Store-operated calcium channels: Potential target for the therapy of hypertension

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca2+ channels to Ca2+ influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca2+ channel inhibitors and Ca2+ antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca2+ channel the voltage independent store-operated Ca2+ channel has been implicated in the regulation and fine tuning of Ca2+ entry in both cardiac and smooth muscle cells. Store-operated Ca2+ channels are activated by the depletion of Ca2+ stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca2+, thereby facilitating agonist-induced Ca2+ influx. Store-operated Ca2+ entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca2+ entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca2+ channels acting at the level of both STIM and Orai channels have been shown to depress Ca2+ influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca2+ channels that act in vascular smooth muscles for the improved treatment of hypertension.