Peixoto-Neves Dieniffer, Wang Qian, Leal-Cardoso Jose H, Rossoni Luciana V, Jaggar Jonathan H
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.
Br J Pharmacol. 2015 Jul;172(14):3484-94. doi: 10.1111/bph.13156. Epub 2015 May 19.
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.
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.
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.
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.
丁香酚是一种存在于某些食用植物中的香草酸类分子，它部分通过内皮依赖性过程使血管舒张；然而，其中涉及的机制尚不清楚。在此，我们研究了丁香酚调节大鼠肠系膜动脉收缩性和全身血压的内皮细胞介导机制。
使用线肌动描记法测量大鼠肠系膜动脉（直径200 - 300μm）的等长张力；使用膜片钳电生理学技术记录内皮细胞中的非选择性阳离子电流（ICat）。在麻醉大鼠中测定平均动脉压（MAP）和心率（HR）。
丁香酚以浓度依赖性方式使内皮完整的动脉舒张，且这种作用因内皮剥脱而减弱。L - NAME（一种一氧化氮合酶抑制剂）、TRAM - 34和蜂毒明肽（分别为中、小电导钙激活钾通道的选择性阻滞剂）以及HC - 067047（一种TRPV4通道抑制剂）可降低丁香酚诱导的内皮完整动脉的舒张作用，但环氧化酶抑制剂吲哚美辛则无此作用。丁香酚激活肠系膜动脉内皮细胞中对HC - 067047敏感的ICat。短干扰RNA（siRNA）介导的TRPV4基因敲低消除了丁香酚诱导的ICat激活。静脉注射丁香酚可使麻醉大鼠的MAP和HR立即出现短暂降低，随后出现持续时间较长的低血压。这种持续性低血压被HC - 067047阻断。
丁香酚激活肠系膜动脉内皮细胞中的TRPV4通道，导致血管舒张，并在体内降低全身血压。丁香酚作为一种抗高血压药物可能具有治疗作用，并且是开发第二代降低血压的TRPV4通道激活剂的可行分子候选物。
