beta3-Adrenergic stimulation produces a decrease of cardiac contractility ex vivo in mice overexpressing the human beta3-adrenergic receptor.
Cardiovasc Res
; 59(2): 288-96, 2003 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-12909312
ABSTRACT
OBJECTIVES:
The regulation of cardiac function by catecholamines involves three populations of beta-adrenoceptor (beta-AR). beta(1)- and beta(2)-AR stimulations produce an increase in contractility and beta(3)-AR stimulation mediates a negative inotropic effect in human ventricular muscle. Because of the lack of suitable animal models, we have generated transgenic mice with cardiac-specific expression of the human beta(3)-AR (TG beta(3) mice).METHODS:
TG beta(3) mice were produced by microinjection of the human beta(3)-AR under the control of the alpha myosin heavy chain promoter. Phenotypic analyses comprised beta(3)-AR mRNA and protein determinations, histological studies, electrocardiogram, contractility and cyclic nucleotide measurements.RESULTS:
TG beta(3) mice presented no histological evidence of myocyte hypertrophy or fibrogenesis. In basal conditions, TG beta(3) mice were characterized by an increase in heart rate and an acceleration of twitch parameters without modification of its amplitude. beta(3)-AR agonists (CL 316243, SR 58611A) decreased contractility at low concentrations (1-100 nM). At high concentrations, the negative inotropic effect was abolished. Pretreatment with nadolol, a beta(1)/beta(2)-AR blocker, blunted the rebound in peak tension elicited by beta(3)-AR agonists suggesting a non-specific action of these compounds on beta(1)- and beta(2)-AR. The involvement of beta(3)-AR in the negative inotropic effect was confirmed by the pretreatment with bupranolol, a non-selective beta-AR antagonist, which fully abolished the effects of SR 58611A. The negative inotropic effect was associated with an increase in intracellular cGMP level.CONCLUSIONS:
We conclude that cardiac overexpression of beta(3)-AR in mice reproduces ex vivo the negative inotropic effects obtained with beta(3)-AR stimulation in human ventricular tissues.
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Base de dados:
MEDLINE
Assunto principal:
Tetra-Hidronaftalenos
/
Agonistas Adrenérgicos beta
/
Receptores Adrenérgicos beta 3
/
Dioxóis
/
Contração Miocárdica
/
Miocárdio
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2003
Tipo de documento:
Article
País de afiliação:
França