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Sodium-calcium exchanger (NCX) inhibitors block an antiporter that controls cytosolic calcium levels. In forward mode, NCX exchanges three sodium ions for one calcium ion and removes calcium from cardiac myocytes after each beat. The cardiac isoform NCX1 was cloned in 1990, and NCX2 and NCX3 are found mainly in brain and skeletal muscle. When intracellular sodium rises, as in ischemia, the exchanger can run in reverse and load cells with calcium. KB-R7943 mesylate inhibits this reverse mode preferentially, as reported in 1996 for cells expressing NCX1. SEA0400 was described in 2001 as a selective exchanger inhibitor, and ORM-10103 and YM-244769 are later examples. CGP 37157 instead acts on the sodium-calcium exchanger of the inner mitochondrial membrane.
