Effect of SEA0400, a novel inhibitor of sodium‐calcium exchanger, on myocardial ionic currents

Abstract

The e ects of 2-[4-[(2,5-di¯uorophenyl) methoxy]phenoxy]-5-ethoxyaniline (SEA0400), a newly synthesized Na + -Ca 2+ exchanger (NCX) inhibitor, on the NCX current and other membrane currents were examined in isolated guinea-pig ventricular myocytes and compared with those of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea (KB-R7943). SEA0400 concentration-dependently inhibited the NCX current with a 10 fold higher potency than that of KB-R7943; 1 mM SEA0400 and 10 mM KB-R7943 inhibited the NCX current by more than 80%. KB-R7943, at 10 mM, inhibited the sodium current, L-type calcium current, delayed recti®er potassium current and inwardly rectifying potassium current by more than 50%, but SEA0400 (1 mM) had no signi®cant e ect on these currents. These results indicate that SEA0400 is a potent and highly selective inhibitor of NCX, and would be a powerful tool for further studies on the role of NCX in the heart and the therapeutic potential of its inhibition.

Suppression of Early and Late Afterdepolarizations by Heterozygous Knockout of the Na + /Ca 2+ Exchanger in a Murine Model

“…It is also the first study to investigate the effects of chronic and specific NCX inhibition on the generation of arrhythmia because synthetic NCX inhibitors lack specificity [19][20][21][22][23] and-to our knowledge-have only been applied acutely as single shot applications and not chronically in the investigation of arrhythmia. 23,24 …”

Topics on the Na+/Ca2+ Exchanger: Pharmacological Characterization of Na+/Ca2+ Exchanger Inhibitors

“…SEA0400 is the second and more potent NCX inhibitor than KB-R7943 developed by Taisho Pharmaceutical (7). SEA0400 does not affect other membrane currents, transporters, or receptors in neurons and heart at the concentrations that inhibit I NCX (7,57). SN-6 was developed from KB-R7943 as the third benzyloxyphenyl NCX inhibitor by Senju Pharmaceutical (8).…”

“…SEA0400 is in principle similar to KB-R7943 and SN-6 because its inhibitory effects on uni-directional outward (IC 50 = 28 nM) and bi-directional I NCX (outward, IC 50 = 40 nM; inward, IC 50 = 32 nM) are more potent than that on uni-directional inward I NCX (negligible inhibition at 10 µM) in guinea-pig ventricular myocytes or in transfected cells expressing NCX1 (57,60). The inhibitory potencies on I NCX1 are SEA0400 >> SN-6 = KB-R7943 in the heart (57,58,61). The selectivity of I NCX inhibitors is SEA0400 > SN-6 > KB-R7943 in the heart (6, 57, 62, 63; Y. Watanabe et al, unpublished observations).…”

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

“…The reduction in [K þ ] i depolarizes the sarcolemma (Baczko et al, 2003;Tanaka et al, 2002), further facilitating reverse mode NCX activity and leads to gradual [Ca 2 þ ] i accumulation. During the early phase of ischemia the major source of the [Ca 2 þ ] i increase is the leaky SR (Zucchi and Ronca-Testoni, 1997), while during the late phase, [Ca 2 þ ] i accumulation via NCX is accelerated (Bourdillon and Poole-Wilson, 1981;Haigney et al, 1992).…”