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 Ca 2+ channels to Ca 2+ influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca 2+ channel inhibitors and Ca 2+ 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 Ca 2+ channel-the voltage independent store-operated Ca 2+ channel-has been implicated in the regulation and fine tuning of Ca 2+ entry in both cardiac and smooth muscle cells. Storeoperated Ca 2+ channels are activated by the depletion of Ca 2+ stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca 2+ , thereby facilitating agonist-induced Ca 2+ influx. Store-operated Ca 2+ 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 Ca 2+ entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of storeoperated Ca 2+ channels acting at the level of both STIM and Orai channels have been shown to depress Ca 2+ 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 Ca 2+ channels that act in vascular smooth muscles for the improved treatment of hypertension.
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