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ORM-10103, a Novel Specific Inhibitor of the Na+/Ca2+ Exchanger, Decreases Early and Delayed Afterdepolarizations in the Canine Heart

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 Tóth, J Gy Papp, A Varró, L Virág

Br J Pharmacol. 2013 Oct;170(4):768-78.

PMID: 23647096

Abstract:

Background and purpose:
At present there are no small molecule inhibitors that show strong selectivity for the Na(+) /Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP488847285	ORM-10103		488847-28-5	Price

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