Persistent sodium currents induced by anthopleurin-A and their relationship to early afterdepolarizations in...

Prolonged Na+ current inactivation was induced in neonatal rat ventricular myocytes by exposure to Anthopleurin-A (80-240 nM). In control whole-cell voltage clamp recordings, prolonged Na+ current inactivated mono-exponentially from peak with time constant, tau h, averaging 1.5 msec +/- 0.2 msec at -30 mV and peak current averaging 0.7 +/- 0.3 nA (n = 10). Steady state inactivation was complete at -50 mV and there was little or no overlap of prolonged Na+ current inactivation and activation processes. One to 3 minutes following exposure to Anthopleurin-A, the rate of inactivation slowed, with tau h increasing to 21 +/- 5 msec at -30 mV, and peak prolonged Na+ current increasing to 1.3 +/- 0.5 nA (n = 10). Steady state inactivation was shifted in a positive direction, and complete inactivation did not occur even at +10 mV. Persistent inward currents were thus induced by Anthopleurin-A. They were most prominent at depolarizations slightly above threshold for activation and were selectively blocked by lidocaine (60 microM). Action potentials were prolonged by Anthopleurin-A, especially at slow stimulation rates, and were accompanied by early afterdepolarizations. The correlation between persistent inward currents and early afterdepolarizations, in terms of voltage dependence, appearance and pharmacology, suggests a possible causal role for persistent Na+ currents in this model of early afterdepolarizations.