Na + currents are required for efficient excitation–contraction coupling in rabbit ventricular myocytes: a possible contribution of neuronal Na + channels

Ca 2+ transients were activated in rabbit ventricular cells by a sequence of action potential shaped voltage clamps. After activating a series of control transients, Na + currents ( I Na ) were inactivated with a ramp from −80 to −40 mV (1.5 s) prior to the action potential clamp. The transients were detected with the calcium indicator Fluo‐4 and an epifluorescence system. With zero Na + in the pipette I Na inactivation produced a decline in the SR Ca 2+ release flux (measured as the maximum rate of rise of the transient) of 27 ± 4% ( n = 9, P < 0.001) and a peak amplitude reduction of 10 ± 3% ( n = 9, P < 0.05). With 5 m m Na + in the pipette the reduction in release flux was greater (34 ± 4%, n = 4, P < 0.05). The ramp effectively inactivates I Na without changing I Ca , and there was no significant change in the transmembrane Ca 2+ flux after the inactivation of I Na . We next evoked action potentials under current clamp. TTX at 100 n m , which selectively blocks neuronal isoforms of Na + channels, produced a decline in SR Ca 2+ release flux of 35 ± 3% ( n = 6, P < 0.001) and transient amplitude of 12 ± 2% ( n = 6, P < 0.05). This effect was similar to the effect of I Na inactivation on release flux. We conclude that a TTX‐sensitive I Na is essential for efficient triggering of SR Ca 2+ release. We propose that neuronal Na + channels residing within couplons activate sufficient reverse Na + –Ca 2+ exchanger (NCX) to prime the junctional cleft with Ca 2+ . The results can be explained if non‐linearities in excitation–contraction coupling mechanisms modify the coupling fidelity of I Ca , which is known to be low at positive potentials.