Cardiac-specific overexpression of Gαq alters excitation-contraction coupling in isolated cardiac myocytes

Transgenic mice with cardiac-specific overexpression of G alpha q exhibit a biochemical and physiological phenotype of load-independent cardiac hypertrophy with contractile dysfunction. To elucidate the cellular basis for altered contractility, we measured cellular contraction, Ca2+ transients, and L-type Ca2+ channel currents (I-Ca) in left ventricular (LV) myocytes isolated from non transgenic (NT) controls or G alpha q hearts. Although baseline contractile function (% shortening) and the amplitude of Ca2+ transients in G alpha q myocytes were similar to NT myocytes, the rates of cellular shortening and relengthening and the duration of Ca2+ transients were prolonged in G alpha q myocytes. Myocytes from G alpha q hearts had larger cell capacitance but no change in I-Ca density. voltage dependence of activation and inactivation. The responses of I-Ca to dihydropyridine drugs and a membrane permeable cAMP analog, 8-(4-chlorophenylthio) cAMP, were not altered; however, the time course of I-Ca inactivation was significantly slower in G alpha q myocytes compared to NT myocytes, The kinetic difference in inactivation was abolished when Ba2+ was used as the charge carrier or when the sarcoplasmic reticulum (SR) Ca2+ was depleted by ryanodine, suggesting that Ca2+-dependent inactivation is reduced in G alpha q myocytes due to altered SR Ca2+ release. Consistent with this hypothesis, the function of SR as assessed by the maximal Ca2+ uptake rates and the apparent affinity of SR Ca2+-ATPase for Ca2+ was reduced in ventricles of G alpha q heart. These results suggest that the reduced SR function contributes to the depressed contractility associated with this form of cardiac hypertrophy. (C) 1999 Academic Press.