SEA0400: A Novel Sodium‐Calcium Exchange Inhibitor with Cardioprotective Properties¹

Abstract

The cardiac sodium-calcium exchanger (NCX) plays an important role in calcium homeostasis. It is the primary mechanism for removing calcium ions that enter myocytes through L-type calcium channels on a beat-to-beat basis. Its direction of transport is determined by the membrane potential and the ionic concentrations of Na + and Ca 2+ , with the forward (or Ca 2+ -efflux) mode of transport being the dominant mode under physiological conditions. In contrast, the Ca 2+ -influx mode (or reverse mode) of NCX becomes important in certain pathophysiological conditions, such as myocardial ischemia and reperfusion. Recent discovery of compounds that inhibit the Ca 2+ -influx mode (or reverse mode) of NCX has generated intense research interest in the pharmacology of NCX. Among the newer NCX inhibitors described to date, 2-[4-[(2,5-difluorophenyl)methoxy]-phenoxy]-5-ethoxyaniline (SEA0400) appears particularly promising in attenuating cardiac, renal, and cerebral ischemia/reperfusion injuries in various experimental models. Moreover, the mixed results that have emerged from clinical trials evaluating the efficacy and safety of inhibitors of the sodium-hydrogen exchanger (an upstream target in relation to the sodium-calcium exchanger) in myocardial protection stimulated interest in evaluating NCX as an alternative therapeutic target. This article reviews the pharmacological profile of SEA0400, as presented in the published literature, and discusses the therapeutic potential of this compound in attenuating myocardial ischemia/reperfusion injury.

Cardiac-Specific Ablation of the Na + -Ca 2+ Exchanger Confers Protection Against Ischemia/Reperfusion Injury

“…In contrast, if NCX operates in reverse mode to bring Ca 2ϩ into the myocyte, then NCX inhibitors should be cardioprotective. Inhibitors of NCX are under development as therapies to reduce ischemic injury, 9,10 and it is important to clearly demonstrate whether inhibition is beneficial. However, the role and direction of NCX during ischemia is debated, as is the relative role of NCX during ischemia versus reperfusion.…”

Modulation of Neuroprotective Effect of Ischemic Post-Conditioning by Dichlorobenzamil a Na+/Ca2+ Exchanger Inhibitor in Mice

“…[19][20][21][22] A significant role of NCX in cardioprotective and renal protective mechanisms of ischemic preconditioning and ischemic postconditioning has also been documented. [19][20][21][22][23] However, role of Na ϩ /Ca 2ϩ exchanger in neuroprotective mechanism of ischemic postconditioning remains to be elucidated. Therefore, the present investigation has been undertaken to investigate the modulatory role of dichlorobenzamil a selective Na ϩ /Ca 2ϩ exchanger inhibitor in ischemic postconditioning mediated neuroprotection in mice.…”

Treatment of lactic acidosis: Appropriate confusion

“…77 A high cell sodium content then may increase intracellular calcium, through the Na/Ca exchanger, impairing cellular function. [77][78][79] Compounding this, the reduced function of the Na/H ATPase as a regulator of intracellular sodium in sepsis may not be adequate to limit cell swelling. 77 Against this background of mechanistic concerns with the use of bicarbonate treatment, it is not surprising that clinical outcomes have been inconsistent at best.…”