NHE-1 inhibition: from protection during acute ischaemia/reperfusion to prevention/reversal of myocardial remodelling

The myocardial Na+/H+ exchanger isoform 1 (NHE-1) represents a major H+ extrusion mechanism for intracellular pH (pH(i)) regulation especially during ischaemia and early reperfusion. Paradoxically, however, its activation contributes to induction of cell injury because Na+/H+ exchange is coupled closely to elevations in intracellular [Ca2+] through the Na+/Ca2+ exchanger. NHE-1 is exquisitely sensitive to intracellular acidosis but other factors may have also stimulatory effects via phosphorylation-dependent processes, like autocrine and paracrine agents as well as hormonal factors such as endothelin-1, angiotensin II and alpha-1-adrenoceptor agonists. In addition, phosphorylation-independent NHE-1 activation mechanisms are known, e.g. cell shrinkage. To date at least 8 NHE isoforms have been identified and designated as NHE-1-8. All, except NHE-6 and NHE-7, which are located intracellularly, are restricted to the sarcolemmal membrane. The NHE-1 subtype is the predominant isoform in the heart, but NHE-6 is also expressed in the heart. Newly developed, selective NHE-1 inhibitors possess potent cardioprotective properties. The efficacy of NHE-1 inhibitors in experimental studies with ischaemia/reperfusion has led to clinical trials for the evaluation of these agents in high-risk patients with coronary artery disease (GUARDIAN Trial) and acute myocardial infarction (ESCAMI Trial). The GUARDIAN trial demonstrated only for the coronary artery by-pass graft (CABG) patient population a reduction in the primary cardiovascular endpoint (death and reoccurring myocardial infarction). However, recent evidence also suggests that NHE-1 inhibition may be conducive to attenuation of remodelling processes after myocardial infarction, independently of infarct size reduction and blood pressure. In addition, in separate preclinical studies, the NHE-1 inhibitor cariporide also prevented and/or caused regression of age-related and hypertension-induced myocardial fibrosis and hypertrophy. NHE-1 inhibitors thus offer substantial promise for clinical development for attenuation of both a) acute responses to myocardial injury, b) chronic post-infarct and hypertension- and age-related responses resulting in the development of heart failure.