title: Eugenol dilates mesenteric arteries and reduces systemic BP by activating endothelial cell TRPV4 channels.
abstract: OBJECTIVE
  Eugenol, a vanilloid molecule found in some dietary plants, relaxes vasculature in part via an endothelium-dependent process; however, the mechanisms involved are unclear. Here, we investigated the endothelial cell-mediated mechanism by which eugenol modulates rat mesenteric artery contractility and systemic BP.
  
  
  METHODS
  The isometric tension of rat mesenteric arteries (size 200-300 μm) was measured using wire myography; non-selective cation currents (ICat ) were recorded in endothelial cells using patch clamp electrophysiology. Mean arterial pressure (MAP) and heart rate (HR) were determined in anaesthetized rats.
  
  
  RESULTS
  Eugenol relaxed endothelium-intact arteries in a concentration-dependent manner and this effect was attenuated by endothelium denudation. L-NAME, a NOS inhibitor, a combination of TRAM-34 and apamin, selective blockers of intermediate and small conductance Ca(2+) -activated K(+) channels, respectively, and HC-067047, a TRPV4 channel inhibitor, but not indomethacin, a COX inhibitor, reduced eugenol-induced relaxation in endothelium-intact arteries. Eugenol activated HC-067047-sensitive ICat in mesenteric artery endothelial cells. Short interfering RNA (siRNA)-mediated TRPV4 knockdown abolished eugenol-induced ICat activation. An i.v. injection of eugenol caused an immediate, transient reduction in both MAP and HR, which was followed by prolonged, sustained hypotension in anaesthetized rats. This sustained hypotension was blocked by HC-067047.
  
  
  CONCLUSIONS
  Eugenol activates TRPV4 channels in mesenteric artery endothelial cells, leading to vasorelaxation, and reduces systemic BP in vivo. Eugenol may be therapeutically useful as an antihypertensive agent and is a viable molecular candidate from which to develop second-generation TRPV4 channel activators that reduce BP.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.|Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Dieniffer
authors.initials: D
authors.lastname: Peixoto-Neves
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Laboratório de Eletrofisiologia, Instituto Superior de Ciências Biomédicas, Universidade Estadual do Ceará, Fortaleza, Ceará, Brazil.
authors.forename: Jose H
authors.initials: JH
authors.lastname: Leal-Cardoso
authors.affiliation: Laboratório de Fisiologia Vascular, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Luciana V
authors.initials: LV
authors.lastname: Rossoni
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Jaggar
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005054:Eugenol / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D005054:Eugenol
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