Selective Na⁺/Ca²⁺ exchanger inhibition prevents Ca²⁺ overload‐induced triggered arrhythmias

Background and Purpose Augmented Na + / Ca 2+ exchanger ( NCX ) activity may play a crucial role in cardiac arrhythmogenesis; however, data regarding the anti‐arrhythmic efficacy of NCX inhibition are debatable. Feasible explanations could be the unsatisfactory selectivity of NCX inhibitors and/or the dependence of the experimental model on the degree of Ca 2+ i overload. Hence, we used NCX inhibitors SEA 0400 and the more selective ORM 10103 to evaluate the efficacy of NCX inhibition against arrhythmogenic Ca 2+ i rise in conditions when [ Ca 2+ ] i was augmented via activation of the late sodium current ( I NaL ) or inhibition of the Na + / K + pump. Experimental Approach Action potentials ( AP s) were recorded from canine papillary muscles and Purkinje fibres by microelectrodes. NCX current ( I NCX ) was determined in ventricular cardiomyocytes utilizing the whole‐cell patch clamp technique. Ca 2+ i transients ( CaTs ) were monitored with a Ca 2+ ‐sensitive fluorescent dye, Fluo‐4. Key Results Enhanced I NaL increased the Ca 2+ load and AP duration ( APD ). SEA 0400 and ORM 10103 suppressed I NCX and prevented/reversed the anemone toxin II ( ATX‐II )‐induced [ Ca 2+ ] i rise without influencing APD , CaT or cell shortening, or affecting the ATX‐II‐induced increased APD . ORM 10103 significantly decreased the number of strophanthidin‐induced spontaneous diastolic Ca 2+ release events; however, SEA 0400 failed to restrict the veratridine‐induced augmentation in P urkinje‐ventricle APD dispersion. Conclusions and Implications Selective NCX inhibition – presumably by blocking rev I NCX (reverse mode NCX current) – is effective against arrhythmogenesis caused by [ Na + ] i ‐induced [ Ca 2+ ] i elevation, without influencing the AP waveform. Therefore, selective I NCX inhibition, by significantly reducing the arrhythmogenic trigger activity caused by the perturbed Ca 2+ i handling, should be considered as a promising anti‐arrhythmic therapeutic strategy.