Enhanced cardiac function in transgenic mice expressing a Ca2+-stimulated adenylyl cyclase

The predominant functional adenylyl cyclases normally expressed in cardiac tissue and coupled to P-adrenergic receptors are inhibited by micromolar Ca 2+ concentration. To modify the overall balance of activities, we have gene rated transgenic mice expressing the Ca2+-stimulatable adenylyl cyclase typ e 8 (AC8) specifically in the heart. AC activity is increased by at least 7 -fold in heart membranes from transgenic animals and is stimulated by Ca2in the same range of concentration that inhibits the endogenous activity. M oreover, the in vivo basal protein kinase A activity was augmented 4-fold. Overexpression of AC8 in the heart has no detrimental consequences on globa l cardiac function. Basal heart rate and contractile function, measured by noninvasive echocardiography, were unchanged. In contrast, on release of pa rasympathetic tone, the intrinsic contractility is heightened and unrespons ive to further beta-adrenergic receptor stimulation. AC8 transgenic mice th us represent an original model to investigate the relative influence of Ca2 + and cAMP on cardiac function within a phenotype of enhanced cardiac contr actility and relaxation.