Calcium-Activated Cl − Current Contributes to Delayed Afterdepolarizations in Single Purkinje and Ventricular Myocytes

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Abstract
Background —The ionic mechanism underlying the transient inward current ( I ti ), the current responsible for delayed afterdepolarizations (DADs), appears to be different in ventricular myocytes and Purkinje fibers. In ventricular myocytes, I ti was ascribed to a Na + -Ca 2+ exchange current, whereas in Purkinje fibers, it was additionally ascribed to a Cl − current and a nonselective cation current. If Cl − current contributes to I ti and thus to DADs, Cl − current blockade may be potentially antiarrhythmogenic. In this study, we investigated the ionic nature of I ti in single sheep Purkinje and ventricular myocytes and the effects of Cl − current blockade on DADs. Methods and Results —In whole-cell patch-clamp experiments, I ti was induced by repetitive depolarizations from −93 to +37 mV in the presence of 1 μmol/L norepinephrine. In both Purkinje and ventricular myocytes, I ti was inward at negative potentials and outward at positive potentials. The anion blocker 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) blocked outward I ti completely but inward I ti only slightly. The DIDS-sensitive component of I ti was outwardly rectifying, with a reversal close to the reversal potential of Cl − currents. Blockade of Na + -Ca 2+ exchange by substitution of extracellular Na + by equimolar Li + abolished the DIDS-insensitive component of I ti . DIDS reduced both DAD amplitude and triggered activity based on DADs. Conclusions —In both Purkinje and ventricular myocytes, I ti consists of 2 ionic mechanisms: a Cl − current and a Na + -Ca 2+ exchange current. Blockade of the Cl − current may be potentially antiarrhythmogenic by lowering DAD amplitude and triggered activity based on DADs.