ORM-10103, a novel specific inhibitor of the Na+/Ca2+ exchanger, decreases early and delayed afterdepolarizations in the canine heart

N. Jost, N. Nagy, C. Corici, Z. Kohajda, A. Horváth, K. Acsai, P. Biliczki, J. Levijoki, P. Pollesello, T. Koskelainen, L. Otsomaa, A. Tõth, J. Gy Papp, A. Varrõ, L. Virág

Research output: Review article

35 Citations (Scopus)

Abstract

Background and Purpose At present there are no small molecule inhibitors that show strong selectivity for the Na+/Ca2+ exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca 2+ currents and on the formation of early and delayed afterdepolarizations. Experimental Approach Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. Key Results ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μM), ORM-10103 did not significantly change the L-type Ca2+ current or the maximum rate of depolarization (dV/dtmax), indicative of the fast inward Na+ current. At 10 μM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca2+ current. ORM-10103 did not influence the Na +/K+ pump or the main K+ currents of canine ventricular myocytes, except the rapid delayed rectifier K+ current, which was slightly diminished by the drug at 3 μM. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μM) in a concentration- dependent manner. Conclusions and Implications ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events. Linked Article This article is commented on by Terracciano and Hancox, pp. 765-767 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12299

Original languageEnglish
Pages (from-to)768-778
Number of pages11
JournalBritish journal of pharmacology
Volume170
Issue number4
DOIs
Publication statusPublished - okt. 1 2013

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ASJC Scopus subject areas

  • Pharmacology

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