Intracellular [Na(+)] modulates synergy between Na(+)/Ca (2+) exchanger and L-type Ca (2+) current in cardiac excitation-contraction coupling during action potentials.

Excitation-contraction coupling (ECC) in cardiac myocytes involves triggering of Ca(2+) release from the sarcoplasmic reticulum (SR) by L-type Ca channels, whose activity is strongly influenced by action potential (AP) profile. The contribution of Ca(2+) entry via the Na(+)/Ca(2+) exchanger (NCX) to trigger SR Ca(2+) release during ECC in response to an AP remains uncertain. To isolate the contribution of NCX to SR Ca(2+) release, independent of effects on SR Ca(2+) load, Ca(2+) release was determined by recording Ca(2+) spikes using confocal microscopy on patch-clamped rat ventricular myocytes with Ca(2+) fixed at 150 nmol/L. In response to AP clamps, normalized Ca(2+) spike amplitudes (ΔF/F (0)) increased sigmoidally and doubled as Na(+) was elevated from 0 to 20 mmol/L with an EC(50) of ~10 mmol/L. This Na(+)-dependence was independent of I (Na) as well as SR Ca(2+) load, which was unchanged under our experimental conditions. However, NCX inhibition using either KB-R7943 or XIP reduced ΔF/F (0) amplitude in myocytes with 20 mmol/L Na(+), but not with 5 mmol/L Na(+). SR Ca(2+) release was complete before the membrane repolarized to -15 mV, indicating Ca(2+) entry into the dyad (not reduced extrusion) underlies Na(+)-dependent enhancement of ECC. Because I (Ca,L) inhibition with 50 mmol/L Cd(2+) abolished Ca(2+) spikes, our results demonstrate that during cardiac APs, NCX enhances SR Ca(2+) release by synergistically increasing the efficiency of I (Ca,L)-mediated ECC.