Effects of Overexpression of the Na-Ca Exchanger on [Ca]i Transients in Murine Ventricular Myocytes

We measured [Ca]i and [Na ]i in isolated transgenic (TG) mouse myocytes overexpressing the Na -Ca exchanger and in wild-type (WT) myocytes. In TG myocytes, the peak systolic level and amplitude of electrically stimulated (ES) [Ca]i transients (0.25 Hz) were not significantly different from those in WT myocytes, but the time to peak [Ca]i was significantly prolonged. The decline of ES [Ca]i transients was significantly accelerated in TG myocytes. The decline of a long-duration (4-s) caffeine-induced [Ca]i transient was markedly faster in TG myocytes, and [Na ]i was identical in TG and WT myocytes, indicating that the overexpressed Na-Ca exchanger is functionally active. The decline of a short-duration (100-ms) caffeine-induced [Ca]i transient in 0 Na /0 Ca solution did not differ between the two groups, suggesting that the sarcoplasmic reticulum (SR) Ca-ATPase function is not altered by overexpression of the Na-Ca exchanger. There was no difference in L-type Ca current density in WT and TG myocytes. However, the sensitivity of ES [Ca]i transients to nifedipine was reduced in TG myocytes. This maintenance of [Ca]i transients in nifedipine was inhibited by Ni 21 and required SR Ca content, consistent with enhanced Ca influx by reverse Na-Ca exchange, and the resulting Ca-induced Ca release from SR. The rate of rise of [Ca]i transients in nifedipine in TG myocytes was much slower than when both the L-type Ca current and the Na-Ca exchange current function together. In TG myocytes, action potential amplitude and action potential duration at 50% repolarization were reduced, and action potential duration at 90% repolarization was increased, relative to WT myocytes. These data suggest that under these conditions, overexpression of the Na-Ca exchanger in TG myocytes accelerates the decline of [Ca]i during relaxation, indicating enhanced forward Na-Ca exchanger function. Increased Ca influx also appears to occur, consistent with enhanced reverse function. These findings provide support for the physiological importance of both these modes of Na-Ca exchange. (Circ Res. 1998;82:657-665.)