title: Enantioselective pharmacokinetics and cardiovascular effects of nebivolol in L-NAME hypertensive rats.
abstract: The cardiovascular effects and pharmacokinetics of nebivolol were assessed in N(G)-nitro-l-arginine methyl ester (L-NAME) hypertensive and normotensive control rats. Male Wistar rats were randomly divided to drink tap water (control) or L-NAME solution for 2 weeks. The effects of nebivolol (3 or 10 mg kg(-1) i.v.) on blood pressure (BP), heart rate and BP variability (BPV) were recorded in awake L-NAME and control rats. Short-term and beat-to-beat BPV was assessed by the s.d. and spectral analysis of the BP recordings. Nebivolol pharmacokinetics was studied by means of traditional blood sampling. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; the clearance and the volume of distribution of l-nebivolol were significantly greater than those of the d-enantiomer. The hypotensive response to nebivolol was significantly enhanced in L-NAME rats (Δmean arterial pressure (MAP): -16.1±1.1%, P<0.05 vs. control rats) compared with normotensive animals (ΔMAP: -1.4±2.1%). An analysis of the beat-to-beat BPV showed a greater reduction in VLF BPV in the L-NAME compare with the control rats. Nebivolol significantly reduced the low-frequency/high-frequency ratio in hypertensive L-NAME animals compared with normotensive rats. Short-term BPV was markedly reduced by nebivolol in both experimental groups, although the attenuation of the s.d. of BP recording was greater in L-NAME rats. In conclusion, the hypotensive efficacy of nebivolol is significantly enhanced in L-NAME rats compared with normotensive animals, which is most likely due to a greater reduction in vascular sympathetic activity. Nebivolol markedly attenuated short-term BPV in both experimental groups, suggesting that β-blockers with additional pharmacological actions provide beneficial cardiovascular effects by controlling high BP and its short-term variability.
authors.affiliation: 1] Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina [2] Institute of Physiopathology and Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Facundo Martín
authors.initials: FM
authors.lastname: Bertera
authors.affiliation: Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Julieta Sofía
authors.initials: JS
authors.lastname: Del Mauro
authors.affiliation: Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Valeria
authors.initials: V
authors.lastname: Lovera
authors.affiliation: Department of Pharmaceutical Technology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Diego
authors.initials: D
authors.lastname: Chiappetta
authors.affiliation: Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Ariel Héctor
authors.initials: AH
authors.lastname: Polizio
authors.affiliation: 1] Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina [2] Institute of Physiopathology and Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Taira
authors.affiliation: 1] Department of Pharmacology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina [2] Institute of Physiopathology and Clinical Biochemistry, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Christian
authors.initials: C
authors.lastname: Höcht
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001578:Benzopyrans / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D004983:Ethanolamines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D019331:NG-Nitroarginine Methyl Ester; D000068577:Nebivolol; D052248:Nitric Oxide Synthase Type I / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
chemical_list: D000319:Adrenergic beta-Antagonists; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D000068577:Nebivolol; D052248:Nitric Oxide Synthase Type I; D019331:NG-Nitroarginine Methyl Ester