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

Background and PurposeAugmented Na+/Ca2+ 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-i(2+) overload. Hence, we used NCX inhibitors SEA0400 and the more selective ORM10103 to evaluate the efficacy of NCX inhibition against arrhythmogenic Ca-i(2+) rise in conditions when [Ca2+](i) was augmented via activation of the late sodium current (I-NaL) or inhibition of the Na+/K+ pump. Experimental ApproachAction potentials (APs) 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-i(2+) transients (CaTs) were monitored with a Ca2+-sensitive fluorescent dye, Fluo-4. Key ResultsEnhanced I-NaL increased the Ca2+ load and AP duration (APD). SEA0400 and ORM10103 suppressed I-NCX and prevented/reversed the anemone toxin II (ATX-II)-induced [Ca2+](i) rise without influencing APD, CaT or cell shortening, or affecting the ATX-II-induced increased APD. ORM10103 significantly decreased the number of strophanthidin-induced spontaneous diastolic Ca2+ release events; however, SEA0400 failed to restrict the veratridine-induced augmentation in Purkinje-ventricle APD dispersion. Conclusions and ImplicationsSelective NCX inhibition - presumably by blocking I-rev(NCX) (reverse mode NCX current) - is effective against arrhythmogenesis caused by [Na+](i)-induced [Ca2+](i) elevation, without influencing the AP waveform. Therefore, selective I-NCX inhibition, by significantly reducing the arrhythmogenic trigger activity caused by the perturbed Ca-i(2+) handling, should be considered as a promising anti-arrhythmic therapeutic strategy.