Seki Takunori, Goto Kenichi, Kiyohara Kanako, Kansui Yasuo, Murakami Noboru, Haga Yoshie, Ohtsubo Toshio, Matsumura Kiyoshi, Kitazono Takanari
From the Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Hypertension. 2017 Jan;69(1):143-153. doi: 10.1161/HYPERTENSIONAHA.116.07110. Epub 2016 Nov 21.
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 Ca-activated K channels (SK and IK) underpins EDH-mediated responses. It was recently reported that Ca influx through endothelial transient receptor potential vanilloid type 4 channel (TRPV4) is a prerequisite for the activation of SK/IK in 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/IK, 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 SK/IK blockers (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 SK activator, were marginally decreased in SHRSP arteries compared with WKY arteries. The expression of endothelial TRPV4 and SK protein was significantly decreased in the SHRSP mesenteric arteries compared with those of WKY, whereas function and expression of IK were 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 SK input to EDH.
内皮依赖性超极化（EDH）介导的反应在高血压中受损，但其潜在机制尚未确定。钙激活钾通道（SK和IK）的小电导和中电导的激活是EDH介导反应的基础。最近有报道称，通过内皮瞬时受体电位香草酸受体4型通道（TRPV4）的钙内流是特定血管床内皮细胞中SK/IK激活的先决条件。在此，我们试图通过使用20周龄易中风自发性高血压大鼠（SHRSP）和年龄匹配的Wistar-Kyoto（WKY）大鼠的离体肠系膜上动脉，来确定高血压中EDH的损害是否归因于TRPV4和S/IK的功能障碍。在WKY动脉中，SK/IK阻滞剂（蜂毒明肽加TRAM-34；1-[(2-氯苯基)二苯基甲基]-1H-吡唑）联合使用以及用选择性拮抗剂RN-1734或HC-067047阻断TRPV4，均可降低EDH介导的反应。与WKY相比，SHRSP动脉中EDH介导的超极化和舒张明显受损。选择性TRPV4激活剂GSK1016790A在WKY动脉中引起强烈的超极化和舒张。相比之下，在SHRSP动脉中，GSK1016790A引起的超极化较小且无舒张。与WKY动脉相比，选择性SK激活剂环己基-[2-(3,5-二甲基-吡唑-1-基)-6-甲基-嘧啶-4-基]-胺引起的SHRSP动脉超极化和舒张略有降低。与WKY相比，SHRSP肠系膜动脉中内皮TRPV4和SK蛋白的表达显著降低，而IK的功能和表达在SHRSP动脉中得以保留。这些发现表明，SHRSP肠系膜上动脉中EDH介导的反应受损是由于EDH的TRPV4和SK输入均减少所致。
