title: Downregulation of Endothelial Transient Receptor Potential Vanilloid Type 4 Channel and Small-Conductance of Ca2+-Activated K+ Channels Underpins Impaired Endothelium-Dependent Hyperpolarization in Hypertension.
abstract: Endothelium-dependent hyperpolarization (EDH)-mediated responses are impaired in hypertension, but the underlying mechanisms have not yet been determined. The activation of small- and intermediate-conductance of Ca2+-activated K+channels (SKCaand IKCa) underpins EDH-mediated responses. It was recently reported that Ca2+influx through endothelial transient receptor potential vanilloid type 4 channel (TRPV4) is a prerequisite for the activation of SKCa/IKCain endothelial cells in specific beds. Here, we attempted to determine whether the impairment of EDH in hypertension is attributable to the dysfunction of TRPV4 and S/IKCa, using isolated superior mesenteric arteries of 20-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched Wistar-Kyoto (WKY) rats. In the WKY arteries, EDH-mediated responses were reduced by a combination of SKCa/IKCablockers (apamin plus TRAM-34; 1-[(2-chlorophenyl)diphenylmethl]-1H-pyrazole) and by the blockade of TRPV4 with the selective antagonist RN-1734 or HC-067047. In the SHRSP arteries, EDH-mediated hyperpolarization and relaxation were significantly impaired when compared with WKY. GSK1016790A, a selective TRPV4 activator, evoked robust hyperpolarization and relaxation in WKY arteries. In contrast, in SHRSP arteries, the GSK1016790A-evoked hyperpolarization was small and relaxation was absent. Hyperpolarization and relaxation to cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine, a selective SKCaactivator, were marginally decreased in SHRSP arteries compared with WKY arteries. The expression of endothelial TRPV4 and SKCaprotein was significantly decreased in the SHRSP mesenteric arteries compared with those of WKY, whereas function and expression of IKCawere preserved in SHRSP arteries. These findings suggest that EDH-mediated responses are impaired in superior mesenteric arteries of SHRSP because of a reduction in both TRPV4 and SKCainput to EDH.
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takunori
authors.initials: T
authors.lastname: Seki
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. kengotou@intmed2.med.kyushu-u.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Kiyohara
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Kansui
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Murakami
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Haga
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohtsubo
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Matsumura
authors.affiliation: From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Takanari
authors.initials: T
authors.lastname: Kitazono
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008638:Mesenteric Arteries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis / Q000235:genetics*; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics*; D014664:Vasodilation
chemical_list: C496899:Kcnn2 protein, rat; D051640:Small-Conductance Calcium-Activated Potassium Channels; D050916:TRPV Cation Channels; C486577:Trpv4 protein, rat; D004247:DNA
keywords: Ca2+-activated K+ channels; TRP cation channels; endothelium; endothelium-dependent hyperpolarization factor; hypertension; mesenteric artery, superior