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

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

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    14 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)345-359
    Number of pages15
    JournalJournal of Hypertension
    Volume25
    Issue number2
    DOIs
    Publication statusPublished - Feb 2007

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