Selective Na /Ca exchanger inhibition prevents Ca overload induced triggered arrhythmias.

Nagy, Norbert and Kormos, Anita and Kohajda, Zsófia and Szebeni, Áron and Szepesi, Judit and Acsai, Károly and Virág, László and Nánási, Péter Pál and Papp, Gyula and Varró, András and Tóth, András (2014) Selective Na /Ca exchanger inhibition prevents Ca overload induced triggered arrhythmias. BRITISH JOURNAL OF PHARMACOLOGY, 171 (24). pp. 5665-5681. ISSN 0007-1188

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Abstract

BACKGROUND AND PURPOSE: A crucial role for augmented Na+ /Ca2+ exchanger (NCX) activity in cardiac arrhythmogenesis is often suggested, however, in related studies the antiarrhythmic efficacy of NCX inhibition was apparently controversial. Feasible explanations could be the unsatisfactory selectivity of NCX inhibitors and/or experimental model dependence of the degree of Ca2+ i overload. In the present study, using NCX inhibitors SEA0400 and the more selective ORM10103, we evaluated the efficacy of NCX inhibition against arrhythmogenic Ca2+ i rise in conditions when [Ca2+ ]i was augmented via activation of the late sodium current (INaL ) or inhibition of the Na+ /K+ pump. EXPERIMENTAL APPROACH: Action potentials (APs) were recorded from canine papillary muscles and Purkinje fibers by microelectrodes. NCX current (INCX ) was determined in ventricular cardiomyocytes utilizing the whole cell patch clamp technique. Ca2+ i transients (CaTs) were monitored with a Ca2+ -sensitive fluorescent dye, Fluo-4. KEY RESULTS: Enhanced INaL increased the Ca2+ -load and AP duration (APD). SEA0400 and ORM-10103 suppressed INCX and prevented/reversed the ATX-II induced [Ca2+ ]i rise without influencing APD, CaT or cell shortening. The APD lengthening effect of ATX-II was neither reduced. ORM-10103 significantly decreased the number of strophantidine-induced spontaneous diastolic Ca2+ releases, however, SEA0400 failed to restrict the veratridine-induced augmentation in Purkinje-ventricle APD dispersion. CONCLUSIONS AND IMPLICATIONS: Selective NCX inhibition - presumably via blocking rev INCX - is effective against arrhythmogenesis caused by [Na+ ]i -induced [Ca2+ ]i elevation, without influencing the AP waveform. Therefore, selective INCX inhibition, by significantly reducing the arrhythmogenic trigger activity caused by the perturbed Ca2+ i handling, should be considered a promising antiarrhythmic therapeutic strategy.

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