To assess functional and cellular effects of myocardial beta 1-adrenoceptor overexpression, alterations of the beta-adrenergic signal transduction pathway and contractile function in transgenic mice with atrial overexpression of the human beta 1-adrenoceptor were investigated. Radioligand binding experiments confirmed a 5- to 6-fold increase in beta-adrenoceptor density and a 2.7-fold increase in high-affinity binding sites in atria of transgenic mice. Dose-response curves for isoprenaline-induced force of contraction showed unchanged maximum effects but significantly increased pD2 values. Basal, MnCl2- and isoprenaline-stimulated adenylyl cyclase activities did not significantly differ, whereas the Gpp(NH)p and forskolin effect tends to be reduced in transgenic mice. The level of Gi alpha (pertussis toxin-catalyzed ADP-ribosylation) was unchanged, whereas the bioactivity of Gs alpha (reconstitution 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, increased beta 1-adrenoceptor density is associated with a decrease in Gs alpha-activity.