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 N(omega)-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.
Sacco
Giuseppe
G
Menarini Ricerche spa, Pharmacology, Via Tito Speri 10, 00040 Pomezia, Rome, Italy. gsacco@menarini-ricerche.it
Evangelista
Stefano
S
Criscuoli
Marco
M
Goso
Cristina
C
Bigioni
Mario
M
Binaschi
Monica
M
Manzini
Stefano
S
Maggi
Carlo Alberto
CA
D000818:Animals; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D007545:Isoproterenol / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D000068577:Nebivolol; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013997:Time Factors
D001578:Benzopyrans; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D000068577:Nebivolol; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D019331:NG-Nitroarginine Methyl Ester