Potential role of cardiac chloride channels and transporters as novel therapeutic targets

Abstract

The heart and blood vessels express a range of anion currents (e.g. ICl.PKA) and symporter/antiporters (e.g. Cl(-)/HCO3(-) exchanger) that translocate chloride (Cl(-)). They have been proposed to contribute to a variety of physiological processes including cellular excitability, cell volume homeostasis and apoptosis. Additionally there is evidence that Cl(-) currents or transporters may play a role in cardiac pathophysiology. Arrhythmogenesis, the process of cardiac ischaemic preconditioning, and the adaptive remodelling process in myocardial hypertrophy and heart failure have all been linked to such channels or transporters. We have explored the possibility that selective targeting of one or more of these may provide benefit in cardiovascular disease. Existing evidence points to an emerging role of cardiac cell anion channels as potential therapeutic targets, the 'disease-specificity' of which may represent a substantial improvement on current targets. However, the limitations of current techniques hitherto applied (such as developmental compensation in gene-modified animals) and pharmacological agents (which do not at present possess sufficient selectivity for the adequate probing of function) have thus far hindered translation to the introduction of new therapy.

Keywords: Chloride; Drug discovery; Heart failure; Ischaemic preconditioning; Sudden cardiac death; Ventricular arrhythmia.