Is selective Na+/Ca2+ exchanger inhibition effective against ischemia/reperfusion induced ventricular arrhythmias?
█ Original article
Tóth András1,2, Kormos Anita2, Szepesi Judit2, Varró András1,2, Nagy Norbert1,2
1MTA-SZTE Keringésfarmakológiai Kutatócsoport, Szeged
2SZTE-ÁOK Farmakológiai és Farmakoterápiai Intézet, Szeged
A crucial role for augmented Na+/Ca2+ exchanger (NCX) activity in cardiac arrhythmogenesis was often suggested, however, the results of the related studies were controversial. A feasible explanation of this controversion could be the unsatisfactory selectivity of the early NCX inhibitors. In our first study performed on isolated canine cardiomyocytes we evaluated the efficacy of NCX inhibition using the relatively selective SEA0400, or a new, highly selective ORM-10103 against arrhythmogenic shifts in intracellular Ca2+ (Ca2+i) handling and action potential (AP) morphology, when (Ca2+)i was augmented via a simulated ischemia/reperfusion (I/R) protocol performed either alone (moderate low-flow protocol) or with simultaneous strophantidine challenge (severe low-flow protocol). In the second study Langendorff perfused rat hearts were exposed to regional I/R protocol and efficacies of NCX, NHE and combined NCX+NHE inhibition against reperfusion induced arrhythmias were compared by analyzing arrhythmia diagrams for incidence and duration of periods of repetitive extrasystoles (ES) and ventricular tachycardia (VT) or fibrillation (VF). Our results confirm that selective, partial NCX inhibition – presumably by blocking fwdINCX – is highly effective against arrhythmogenic after depolarizations and triggered activity caused by the perturbed Ca2+i handling, but it fails to normalize untoward arrhythmogenic changes in AP morphology. In perfused hearts NHE inhibition was markedly more efficient in reducing reperfusion-induced substrate-dependent arrhythmias, however, combined inhibition failed to improve the antiarrhythmic efficacy reached by NCX blockade alone.