Effects of overexpression of the Na$^+$-Ca$^2+$ exchanger on Ca$^2+$i transients in murine ventricular myocytes.
A. Yao, Z. Su, A. Nonaka, I. Zubair, L. Lu, K. Philipson, J. Bridge, and W. Barry.
Circ. Res. 82 (6): 657-65 (April 1998)

We measured Ca$^2+$i and Na$^+$i in isolated transgenic (TG) mouse myocytes overexpressing the Na$^+$-Ca$^2+$ exchanger and in wild-type (WT) myocytes. In TG myocytes, the peak systolic level and amplitude of electrically stimulated (ES) Ca$^2+$i transients (0.25 Hz) were not significantly different from those in WT myocytes, but the time to peak Ca$^2+$i was significantly prolonged. The decline of ES Ca$^2+$i transients was significantly accelerated in TG myocytes. The decline of a long-duration (4-s) caffeine-induced Ca$^2+$i transient was markedly faster in TG myocytes, and Na$^+$i was identical in TG and WT myocytes, indicating that the overexpressed Na$^+$-Ca$^2+$ exchanger is functionally active. The decline of a short-duration (100-ms) caffeine-induced Ca$^2+$i transient in 0 Na$^+$/0 Ca$^2+$ solution did not differ between the two groups, suggesting that the sarcoplasmic reticulum (SR) Ca$^2+$-ATPase function is not altered by overexpression of the Na$^+$-Ca$^2+$ exchanger. There was no difference in L-type Ca$^2+$ current density in WT and TG myocytes. However, the sensitivity of ES Ca$^2+$i transients to nifedipine was reduced in TG myocytes. This maintenance of Ca$^2+$i transients in nifedipine was inhibited by Ni2+ and required SR Ca$^2+$ content, consistent with enhanced Ca$^2+$ influx by reverse Na$^+$-Ca$^2+$ exchange, and the resulting Ca$^2+$-induced Ca$^2+$ release from SR. The rate of rise of Ca$^2+$i transients in nifedipine in TG myocytes was much slower than when both the L-type Ca$^2+$ current and the Na$^+$-Ca$^2+$ 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$^2+$ exchanger in TG myocytes accelerates the decline of Ca$^2+$i during relaxation, indicating enhanced forward Na$^+$-Ca$^2+$ exchanger function. Increased Ca$^2+$ 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$^2+$ exchange.
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