Inhibitors of sodium-hydrogen exchange as therapeutic agents for the treatment of heart disease

Abstract

Na+-H+ exchanger (NHE) is a family of transporters of critical importance to the regulation of intracellular pH values, which act by removing protons in exchange for concomitant Na+ influx. There are at least eight isoforms in the NHE family that have thus far been cloned, which have been given the designation NHE-1 to NHE-8. NHE-1 is the so-called housekeeping isoform found in most tissues and is the major isoform in the cardiac cell. There is now very compelling evidence that its activation contributes to paradoxical induction of cell injury and NHE-1-selective inhibitors have been extensively demonstrated to possess excellent cardioprotective properties which appear to be superior to other strategies. Recent evidence also suggests that NHE inhibition may be conducive to attenuating the remodelling process after myocardial infarction, independently of infarct size reduction and attenuation of subsequent postinfarction heart failure. As such, inhibitors of NHE-1 offer substantial promise for clinical development for protecting the myocardium against acute injury as well as chronic postinfarction responses resulting in the evolution to heart failure. An evaluation of patent disclosures reveals a variety of NHE-1-specific inhibitors under development. Generally, these agents are guanidine compounds demonstrating relatively equal efficacy in terms of cardiac protection, although they differ substantially in terms of potency and selectivity towards NHE-1 versus other NHE isoforms. A large number of beneficial properties has been claimed for these compounds that could benefit conditions such as hypertension, atherosclerosis, shock, thrombosis, myocardial infarction, heart failure and others. However, based on experimental data, it is most likely that protection of the ischaemic and reperfused myocardium such as during coronary artery surgery, as well as limiting myocardial remodelling and heart failure, will emerge as the two primary targets for NHE-1 inhibitors in cardiovascular therapeutics.