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

• Published in: British journal of pharmacology Vol. 171; no. 24; p. 5665
• Main Authors: Nagy, Norbert, Kormos, Anita, Kohajda, Zsófia, Szebeni, Áron, Szepesi, Judit, Pollesello, Piero, Levijoki, Jouko, Acsai, Károly, Virág, László, Nánási, Péter P, Papp, Julius Gy, Varró, András, Tóth, András
• Format: Journal Article
• Language: English
• Published: England 01.12.2014
• Subjects: Action Potentials - drug effects; Aniline Compounds - pharmacology; Animals; Arrhythmias, Cardiac - etiology; Benzopyrans - pharmacology; Calcium - metabolism; Cnidarian Venoms - pharmacology; Dogs; Hypercalcemia - complications; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Papillary Muscles - drug effects; Papillary Muscles - metabolism; Patch-Clamp Techniques; Phenyl Ethers - pharmacology; Purkinje Fibers - drug effects; Purkinje Fibers - metabolism; Pyridines - pharmacology; Sodium-Calcium Exchanger - antagonists & inhibitors
• ISSN: 1476-5381
• DOI: 10.1111/bph.12867

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 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(+) /K(+) pump. 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. Ca(2+) i transients (CaTs) were monitored with a Ca(2+) -sensitive fluorescent dye, Fluo-4. Enhanced 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. Selective NCX inhibition - presumably by blocking rev INCX (reverse mode NCX current) - is effective against arrhythmogenesis caused by [Na(+) ]i -induced [Ca(2+) ]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.