Role of Na + :Ca 2+ Exchange Current in Cs + ‐Induced Early Afterdepolarizations in Purkinje Fibers

Na + :Ca 2+ Exchanger and EADs. Introduction: The ionic mechanisms for early afterdepolarizations (EADs) have not been fully clarified. It has been suggested that L‐type Ca 2+ 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 + :Ca 2+ 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 [Ca 2+ ] 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 |Ca 2+ ] 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 [Ca 2+ ] o , and reduced [Na + ] o , and the migration of EADs to more positive Vm after exposures to high |Ca 2+ ] o , are compatible with I Nc:Ca as the major charge carrier for L‐EADs.