Crucial importance of the endothelial K + channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction

Skeletal muscle activity requires substantial increases in blood flow, and the underlying vasodilation involves endothelial activity, but the contribution of the endothelium‐dependent hyperpolarizing factor (EDHF) is only poorly defined. In EDHF signaling, endothelial hyperpolarization mediated by the Ca 2+ ‐activated K + channels SK3 and IK1 is a key step and also initiates gap junction‐dependent conducted dilations. We assessed the role of SK3, IK1, and connexin40 (Cx40) in muscular contraction‐induced dilations in the microcirculation in vivo . Hitherto, arterioles were observed in the electrically stimulated cremaster skeletal muscle of anesthetized mice lacking SK3, IK1, or Cx40 using intravital microscopy. Genetic deficiency of SK3, but not of IK1, strongly attenuated dilations to muscular contraction. Similarly, pharmacologic blockade of SK3 by the specific blocker UCL1684 impaired such dilations in wild‐type and IK1‐deficient mice. In contrast, IK1 was required for acetylcholine‐induced dilations. Genetic deficiency of Cx40 also attenuated dilations induced by muscular contraction but not by acetylcholine. These data support the concept that endothelial hyperpolarization through activation of SK3 contributes to exercise hyperemia and the hyper‐polarization ascends the vascular tree through gap junctions formed by Cx40 to orchestrate dilation. The differential impact of SK3‐ and IK1‐deficiency on dilations to distinct stimuli suggests stimulus‐dependent activation of these endothelial channels.—Milkau, M., Köhler, R., de Wit, C. Crucial importance of the endothelial K + channel SK3 and connexin40 in arteriolar dilations during skeletal muscle contraction. FASEB J . 24, 3572–3579 (2010). www.fasebj.org