b - Adrenergic stimulation produces a decrease of cardiac contractility 3 ex vivo in mice overexpressing the human b - adrenergic receptor 3 a b b c ` ́

Objectives: The regulation of cardiac function by catecholamines involves three populations of b-adrenoceptor (b-AR). b and b -AR 1 2 stimulations produce an increase in contractility and b -AR stimulation mediates a negative inotropic effect in human ventricular muscle. 3 Because of the lack of suitable animal models, we have generated transgenic mice with cardiac-specific expression of the human b -AR 3 (TGb mice). Methods: TGb mice were produced by microinjection of the human b -AR under the control of the a myosin heavy chain 3 3 3 promoter. Phenotypic analyses comprised b -AR mRNA and protein determinations, histological studies, electrocardiogram, contractility 3 and cyclic nucleotide measurements. Results: TGb mice presented no histological evidence of myocyte hypertrophy or fibrogenesis. In 3 basal conditions, TGb mice were characterized by an increase in heart rate and an acceleration of twitch parameters without modification 3 of its amplitude. b -AR agonists (CL 316243, SR 58611A) decreased contractility at low concentrations (1–100 nM). At high 3 concentrations, the negative inotropic effect was abolished. Pretreatment with nadolol, a b /b -AR blocker, blunted the rebound in peak 1 2 tension elicited by b -AR agonists suggesting a non-specific action of these compounds on b and b -AR. The involvement of b -AR in 3 1 2 3 the negative inotropic effect was confirmed by the pretreatment with bupranolol, a non-selective b-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 b -AR in mice reproduces ex vivo the negative inotropic effects obtained with b -AR stimulation 3 3 in human ventricular tissues.  2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.