THEMED SECTION: ENDOTHELIUM IN PHARMACOLOGY REVIEW Endothelial Ca2+-activated K+ channels in normal and impaired EDHF–dilator responses – relevance to cardiovascular pathologies and drug discovery

The arterial endothelium critically contributes to blood pressure control by releasing vasodilating autacoids such as nitric oxide, prostacyclin and a third factor or pathway termed ‘endothelium-derived hyperpolarizing factor’ (EDHF). The nature of EDHF and EDHF-signalling pathways is not fully understood yet. However, endothelial hyperpolarization mediated by the Ca2+activated K+ channels (KCa) has been suggested to play a critical role in initializing EDHF–dilator responses in conduit and resistance-sized arteries of many species including humans. Endothelial KCa currents are mediated by the two KCa subtypes, intermediate-conductance KCa (KCa3.1) (also known as, a.k.a. IKCa) and small-conductance KCa type 3 (KCa2.3) (a.k.a. SKCa). In this review, we summarize current knowledge about endothelial KCa3.1 and KCa2.3 channels, their molecular and pharmacological properties and their specific roles in endothelial function and, particularly, in the EDHF–dilator response. In addition we focus on recent experimental evidences derived from KCa3.1and/or KCa2.3-deficient mice that exhibit severe defects in EDHF signalling and elevated blood pressures, thus highlighting the importance of the KCa3.1/KCa2.3-EDHF–dilator system for blood pressure control. Moreover, we outline differential and overlapping roles of KCa3.1 and KCa2.3 for EDHF signalling as well as for nitric oxide synthesis and discuss recent evidence for a heterogeneous (sub) cellular distribution of KCa3.1 (at endothelial projections towards the smooth muscle) and KCa2.3 (at inter-endothelial borders and caveolae), which may explain their distinct roles for endothelial function. Finally, we summarize the interrelations of altered KCa3.1/KCa2.3 and EDHF system impairments with cardiovascular disease states such as hypertension, diabetes, dyslipidemia and atherosclerosis and discuss the therapeutic potential of KCa3.1/KCa2.3 openers as novel types of blood pressure-lowering drugs. British Journal of Pharmacology (2009) 157, 509–526; doi:10.1111/j.1476-5381.2009.00132.x; published online 19 March 2009