.c.v. route, while the effects of the drug on blood pressure by i.v. route were due to the d-enantiomer. The bradycardic effect of the racemic form given i.v. was dose-related and, at the highest dose (1 mg/kg), was more pronounced as compared to i.c.v. route. d-Nebivolol was responsible for chronotropic effects by both the i.v. and i.c.v. route, although by i.c.v. route l-nebivolol also induced a reduction in heart rate. The nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) administered at 5 mg/kg i.v. bolus+0.1 mg/kg/min infusion or at 2.5 mg/kg i.c.v. counteracted the effects of d/l-nebivolol (either 1 mg/kg i.v. or 0.5 mg/kg i.c.v.) on blood pressure, while it did not inhibit the cardiovascular changes induced by isoprenaline (300 ng/kg i.v.) or calcitonin gene-related peptide (CGRP; 400 ng/kg i.v.). In addition, i.c.v. effects of d/l-nebivolol on blood pressure and heart rate were not affected by pre-treatment with atropine (2 mg/kg i.v.). The present findings demonstrate that d/l-nebivolol produced haemodynamic changes following both peripheral and central administration; these latter findings are mainly due to its l-enantiomer and these effects involve the l-arginine/nitric oxide pathway.