The sodium pump modulates the influence of I(Na) on Ca$^2+$i transients in mouse ventricular myocytes.
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Biophys. J. 80 (3): 1230--1237 (March 2001)

To investigate whether activity of the sarcolemmal Na pump modulates the influence of sodium current on excitation-contraction (E-C) coupling, we measured Ca$^2+$(i) transients (fluo-3) in single voltage-clamped mouse ventricular myocytes (Na$^+$(pip) = 15 or 0 mM) when the Na pump was activated (4.4 mM K$^+$(o)) and during abrupt inhibition of the pump by exposure to 0 K with a rapid solution-switcher device. After induction of steady state Ca$^2+$(i) transients by conditioning voltage pulses (0.25 Hz), inhibition of the Na pump for 1.5 s immediately before and continuing during a voltage pulse (200 ms, -80 to 0 mV) caused a significant increase (15 +/- 2\%; n = 16; p < 0.01) in peak systolic Ca$^2+$(i) when Na$^+$(pip) was 15 mM. In the absence of sodium current (I(Na), which was blocked by 60 microM tetrodotoxin (TTX)), inhibition of the Na pump immediately before and during a voltage pulse did not result in an increase in peak systolic Ca$^2+$(i). Abrupt blockade of I(Na) during a single test pulse with TTX caused a slight decrease in peak Ca$^2+$(i), whether the pump was active (9\%) or inhibited (10\%). With the reverse-mode Na/Ca exchange inhibited by KB-R 7943, inhibition of the Na pump failed to increase the magnitude of the peak systolic Ca$^2+$(i) (4 +/- 1\%; p = NS) when Na$^+$(pip) was 15 mM. When Na$^+$(pip) was 0 mM, the amplitude of the peak systolic Ca$^2+$(i) was not altered by abrupt inhibition of the Na pump immediately before and during a voltage pulse. These findings in adult mouse ventricular myocytes indicate the Na pump can modulate the influence of I(Na) on E-C coupling in a single beat and provide additional evidence for the existence of Na fuzzy space, where Na$^+$ can significantly modulate Ca$^2+$ influx via reverse Na/Ca exchange.
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