Inositol Trisphosphate Promotes Na-Ca Exchange Current by Releasing Calcium From Sarcoplasmic Reticulum in Cardiac Myocytes

An early inward tail current evoked by membrane depolarization (from-80 to-40 mV) sufficient to activate sodium but not calcium current was studied in single voltage-clamped ventricular myocytes isolated from guinea pig hearts. Like forward-mode Na-Ca exchange, this early inward tail current required [Na+], and [Ca211J and is thought to follow earlier reverse-mode Na-Ca exchange that triggers Ca2 ' release from sarcoplasmic reticulum. The dependence of the early inward tail current on [Ca21]1 was supported by the ability of small (+10 mV) and large (+80 mV) voltage jumps from-40 mV to decrease and increase, respectively, the size of early inward tail currents evoked by subsequent voltage steps from-80 to-40 mV. As expected, tetrodotoxin selectively inhibited the early inward tail current but not the late inward tail current that followed voltage jumps to +40 mV test potentials. Although tetrodotoxin also blocked the fast Na+ current, replacement of extracellular Na+ by Li+ sustained the fast Na+ current. However, Li+, which does not support Na-Ca exchange, reversibly suppressed both the early and late inward tail currents. Inhibitors (ryanodine and caffeine) and promoters (intracellularly dialyzed inositol 1,4,5-trisphosphate) of sarcoplasmic reticulum Ca2+ release decreased and increased, respectively, the magnitude of the early inwar