Activators of SKCa and IKCa channels enhance agonist‐evoked vasodilation and endothelial NO synthesis

Abstract

Pharmacologic blockade of small‐ and intermediate conductance, Ca2+‐activated K+ channels (SKCa and IKCa channels, respectively) is known to interfere with agonist‐evoked vasorelaxation via nitric oxide (NO) synthesis and the pathway involving an ‘endothelium‐derived hyperpolarizing factor’ (EDHF). Given these important functional effects of vascular SKCa and IKCa channels, we examined the hypothesis that activation of these channels may augment the normal cellular pathway(s) underlying agonist‐mediated vasorelaxation. In single human umbilical vein endothelial cells (HUVECs), the SKCa/IKCa channel openers NS309 and DCEBIO in combination (1 μM each) enhanced ATP‐evoked cytosolic Ca2+ elevation and NO synthesis, as monitored by Fluo−3 and DAF‐FM, respectively. NS309 and DCEBIO also enhanced ATP‐induced membrane hyperpolarization. On their own, these channel openers produced significant membrane hyperpolarization and modest Ca2+ elevations, but did not induce NO production. In rat cremaster arterioles pressurized to ∼50 mm Hg, NS309 and DCEBIO alone evoked a significant reduction of myogenic tone and further augmented ACh‐induced vasodilation. Removing the endothelium by passage of an air bubble through the vessel lumen significantly diminished the vasodilatory responses to either ACh or NS309 and DCEBIO, indicating a predominant endothelial site of action for these agents.