Background-It has been proposed that activation of endothelial SK3 (K Ca 2.3) and IK1 (K Ca 3.1) K ϩ channels plays a role in the arteriolar dilation attributed to an endothelium-derived hyperpolarizing factor (EDHF). However, our understanding of the precise function of SK3 and IK1 in the EDHF dilator response and in blood pressure control remains incomplete. To clarify the roles of SK3 and IK1 channels in the EDHF dilator response and their contribution to blood pressure control in vivo, we generated mice deficient for both channels. Methods and Results-Expression and function of endothelial SK3 and IK1 in IK1Ϫ/Ϫ /SK3 T/T mice was characterized by patch-clamp, membrane potential measurements, pressure myography, and intravital microscopy. Blood pressure was measured in conscious mice by telemetry. Combined IK1/SK3 deficiency in IK1Ϫ/Ϫ /SK3 T/T (ϩdoxycycline) mice abolished endothelial K Ca currents and impaired acetylcholine-induced smooth muscle hyperpolarization and EDHFmediated dilation in conduit arteries and in resistance arterioles in vivo. IK1 deficiency had a severe impact on acetylcholine-induced EDHF-mediated vasodilation, whereas SK3 deficiency impaired NO-mediated dilation to acetylcholine and to shear stress stimulation. As a consequence, SK3/IK1-deficient mice exhibited an elevated arterial blood pressure, which was most prominent during physical activity. Overexpression of SK3 in IK1Ϫ/Ϫ /SK3 T/T mice partially restored EDHF-and nitric oxide-mediated vasodilation and lowered elevated blood pressure. The IK1-opener SKA-31 enhanced EDHF-mediated vasodilation and lowered blood pressure in SK3-deficient IK1 ϩ/ϩ /SK3 T/T (ϩdoxy-cycline) mice to normotensive levels. Conclusions-Our study demonstrates that endothelial SK3 and IK1 channels have distinct stimulus-dependent functions, are major players in the EDHF pathway, and significantly contribute to arterial blood pressure regulation. Endothelial K Ca channels may represent novel therapeutic targets for the treatment of hypertension.

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 KCa3.1‐ and/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 This article is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009