FUNCTIONAL COUPLING OF OVEREXPRESSED BETA-1-ADRENOCEPTORS IN THE MYOCARDIUM OF TRANSGENIC MICE

To assess functional and cellular effects of myocardial beta 1-adrenoc eptor overexpression, alterations of the beta-adrenergic signal transd uction pathway and contractile function in transgenic mice with atrial overexpression of the human beta 1-adrenoceptor were investigated. Ra dioligand binding experiments confirmed a 5- to 6-fold increase in bet a-adrenoceptor density and a 2.7-fold increase in high-affinity bindin g sites in atria of transgenic mice. Dose-response curves for isoprena line-induced force of contraction showed unchanged maximum effects but significantly increased pD(2) values. Basal, MnCl2- and isoprenaline- stimulated adenylyl cyclase activities did not significantly differ, w hereas the Gpp(NH)p and forskolin effect tends to be reduced in transg enic mice. The level of Gi alpha (pertussis toxin-catalyzed ADP-ribosy lation) was unchanged, whereas the bioactivity of Gs alpha (reconstitu tion experiments into S49 cyc(-) cell membranes) was reduced by about 19% in the transgenic group. These results suggest that overexpressed beta 1-adrenoceptors act as functional spare receptors. In addition, i ncreased beta 1-adrenoceptor density is associated with a decrease in Gs alpha-activity. (C) 1998 Academic Press.