Negative inotropic effects of isoprenaline on isolated left atrial assays from aged transgenic mice with cardiac over‐expression of human β 2 ‐adrenoceptors

The action of isoprenaline has been evaluated in an isolated, left atrial assay, from aged transgenic mice with cardiac‐specific over‐expression of the β 2 ‐adrenoceptor. In the assay, isoprenaline produced a negative inotropic concentration‐response curve that was not altered by incubation with CGP‐20712A (1 μ M ), a β 1 ‐adrenoceptor antagonist. However, after incubation with ICI‐118,551 (300 n M ), a selective β 2 ‐adrenoceptor antagonist, isoprenaline produced a positive inotropic concentration‐effect curve that 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 β 2 ‐adrenoceptors. In the presence of CGP‐20712A (300 n M ), the positive curve was shifted to the right, suggesting that the positive inotropic effect was mediated, at least in part, by β 1 ‐adrenoceptors. These results differ substantially from those previously obtained in young transgenic mice. An outline of an explanatory model, based on a concept of over‐expressed receptors ‘stealing’ G‐proteins, is suggested. British Journal of Pharmacology (2000) 129 , 1285–1288; doi: 10.1038/sj.bjp.0703238