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Here, we investigated the endothelial cell\u2010mediated mechanism by which eugenol modulates rat mesenteric artery contractility and systemic BP.<\/jats:p><\/jats:sec>Experimental Approach<\/jats:title>The isometric tension of rat mesenteric arteries (size 200\u2013300\u2009\u03bc<\/jats:styled-content>m) was measured using wire myography; non\u2010selective cation currents (I<\/jats:styled-content>Cat<\/jats:sub>) were recorded in endothelial cells using patch clamp electrophysiology. Mean arterial pressure (MAP<\/jats:styled-content>) and heart rate (HR<\/jats:styled-content>) were determined in anaesthetized rats.<\/jats:p><\/jats:sec>Key Results<\/jats:title>Eugenol relaxed endothelium\u2010intact arteries in a concentration\u2010dependent manner and this effect was attenuated by endothelium denudation. L<\/jats:styled-content>\u2010NAME<\/jats:styled-content>, a NOS<\/jats:styled-content> inhibitor, a combination of TRAM<\/jats:styled-content>\u201034 and apamin, selective blockers of intermediate and small conductance Ca2+<\/jats:sup><\/jats:roman><\/jats:styled-content>\u2010activated K<\/jats:styled-content>+<\/jats:sup> channels, respectively, and HC<\/jats:styled-content>\u2010067047, a TRPV<\/jats:styled-content>4 channel inhibitor, but not indomethacin, a COX<\/jats:styled-content> inhibitor, reduced eugenol\u2010induced relaxation in endothelium\u2010intact arteries. Eugenol activated HC<\/jats:styled-content>\u2010067047\u2010sensitive ICat<\/jats:sub><\/jats:styled-content> in mesenteric artery endothelial cells. Short interfering RNA<\/jats:styled-content> (siRNA<\/jats:styled-content>)\u2010mediated TRPV<\/jats:styled-content>4 knockdown abolished eugenol\u2010induced ICat<\/jats:sub><\/jats:styled-content> activation. An i.v. injection of eugenol caused an immediate, transient reduction in both MAP<\/jats:styled-content> and HR<\/jats:styled-content>, which was followed by prolonged, sustained hypotension in anaesthetized rats. This sustained hypotension was blocked by HC<\/jats:styled-content>\u2010067047.<\/jats:p><\/jats:sec>Conclusions and Implications<\/jats:title>Eugenol activates TRPV<\/jats:styled-content>4 channels in mesenteric artery endothelial cells, leading to vasorelaxation, and reduces systemic BP<\/jats:styled-content>\u2005in vivo<\/jats:italic>. Eugenol may be therapeutically useful as an antihypertensive agent and is a viable molecular candidate from which to develop second\u2010generation TRPV<\/jats:styled-content>4 channel activators that reduce BP<\/jats:styled-content>.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13156","type":"journal-article","created":{"date-parts":[[2015,4,2]],"date-time":"2015-04-02T21:46:17Z","timestamp":1428011177000},"page":"3484-3494","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV<\/scp>4 channels"],"prefix":"10.1111","volume":"172","author":[{"given":"Dieniffer","family":"Peixoto\u2010Neves","sequence":"first","affiliation":[{"name":"Department of Physiology University of Tennessee Health Science Center Memphis TN USA"},{"name":"Laborat\u00f3rio de Eletrofisiologia, Instituto Superior de Ci\u00eancias Biom\u00e9dicas Universidade Estadual do Cear\u00e1 Fortaleza Cear\u00e1 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Physiology University of Tennessee Health Science Center Memphis TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose H","family":"Leal\u2010Cardoso","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Eletrofisiologia, Instituto Superior de Ci\u00eancias Biom\u00e9dicas Universidade Estadual do Cear\u00e1 Fortaleza Cear\u00e1 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luciana V","family":"Rossoni","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Fisiologia Vascular, Instituto de Ci\u00eancias Biom\u00e9dicas Universidade de S\u00e3o Paulo S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan 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