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beta3-Adrenergic stimulation produces a decrease of cardiac contractility ex vivo in mice overexpressing the human
Geneviève Tavernier1, Gilles Toumaniantz, Mortéza Erfanian
1Unité 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.
Cardiovascular Research
|August 12, 2003
Summary
Transgenic mice with cardiac beta-3 adrenoceptors (beta-AR) were created to study heart function. These mice exhibit negative inotropic effects, mimicking human ventricular muscle responses to beta-3 AR stimulation.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Adrenergic Receptor Signaling
Background:
- Catecholamines regulate cardiac function via three beta-adrenoceptor (beta-AR) populations.
- beta(1)- and beta(2)-AR stimulation increases cardiac contractility.
- beta(3)-AR stimulation mediates a negative inotropic effect in human ventricular muscle.
Purpose of the Study:
- To investigate the role of beta(3)-AR in cardiac function.
- To develop a suitable animal model for studying beta(3)-AR effects in the heart.
- To characterize the cardiac phenotype of mice with cardiac-specific human beta(3)-AR expression.
Main Methods:
- Generation of transgenic mice (TG beta(3) mice) with cardiac-specific human beta(3)-AR expression using the alpha myosin heavy chain promoter.
- Phenotypic analysis including mRNA and protein determination, histology, electrocardiogram, contractility, and cyclic nucleotide measurements.
- Administration of beta(3)-AR agonists (CL 316243, SR 58611A) and beta-AR blockers (nadolol, bupranolol).
Main Results:
- TG beta(3) mice showed no cardiac hypertrophy or fibrosis.
- Basal conditions revealed increased heart rate and accelerated twitch parameters.
- beta(3)-AR agonists decreased contractility, an effect dependent on beta(3)-AR activation and associated with increased intracellular cGMP.
- Non-specific effects of agonists on beta(1)/beta(2)-AR were observed at higher concentrations.
Conclusions:
- Cardiac overexpression of beta(3)-AR in mice successfully reproduces the negative inotropic effects observed in human ventricular tissues.
- This transgenic model provides a valuable tool for studying beta(3)-AR function in the heart.
- The findings elucidate the distinct role of beta(3)-AR in modulating cardiac contractility.