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

Abstract

/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 2+ i overload. Hence, we used NCX inhibitors SEA0400 and the more selective ORM10103 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 (INaL) or inhibition of the Na EXPERIMENTAL APPROACHAction potentials (APs) were recorded from canine papillary muscles and Purkinje fibres by microelectrodes. NCX current (INCX) was determined in ventricular cardiomyocytes utilizing the whole-cell patch clamp technique. Ca KEY RESULTSEnhanced INaL increased the Ca 2+ load and AP duration (APD). SEA0400 and ORM10103 suppressed INCX 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. ORM10103 significantly decreased the number of strophanthidin-induced spontaneous diastolic Ca 2+ release events; however, SEA0400 failed to restrict the veratridine-induced augmentation in Purkinje-ventricle APD dispersion. CONCLUSIONS AND IMPLICATIONSSelective NCX inhibition -presumably by blocking revINCX (reverse mode NCX current) -is effective against arrhythmogenesis caused by [Na]i elevation, without influencing the AP waveform. Therefore, selective INCX 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.

Characterization of different aspects of selective NCX inhibition in the heart

“…Therefore, the most important requirement for a NCX inhibitorbeyond potent blocking of NCX -is a minimal influence on the I CaL current. In previous studies of our laboratory (10,28,55,83,84), we reported that ORM-10103 effectively (Figure 7.) and selectively inhibits NCX in dog ventricular myocytes without influencing the I CaL current (figure not shown). Furthermore it was effective against triggered arrhythmias, namely it clearly decreased the amplitude of pharmacologically induced EAD and reduced the DAD incidence.…”

“…However, the lack of appropriate selectivity of the applied NCX inhibitors has made the data interpretation difficult and some important points are not fully clarified. The inotropic effect of selective NCX inhibition was expected however many studies reported lack of effect after selective NCX inhibition (28,30,31,78). Indeed, these compounds influenced the I CaL in some extent suggesting some reduction in the Ca 2+ influx which may counterbalance the inotropic effect.…”

“…Further possibility could be the PMCA which may also contribute to Ca 2+ extrusion (86) and therefore it may compensate for the reduced NCX function. Based on our previous study (28), where the NCX was measured in the presence of intact Ca 2+ cycle, we proposed that under normal condition, the inward NCX current has relatively low amplitude thus the inhibition of this small current may be fully compensated by the above mentioned mechanisms.…”

“…In healthy myocardium the cells are well coupled electrically, and this electronic interaction largely minimizes the repolarization changes at tissue level, while these alterations could be augmented at cellular level which may explain the marginal effect in epicardial tissue (4). Previous studies (28,77) seem to support our suggestion that under normal condition only small net NCX current is evoked during the AP and the influence of the inhibition of this small current may be compensated for by the repolarization reserve (9). The momentary magnitude of NCX current under the AP depends on the actual voltage, intracellular Na + and Ca 2+ levels.…”

Prevention of intracellular calcium overload by blocking NCX

“…Experimental data on the antiarrhythmic effects of SEA0400 are sparse and contradictory, although mostly positive [47][48][49][50], while similar data for ORM-10103 have become available only very recently [41,51,52]. SEA0400 has a moderate inhibitory effect on the L-type Ca 2+ channels [40], while ORM-10103 has a minor effect on IKr; neither of these pleiotropic effects could substantially modulate the observed antiarrhythmic efficacy of the NCX inhibition.…”