Cl^- current blockade reduces triggered activity based on delayed afterdepolarisations

Increasing evidence suggests that a Ca²⁺-activated Cl^- current (I_Cl(Ca)) contributes to the transient inward current (I_ti), the current responsible for proarrhythmic delayed after-depolarisations (DADs). Because the equilibrium potential for Cl^- ions (E_Cl) in myocytes is around - 50 mV, activation of the I_Cl(Ca) results in an inward depolarising current at resting membrane potential and I_Cl(Ca) may thus be responsible for a part of the depolarisation during a DAD. In this study, we investigated the ionic nature of I_ti and the effects of Cl^- current blockade on DADs.

The ionic mechanisms of I_ti 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 I_ti were elicited by repetitive depolarisations from -93 mV to +37 mV in the presence of the drug. The current-voltage relation of I_ti reversed in sign around -20 mV. The outward I_ti was completely blocked by the anion current blocker 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), whereas the inward I_ti was only slightly affected. The DIDS-sensitive component of I_ti was outwardly rectifying with a reversal potential close to E_Cl. The DIDS-insensitive component of I_ti 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.

In sheep ventricular myocytes, I_ti 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.