Selective Na +/ Ca 2+ exchanger inhibition prevents Ca 2+ overload-induced triggered arrhythmias

Norbert Nagy, Anita Kormos, Zsõfia Kohajda, Áron Szebeni, Judit Szepesi, Piero Pollesello, Jouko Levijoki, Károly Acsai, Lászlõ Virág, Péter P. Nánási, Julius Gy Papp, András Varrõ, András Tõth

Research output: Article

25 Citations (Scopus)

Abstract

Background and Purpose Augmented 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 Ca2+i overload. Hence, we used NCX inhibitors SEA0400 and the more selective ORM10103 to evaluate 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 fibres 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 ORM10103 suppressed INCX 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 Implications Selective NCX inhibition - presumably by blocking revINCX (reverse mode NCX current) - 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 as a promising anti-arrhythmic therapeutic strategy.

Original languageEnglish
Pages (from-to)5665-5681
Number of pages17
JournalBritish journal of pharmacology
Volume171
Issue number24
DOIs
Publication statusPublished - dec. 2014

ASJC Scopus subject areas

  • Pharmacology

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