Improvement of endothelium-dependent vasodilations by XXXX and SKA-20, activators of small- and intermediate-conductance Ca2+ -activated K+ -channels.

@entity72532 @entity34824 @entity51264 @entity4059 @entity19 @entity4299 @entity409 @entity49 @entity1617 @entity13471
AIM: Endothelial membrane hyperpolarization mediated by @entity34824 and @entity51264 channels has been demonstrated to initiate @entity4059 ( @entity4059 )-type vasodilations. Moreover, pharmacological potentiation of @entity34824 / @entity51264 channels has been suggested to improve @entity4059 . Herein, we determined whether the @entity34824 / @entity51264 activator @entity72532 and its derivative SKA-20 improve @entity409 in @entity34824 -/- and @entity13471 -/- @entity19 . METHODS: Membrane potentials were measured using patch-clamp electrophysiology on carotid artery (CA) endothelial cells (CAEC) from wild-type (wt) and @entity34824 -/- @entity19 . Endothelium-dependent vasodilations were determined by pressure myography in CA. RESULTS: @entity72532 (1  m) activated @entity34824 and @entity51264 channels and induced membrane hyperpolarization in CAEC of wt (/\MP -45 mV). These responses were significantly reduced in CAEC of @entity34824 -/- (/\MP -8 mV). @entity72532 (200 nm, 500 nm) and SKA-20 (300 nm) significantly enhanced @entity4059 vasodilations in wt. SKA-20 also improved vasodilations during NO synthesis. In @entity34824 -/-, the @entity49 were unchanged at 200 nm @entity72532 , but were significantly improved at 500 nm. @entity4059 vasodilations were slightly enhanced at 300 nm SKA-20, but vasodilations during NO synthesis were unchanged. @entity72532 (500 nm) enhanced the impaired endothelium-dependent vasodilation in @entity13471 -/- @entity19 twofold. Pharmacological inhibition of the soluble @entity4299 hydrolase by t-AUCB (1  m) in contrast did not increase @entity1617 -induced @entity4059 - or NO-mediated vasodilations in wt and @entity34824 -/-. CONCLUSION: Normal and defective endothelium-dependent vasodilations in @entity19 carotid arteries can be improved by pharmacological enhancement of @entity34824 / @entity51264 functions. These findings further support the concept that pharmacological activation of endothelial @entity51264 / @entity34824 could offer a novel endothelium-specific antihypertensive strategy.
