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

Abstract

BACKGROUND AND PURPOSEAt 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 APPROACHIon 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 RESULTSORM-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 IMPLICATIONSORM-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

Efficacy of selective NCX inhibition by ORM-10103 during simulated ischemia/reperfusion

“…A number of previous studies provided important information on the consequences of NCX inhibition in healthy and diseased hearts (Inserte et al, 2002;MacDonald and Howlett, 2008), however, correct interpretation of these results was seriously hampered by the lack of selectivity of the used inhibitors. Therefore, in the present study we evaluated the efficacy of a new, selective NCX inhibitor, ORM-10103 (Jost et al, 2013) to protect canine ventricular cardiomyocytes during simulated ischemia/reperfusion.…”

“…In order to reach maximal, but still selective inhibition of the exchanger, ORM-10103 has been used in 10 mM dose. At this dose no apparent effect of the inhibitor on further ion transporters (except a small inhibition of I Kr ) could be observed (Jost et al, 2013). 1) Viability measurements: Two subsets of experiments were performed.…”

“…Though [Ca 2 þ ] i changes are important modulators of the AP (Louch et al, 2002), it is more dependent on the balance of the inward Na þ , Ca 2 þ and outward K þ currents. Except for a minimal decrease in the fast component of the delayed rectifier potassium current (I Kr ) neither of these factors are affected by ORM-10103 (Jost et al, 2013). This may be the primary cause for the minimal sensitivity of the AP to selective NCX blockade.…”

“…However, the inhibitors used in these studies were not fully selective (Birinyi et al, 2005), consequently the overall effect of NCX inhibition could not be quantitatively analyzed. Therefore, the aim of the present study was to evaluate the cardioprotective effect of a novel, selective NCX inhibitor, ORM-10103 (Jost et al, 2013) in isolated canine ventricular cardiomyocytes in conditions of simulated ischemia/reperfusion. This aim was accomplished by analyzing the primary, simulated ischemia/reperfusion induced shifts in characteristic variables on the CaT and AP and evaluating the modulatory effects of selective, partial NCX inhibition on these shifts.…”

Prevention of intracellular calcium overload by blocking NCX

“…One may also speculate that since the NHE and NCX seem to play a joint key role in the induction of ischaemia/reperfusion-induced [Ca 2+ ]i overload, the deteriorative effects might be better attenuated by simultaneously inhibiting both the NHE and NCX. For this purpose, a well-known, well-characterised NHE inhibitor, cariporide [39], and two NCX inhibitors, the fairly selective SEA0400 [40] and the novel, more selective ORM-10103 [41], were used.…”