Is timing everything? Therapeutic potential of modulators of cardiac Na(+) transporters

Sodium ion (Na(+)) transporters have roles in the modulation of cardiomyocyte pH and Na(+) and Ca(2+) handling. Activation of the cardiac Na(+)-H(+) exchanger 1 (NHE1) during ischaemia induces arrhythmias, myocardial stunning and irreversible cell injury. As the benefits of NHE1 inhibitors (e.g., amiloride, cariporide) in models of myocardial infarction are usually much greater when used as pretreatment, rather than during or after ischaemia, it is probably not surprising that clinical trials with cariporide in ischaemia have shown little shortterm benefit. NHE1 inhibitors have been shown to be beneficial in animal models of ventricular fibrillation and resuscitation, cardioplegia, hypertrophy and heart failure, and their therapeutic potential in these conditions should be further developed. The Na(+)-HCO(3)(-) cotransporter (NBC) is also stimulated by intracellular acidification, and part of the benefit of angiotensin-converting enzyme inhibitors after myocardial infarction may be due to inhibition of the NBC. Selective inhibitors of the NBC are required to determine the therapeutic potential of this mechanism. The Na(+)-Ca(2+) exchanger (NCX) has a major role in cardiac Na(+) and Ca(2+) homeostasis and influences cardiac electrical activity. The NCX also has a role in ischaemia/infarction, arrhythmias, hypertrophy and heart failure. NCX inhibitors may have beneficial effects in animal models of ischaemia and reperfusion injury and the therapeutic benefit of these should be further studied in animal models.