ABSTRACT
OBJECTIVES: Increasing evidence suggests that a Ca2+-activated Cl- current (ICl(Ca)) contributes to the transient inward current (Iti), the current responsible for proarrhythmic delayed after-depolarisations (DADs). Because the equilibrium potential for Cl- ions (ECl) in myocytes is around - 50 mV, activation of the ICl(Ca) results in an inward depolarising current at resting membrane potential and ICl(Ca) may thus be responsible for a part of the depolarisation during a DAD. In this study, we investigated the ionic nature of Iti and the effects of Cl- current blockade on DADs. METHODS AND RESULTS: The ionic mechanisms of Iti and underlying DADs were studied in sheep ventricular myocytes using the patch-clamp methodology. The DADs were induced in the myocytes by exposure to 1 µM noradrenaline and the Iti were elicited by repetitive depolarisations from -93 mV to +37 mV in the presence of the drug. The current-voltage relation of Iti reversed in sign around -20 mV. The outward Iti was completely blocked by the anion current blocker 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), whereas the inward Iti was only slightly affected. The DIDS-sensitive component of Iti was outwardly rectifying with a reversal potential close to ECl. The DIDS-insensitive component of Iti was abolished by blockade of the Na+-Ca2+ exchanger by substitution of extracellular Na+ by equimolar Li+. Interestingly, DIDS reduced the DAD amplitude and triggered activity based on DADs. CONCLUSION: In sheep ventricular myocytes, Iti consists of two ionic mechanisms: a Cl- current and a Na+-Ca2+ exchange current. Blockade of the Cl- current may be potentially antiarrhythmic by lowering DAD amplitude and triggered activity based on DADs.
