Modulation of transient outward current by extracellular protons and Cd2+ in rat and human ventricular myocytes

1. The effects of extracellular acidosis and Cd2+ on the transient outward current (Ito) have been investigated in rat and human ventricular myocytes, using the whole-cell patch-clamp technique. 2. In rat myocytes, exposure to acidic extracellular solution (pH 6.0) shifted both steady-state activation and inactivation curves to more positive potentials, by 20.5 +/- 2.7 mV (mean +/- S.E.M.; n = 4) and 19.8 +/- 1.2 mV, respectively. Cd2+ also shifted the activation and inactivation curves in a positive direction in a concentration-dependent manner. 3. In human myocytes, the steady-state activation and inactivation curves were located at more positive potentials. The effect of Cd2+ was similar, but acidosis had less effect than in rat myocytes (e.g. pH 6.0 shifted activation by only 7.2 +/- 2.2 mV and inactivation by 13.7 +/- 0.5 mV; n = 4). 4. In both species, the effect of acidosis decreased with increasing concentrations of Cd2+ and vice versa, suggesting competition between H+ and Cd2+ for a common binding site. 5. The data indicate that acidosis and divalent cations influence Ito via a similar mechanism and act competitively in both rat and human myocytes, but that human cells are less sensitive to the effects of acidosis.