title: Metformin Restores Intermediate-Conductance Calcium-Activated K⁺ Channel- and Small-Conductance Calcium-Activated K⁺ Channel-Mediated Vasodilatation Impaired by Advanced Glycation End Products in Rat Mesenteric Artery. [Corrected].
abstract: The present study was designed to investigate the effect of metformin on the impairment of intermediate-conductance and small-conductance Ca(2+)-activated potassium channels (IKCa and SKCa)-mediated relaxation in diabetes and the underlying mechanism. The endothelial vasodilatation function of mesenteric arteries was assessed with the use of wire myography. Expression levels of IKCa and SKCa and phosphorylated Thr(172) of AMP-activated protein kinase (AMPK) were measured using Western blot technology. The channel activity was observed using a whole-cell patch voltage clamp. Reactive oxygen species (ROS) were measured using dihydroethidium and 2',7'-dichlorofluorescein diacetate. Metformin restored the impairment of IKCa- and SKCa-mediated vasodilatation in mesenteric arteries from streptozotocin-induced type 2 diabetic rats and that from normal rats incubated with advanced glycation end products (AGEs) for 3 hours. In cultured human umbilical vein endothelial cells (HUVECs), 1 μM metformin reversed AGE-induced increase of ROS and attenuated AGE- and H2O2- induced downregulation of IKCa and SKCa after long-term incubation (>24 hours). Short-term treatment (3 hours) with 1 μM metformin reversed the decrease of IKCa and SKCa currents induced by AGE incubation for 3 hours without changing the channel expression or the AMPK activation in HUVECs. These results are the first to demonstrate that metformin restored IKCa- and SKCa-mediated vasodilatation impaired by AGEs in rat mesenteric artery, in which the upregulation of channel activity and protein expression is likely involved.
authors.affiliation: Department of Physiology and Pathophysiology (L.-M.Z., Y.W., Y.Y., R.G., X.-L.D.) and Cardiovascular Research Center (L.-M.Z., Y.W., N.-P.W., X.-L.D.), School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Nangang District, Harbin, Heilongjiang, China (L.-M.Z.).
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Zhao
authors.affiliation: Department of Physiology and Pathophysiology (L.-M.Z., Y.W., Y.Y., R.G., X.-L.D.) and Cardiovascular Research Center (L.-M.Z., Y.W., N.-P.W., X.-L.D.), School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Nangang District, Harbin, Heilongjiang, China (L.-M.Z.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology (L.-M.Z., Y.W., Y.Y., R.G., X.-L.D.) and Cardiovascular Research Center (L.-M.Z., Y.W., N.-P.W., X.-L.D.), School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Nangang District, Harbin, Heilongjiang, China (L.-M.Z.).
authors.forename: Yong
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Physiology and Pathophysiology (L.-M.Z., Y.W., Y.Y., R.G., X.-L.D.) and Cardiovascular Research Center (L.-M.Z., Y.W., N.-P.W., X.-L.D.), School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Nangang District, Harbin, Heilongjiang, China (L.-M.Z.).
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.affiliation: Department of Physiology and Pathophysiology (L.-M.Z., Y.W., Y.Y., R.G., X.-L.D.) and Cardiovascular Research Center (L.-M.Z., Y.W., N.-P.W., X.-L.D.), School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Nangang District, Harbin, Heilongjiang, China (L.-M.Z.).
authors.forename: Nan-Ping
authors.initials: NP
authors.lastname: Wang
authors.affiliation: Department of Physiology and Pathophysiology (L.-M.Z., Y.W., Y.Y., R.G., X.-L.D.) and Cardiovascular Research Center (L.-M.Z., Y.W., N.-P.W., X.-L.D.), School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, China; and Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Nangang District, Harbin, Heilongjiang, China (L.-M.Z.) dengxl@mail.xjtu.edu.cn.
authors.forename: Xiu-Ling
authors.initials: XL
authors.lastname: Deng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D024681:Potassium Channels, Calcium-Activated / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D017127:Glycation End Products, Advanced; D024681:Potassium Channels, Calcium-Activated; D017382:Reactive Oxygen Species; D008687:Metformin; D055372:AMP-Activated Protein Kinases