Na+/Ca2+ exchange inhibitors: potential drugs to mitigate the severity of ischemic injury.

Each year more than a million Americans suffer heart attacks and strokes. Most of these events result from the sudden thrombotic occlusion of a coronary or cerebral artery at the site of an atherosclerotic plaque (Corti et al., 2002). Tissue solely supplied by the occluded artery becomes hypoxic/anoxic. Oxygenation of surrounding tissue with collateral blood supply may also be compromised. At the cellular level, acute hypoxia/anoxia induces a switch from oxidative metabolism to glycolysis. This diminishes the energy supply in the affected cells and increases acid production, initiating processes leading to cell injury or death. A major goal of medicine today is to prevent the initial thrombotic event or, failing that, to minimize the resulting tissue damage. There are two aspects to minimizing tissue damage. One is to reduce the metabolic effects of ischemia on the tissue surrounding the anoxic region (that is, to reduce infarct size by preserving peripheral tissue). The second is to reperfuse the occluded vessel by thrombolysis or angioplasty to prevent anoxic cell death (Corti et al., 2002). During reperfusion, however, formation of reactive oxygen species in the ischemic tissue can also cause cellular damage (Li and Jackson, 2002; Zeitz et al., 2002). Thus, understanding the physiological basis of ischemicand reperfusion-induced cell injury and death is critical to identifying new therapeutic modalities. The elevation of intracellular calcium after ischemia and reperfusion is a major mediator of subsequent cellular injury and death (Banasiak et al., 2000; Orrenius et al., 2003). The Na /Ca exchanger (NCX) plays a central role in elevating intracellular calcium during ischemia and reperfusion in cardiac, neural and renal tissue (Stys et al., 1992; Blaustein and Lederer, 1999; Tomes and Agrawal, 2002; Zeitz et al., 2002; Yamashita et al., 2003; Craner et al., 2004). As such, the NCX is a promising new target for drugs to reduce hypoxic cell injury (Mochizuki and Jiang, 1998; Shigekawa and Iwamoto, 2001). In this issue of Molecular Pharmacology, Iwamoto et al. (2004) report the initial characterization of a new Na /Ca exchange inhibitor, SN-6. They report the tantalizing result that when administered at the time of reoxygenation (in a cell culture model, at least), SN-6 reduces subsequent cell injury/death. The human genome contains three genes encoding Na / Ca exchangers (NCX1, NCX2, NCX3) that undergo extensive alternative splicing (Philipson et al., 2002). Expression of these three NCX isoforms is tissue-specific. NCX1 is highly expressed in the heart, brain, and kidney and at lower levels in most other tissues. NCX2 and NCX3 are both almost exclusively expressed in brain and skeletal muscle (Blaustein and Lederer, 1999; Gibney et al., 2002; Philipson et al., 2002). An NCX1 knockout is embryonic lethal, whereas an NCX2 knockout increases hippocampal long-term potentiation and improves performance on learning and memory tests (Reuter et al., 2002b; Jeon et al., 2003). The NCX family is part of a larger gene superfamily that also includes K -dependent Na /Ca exchangers, bacterial Na /Ca exchangers, and bacterial Ca /H exchangers (Blaustein and Lederer, 1999; Philipson et al., 2002). The NCX ion translocation pathway is formed by nine transmembrane (TM) segments and two reentrant loops, referred to as repeats (Fig. 1A) (Philipson et al., 2002). The two repeats seem to be nearby in the folded protein structure because cysteines engineered into the TM segments flanking the N-terminal repeat form disulfide bonds with cysteines engineered into the TMs flanking the C-terminal repeat (Qiu et al., 2001). Inactivation processes decrease the NCX transport rate Article, publication date, and citation information can be found at http:// molpharm.aspet.org. DOI: 10.1124/mol.104.000232