beta3-Adrenergic stimulation produces a decrease of cardiac contractility ex vivo in mice overexpressing the human beta3-adrenergic receptor.
OBJECTIVE
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.
Tavernier
Geneviève
G
Unité de recherches sur les obésités, Institut National de la Santé et de la Recherche Médicale Unité 586, Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France.
Toumaniantz
Gilles
G
Erfanian
Mortéza
M
Heymann
Marie France
MF
Laurent
Karine
K
Langin
Dominique
D
Gauthier
Chantal
C
D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002046:Bupranolol / Q000494:pharmacology; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism; D003864:Depression, Chemical; D004149:Dioxoles / Q000378:metabolism / Q000494:pharmacology*; D004562:Electrocardiography; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D009248:Nadolol / Q000494:pharmacology; D022702:Receptors, Adrenergic, beta-3 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004149:Dioxoles; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; D009248:Nadolol; D002046:Bupranolol; D006152:Cyclic GMP; C076252:amibegron