Vascular K_Ca-channels as therapeutic targets in hypertension and restenosis disease

Importance of the field: Cardiovascular disease is a leading cause of death in modern societies. Hyperpolarizing Ca²⁺-activated K⁺ channels (K_Ca) are important membrane proteins in the control of arterial tone and pathological vascular remodelling and thus could serve as new drug targets. Areas covered in this review: We summarize recent advances in the field of vascular K_Ca and their roles in cardiovascular pathologies such as hypertension and restenosis disease and draw attention to novel small-molecule channel modulators and their possible therapeutic utility. This review focuses on literature from the last four to five years. What the reader will gain: Pharmacological opening of endothelial KCa3.1/ KCa2.3 channels stimulates endothelium-derived-hyperpolarizing-factormediated arteriolar dilation and lowers blood pressure. Inhibition of smooth muscle KCa3.1 channels has beneficial effects in restenosis disease and atherosclerosis. We consider the therapeutic potential of KCa3.1/KCa2.3 openers as novel endothelium-specific antihypertensive drugs as well as of KCa3.1- blockers for the treatment of pathological vascular remodelling and discuss advantages and disadvantages of the pharmacotherapeutic approaches. Take home message: Pharmacological manipulation of vascular K_Ca channels by novel small-molecule modulators offers new venues for alternative treatments of hypertension, restenosis and atherosclerosis. Additional efforts are required to optimize these compounds and to validate them as cardiovascular-protective drugs.