Depolarization evoked by acetylcholine in mesenteric arteries of hypertensive rats attenuates endothelium-dependent hyperpolarizing factor

Kenichi Goto, Frank R. Edwards, Caryl E. Hill

研究成果: Contribution to journalArticle査読

11 被引用数 (Scopus)

抄録

OBJECTIVE: During blockade of endothelium-dependent hyperpolarizing factor (EDHF), acetylcholine evoked larger and faster depolarization in mesenteric arteries of spontaneously hypertensive rats (SHR) than normotensive Wistar-Kyoto (WKY) rats. We studied the mechanism underlying this response and its role in the attenuation of EDHF. METHODS: Electrophysiology, computational modelling and myography were used to study changes in membrane potential and effects on contractility. RESULTS: The large acetylcholine-evoked depolarization in SHR was accompanied by contraction, but this was not seen in WKY rats. The depolarization depended on release of intracellular Ca but was unaffected by nonselective cation channel inhibitors, gadolinium, lanthanum or amiloride. The depolarization was significantly reduced by the Ca-dependent Cl channel inhibitors, niflumic acid or flufenamic acid, or alterations in Cl gradients using bumetanide (Na/K/Cl transporter inhibitor) or external Cl replacement with isethionate. These drugs altered the time course of EDHF-evoked hyperpolarizations in SHR, making them indistinguishable from those in WKY rats. EDHF-induced relaxation was less sensitive to acetylcholine in SHR than in WKY rats, but this difference was eliminated following artery pretreatment with bumetanide. Computational modelling in which the SHR fast depolarizing response was selectively modulated mimicked physiologically acquired results obtained in SHR and WKY rats during Cl-channel blockade. CONCLUSIONS: Acetylcholine evokes a fast depolarization in SHR but not in WKY rats, mediated by the opening of Ca-dependent Cl channels. The depolarization is responsible for a constriction that reduces EDHF-mediated relaxation. Data suggest that Ca-dependent Cl channels may provide a novel therapeutic target for improvement of endothelial dysfunction during hypertension.

本文言語英語
ページ(範囲)345-359
ページ数15
ジャーナルJournal of hypertension
25
2
DOI
出版ステータス出版済み - 2 2007

All Science Journal Classification (ASJC) codes

  • 内科学
  • 生理学
  • 循環器および心血管医学

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