Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Authors
Bertera, Facundo; Di Verniero, Carla Andrea; Mayer, Marcos Alejandro; Chiappetta, Diego Andrés; Buontempo, Fabián; Polizio, Ariel Héctor; Taira, Carlos Alberto; Höcht, Christian
Publication Year
2011
Language
English
Format
article
Status
Published version
Description
The cardiovascular effects and mechanism of antihypertensive response of carvedilol were assessed in fructose fed rats using pharmacokinetic–pharmacodynamic (PK-PD) modelling. Male Sprague Dowley rats were randomly divided into two groups: control rats received water for 6 weeks while fructose rats received fructose solution (10 %w/v) during 6 weeks. Effects of carvedilol (1-3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Enantioselective carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK-PD modelling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis. A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Fructose feeding increased volume of distribution of both enantiomers. Although PK-PD properties of S-carvedilol chronotropic effect were not altered in fructose rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in fructose rats. Carvedilol showed enantioselective non-linear pharmacokinetic properties in both groups with increased distribution in fructose fed rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in fructose rats compared with control rats, which is not related to enhanced sympatholytic activity. Therefore, pleiotropic effects of carvedilol, such as antioxidant activity, seem to contribute to its enhanced antihypertensive activity in this experimental model of metabolic syndrome.
Fil: Bertera, Facundo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Di Verniero, Carla Andrea. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología. Cátedra de Farmacología; Argentina
Fil: Mayer, Marcos Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Chiappetta, Diego Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Tecnología Farmacéutica; Argentina
Fil: Buontempo, Fabián. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina
Fil: Polizio, Ariel Héctor. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Taira, Carlos Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Fil: Höcht, Christian. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina
Subject
CARVEDILOL
ENANTIOSELECTIVE PHARMACOKINETICS
HYPERTENSION
PK-PD MODELLING
SYMPATHETIC VASCULAR ACTIVITY
METABOLIC SYNDROME
FRUCTOSE
Farmacología y Farmacia
Medicina Básica
CIENCIAS MÉDICAS Y DE LA SALUD
Access level
Restricted access
License
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repository
CONICET Digital (CONICET)
Institution
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identifier
oai:ri.conicet.gov.ar:11336/14140