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

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Abstract
The ionic mechanisms for early afterdepolarizations (EADs) have not been fully clarified. It has been suggested that L-type Ca2+ current (ICaL) is the primary current generating EADs that occur near the plateau level (E-EADs) of the membrane potential (Vm) when ICaL 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 (INa:Ca) as opposed to ICaL and other currents in the generation of EADs occurring later during repolarization (L-EADs). 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 [Ca2+]o, L-EADs migrated toward less negative Vm when [Ca2+]o was reestablished to 1.8 mM in the presence of Cs+. Reduction of [Na+]o from 147.5 to 112.5 mM by substitution with Li+ or sucrose also rapidly depressed L-EADs. 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 INa: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 INa:Ca as the major charge carrier for L-EADs.