Negative inotropic effects of isoprenaline on isolated left atrial assays from aged transgenic mice with cardiac over-expression of human beta(2)-adrenoceptors

The action of isoprenaline has been evaluated in an isolated, left atrial a ssay, from aged transgenic mice with cardiac-specific over-expression of th e beta(2)-adrenoceptor. In the assay, isoprenaline produced a negative inot ropic concentration-response curve that was not altered by incubation with CGP-20712A (1 mu M), a beta(1)-adrenoceptor antagonist. However, after incu bation with ICI-118,551 (300 nM), a selective beta(2)-adrenoceptor antagoni st, isoprenaline produced a positive inotropic concentration-effect curve t hat was located to the left of the negative inotropic curve. This suggests that the negative inotropic effect was mediated by a homogenous population of negatively-coupled beta(2)-adrenoceptors. In the presence of CGP-20712A (300 nM), the positive curve was shifted to the right, suggesting that the positive inotropic effect was mediated, at least in part, by beta(1)-adreno ceptors. These results differ substantially from those previously obtained in young transgenic mice. An outline of an explanatory model, based on a co ncept of over-expressed receptors 'stealing' G-proteins, is suggested.