Role of Na+:Ca2+ Exchange Current in Cs+-Induced Early Afterdepolarizations in Purkinje Fibers

Na⁺:Ca²⁺ Exchanger and EADs. Introduction: The ionic mechanisms for early afterdepolarizations (EADs) have not been fully clarified. It has been suggested that L-type Ca²⁺ current (I_caL) is the primary current generating EADs that occur near the plateau level (E-EADs) of the membrane potential (Vm) when I_caL is enhanced. The purpose of these studies was to determine accurately the range of Vm at which EADs occur in Purkinje fibers with K⁺ currents blocked by Cs⁺ and to investigate the importance of Na⁺:Ca²⁺ exchange current (I_Na:ca) as opposed to l_CaL and other currents in the generation of EADs occurring later during repolarization (L-EADs). Methods and Results: Shortened Purkinje strands from dogs and guinea pigs were superfused with physiologic solution containing Cs⁺ (3.6 mM) and a low [K⁺]_o (3.0 or 2.0 mM) to induce EADs. The Vm of origin of EADs and their evolution were measured with the aid of phase plane plots of the rate of repolarization against Vm. L-EADs occurred over a wide range of Vm (?35 to ?90 mV), generally more negative in guinea pig than in dog. Elevation of [Ca²⁺]_o, from 1.8 to 3.6 mM suppressed L-EADs within a few cycles, and they returned with continued exposure. After repeated exposures to high [Ca^:2+]₀, L-EADs migrated toward less negative Vm when |Ca²⁺]₀, was reestablished to 1.8 mM in the presence of Cs⁺. Reduction of [Na⁺]₀ from 147.5 to 112.5 mM by substitution with Li⁺ or sucrose also rapidly depressed L-EADs. Conclusions: The observation of Cs⁺-induced L-EADs over a wide range of Vm indicates that there is not a single inward gated current as a common ionic mechanism for L-EADs but does not exclude an important role for I_Na:Ca, which can operate over a wide range of Vm. The rapid suppression of L-EADs with elevated [Ca²⁺]_o, and reduced [Na⁺]_o, and the migration of EADs to more positive Vm after exposures to high |Ca²⁺]_o, are compatible with I_Nc:Ca as the major charge carrier for L-EADs.