SODIUM CURRENT-INDUCED CALCIUM SIGNALS IN ISOLATED GUINEA-PIG VENTRICULAR MYOCYTES

1. Na+ current (I-Na)-induced Ca2+ transients were studied in ventricular myocytes isolated from adult guinea-pig hearts. The fluorescent Ca2+ indicator fluo-3 or a mixture of fluo-3 and fura-red were used in conjunction with confocal microscopy to follow the intracellular Ca2+ concentration while membrane currents were measured simultaneously with the whole-cell configuration of the patch-clamp technique. 2. Ca2+ release from the sarcoplasmic reticulum (SR) could be triggered either by Ca2+ current (I-Ca) or Na+ current (I-Na). Analysis of I-Na-induced Ca2+ signals at higher temporal resolution revealed a. faster upstroke of these transients when compared with those triggered by I-Ca. 3. In the presence of 20 mu M ryanodine to block SR Ca2+ release I-Ca elicited a verapamil-sensitive Ca2+ transient with a slow upstroke. I-Na also induced a residual Ca2+ transient that was insensitive to 10 mu M verapamil and characterized by a rapid upstroke. 4. The existence of a residual Ca2+ transient in the absence of SR Ca2+ release and L-type I-Ca indicates that I-Na is indeed able to evoke an increase in [Ca2+](i) without uncontrolled activation of Ca2+ channels. 5. Substitution of extracellular Na+ by Li+ suppressed I-Na-induced Ca2+ transients, suggesting that the Ca2+ release and the residual Ca2+ transient can only be elicited by influx of Naf and not by Li+. This result supports the notion that both the residual Ca2+ transient as well as the I-Na-induced Ca2+ release are mediated by the Na+-Ca2+ exchange. 6. We conclude that during I-Na [Na+] increased underneath the cell membrane and activated the Ca2+ influx mode of the Na+-Ca2+ exchange. The Na+ current may serve as a safety factor in cardiac excitation-contraction coupling by accelerating the Ca2+ concentration changes responsible for signal transduction in the subsarcolemmal space.