Na+/Ca2+ Exchange Inhibitors: A New Class of Calcium Regulators

The Na+/Ca2+ exchanger (NCX) is a bidirectional transporter that normally extrudes Ca2+ from the cell (forward mode), but also brings Ca2+ into the cell (reverse mode) under special conditions such as intracellular Na+ (Na+ i) accumulation or membrane depolarization. There are three mammalian NCX isoforms: NCX1 is widely expressed in the heart, kidney, brain, blood vessels, and so on; whereas the expression of NCX2 and NCX3 is limited mainly to the brain and skeletal muscle. The pharmacology of NCX inhibitors has been studied extensively since the development of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in 1996. Currently, experiments are actively progressing with more selective inhibitors: SEA0400, SN-6, and YM-244769. Intriguingly, the inhibitory potency of benzyloxyphenyl NCX inhibitors is directly coupled to the rate of Na+ i-dependent inactivation. Therefore, the benzyloxyphenyl inhibitors are apparently dormant during the forward mode under normal conditions (low Na+ i), but become effective during the reverse mode under pathological conditions (high Na+ i). This should be an ideal profile for calcium regulators against Na+ i-related diseases, such as ischemia/reperfusion injuries, salt-dependent hypertension, and digitalis arrhythmia. Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action. It is possible that this property is partly responsible for their antiarrhythmic and cardioprotective effects. This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator.