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We investigated the mechanisms responsible for altered contractile and relaxation function in overexpressed Gs[small alpha, Greek] myocytes.Although baseline contractile function (percent contraction) in Gs[small alpha, Greek] mice was similar to that of wild-type (WT) mice, left ventricular myocyte contraction, fura-2 Ca2+ transients, and Ca2+ channel currents (Ica) were greater in Gs[small alpha, Greek] mice in response to 10-8 M isoproterenol (ISO) compared with WT mice. The late phase of relaxation of the isolated myocytes and fura-2 Ca2+ transients was accelerated at baseline in Gs[small alpha, Greek] but did not increase further with ISO. In vivo measurements using echocardiography also demonstrated enhanced relaxation at baseline in Gs[small alpha, Greek] mice. Forskolin and CaCl2 increased contraction similarly in WT and Gs[small alpha, Greek] mice. Rp-cAMP, an inhibitor of protein kinase, blocked the increases in contractile response and Ca2+ currents to ISO in WT and to forskolin in both WT and Gs[small alpha, Greek]. It also blocked the accelerated relaxation in Gs[small alpha, Greek] at baseline but not the contractile response to ISO in Gs[small alpha, Greek] myocytes. Baseline measurements of cAMP and phospholambation phosphorylation were enhanced in Gs[small alpha, Greek] compared with WT. These data indicate that overexpression of Gs[small alpha, Greek] accelerates relaxation at end diastolic but does not affect baseline systolic function in isolated myocytes. However, the enhanced responses to sympathetic stimulation partly reflect increased Ca2+ channel activity, i.e the cellular mechanisms mediating these effects appear to involve a cAMP-independent as well as a cAMP-dependent pathway.J.Clin. Invest. 103:1089-1097 (1999).