REDUCED CALCIUM CURRENT-DENSITY IN SINGLE MYOCYTES ISOLATED FROM HYPERTROPHIED FAILING GUINEA-PIG HEARTS

The present study explored the possibility that an alteration in the transmembrane calcium current (I-Ca), through its ability to modulate Ca2+ release from the sarcoplasmic reticulum, could contribute to the depressed peak [Ca2+](i) we previously observed in hypertrophied failing myocardium. Whole-cell patch clamp was used to measure I-Ca in single guinea pig ventricular myocytes isolated from hearts of normal guinea pigs and from guinea pig hearts in which hypertrophy and failure were induced by gradually developing left ventricular pressure overload subsequent to ascending aortic banding of young animals. Membrane capacitance (C-m) was significantly greater, and I-Ca, normalized for C-m, was significantly lower in myocytes from hypertrophied failing hearts. Myocytes from hypertrophied failing hearts did not differ significantly from normal myocytes in terms of the voltage-dependence of the activation variable (d) of I-Ca (except at -30 mV), the time course of removal of inactivation of I-Ca, and the time constant of decay of I-Ca. Measurement of the voltage dependence of the inactivation Variable (f) of I-Ca showed that significantly more steady-state inactivation was present at 0, -10, and -20 mV in myocytes from hypertrophied failing hearts. Multiple regression analysis of all data indicated that I-Ca density decreased with increasing myocyte membrane area (as reflected by C-m) irrespective of any specific effects of hypertrophy and heart failure. We conclude that I-Ca, normalized for C-m, is significantly reduced in myocytes isolated from hypertrophied failing hearts, probably by a process associated with increased cell size, per se.