Advanced glycation end products impair K_Ca3.1- and K _Ca2.3-mediated vasodilatation via oxidative stress in rat mesenteric arteries

The present study was designed to investigate the role of advanced glycation end products (AGEs) in intermediate-conductance and small-conductance Ca²⁺-activated potassium channels (K_Ca3.1 and K _Ca2.3)-mediated relaxation in rat resistance arteries and the underlying mechanism. The endothelial function of mesenteric arteries was assessed with the use of wire myography. Expression levels of K_Ca3.1 and K_Ca2.3 were measured by using Western blot. Reactive oxygen species (ROS) were measured by using dihydroethidium and 2′, 7′-dichlorofluorescein diacetate. K_Ca3.1 and K _Ca2.3-mediated vasodilatation responses to acetylcholine and NS309 (opener of K_Ca3.1 and K_Ca2.3) were impaired by incubation of the third-order mesenteric arteries from normal rats with AGEs (200 μg ml^-1 for 3 h). In cultured human umbilical vein endothelial cells (HUVECs), AGEs increased ROS level and decreased the protein expression of K_Ca3.1 and K_Ca2.3. Antioxidant alpha lipoic acid restored the impairment in both vasodilatation function and expression of K _Ca3.1 and K_Ca2.3. H₂O₂ could mimic the effect of AGEs on the protein expression of K_Ca3.1 and K _Ca2.3 in cultured HUVECs. These results demonstrate for the first time that AGEs impaired K_Ca3.1 and K_Ca2.3-mediated vasodilatation in rat mesenteric arteries via downregulation of both K _Ca3.1 and K_Ca2.3, in which the enhanced oxidative stress was involved.