Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers
Enhanced vasoconstrictor prostanoid production by sinusoidal endothelial cells increases portal perfusion pressure in cirrhotic rat livers
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DOI：
10.1016/j.jhep.2007.03.014
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发表时间：
2007-08-01
影响因子：
25.7
通讯作者：
Garcia-Pagan, Joan Carles
中科院分区：
文献类型：
--
作者：
Gracia-Sancho, Jorge;Lavina, Barbara;Garcia-Pagan, Joan Carles
背景/目的：环氧化酶-1 （COX-1）在肝硬化大鼠肝窦内皮细胞（SEC）中过度表达，并通过增强血管收缩剂前列腺素的产生，有助于增加肝内抵抗。我们的研究旨在探讨AA生物利用度增强对肝硬化肝脏血管张力的调节作用，并确定前列腺素参与其中。方法：从对照和肝硬化大鼠肝脏中分离出SEC，分别与AA、甲氧苄胺或载体孵育。定量测定TXA(2)。此外，用载药、SC-560 （COX-1抑制剂）、fureglate （TXA2合成抑制剂）和SQ-29548 (PGH（2)/TXA(2)受体阻滞剂）预孵育的大鼠肝脏，绘制门脉灌注压（PP）对AA的反应曲线。测定对照组和肝硬化患者的cPLA2活性。结果：AA和甲氧沙明孵育可显著增加肝硬化- sec的TXA2释放，而对照组- sec则无此作用。AA使PP呈剂量依赖性增加，与TXA2释放增加有关。这些反应在肝硬化患者中明显更大。COX-1抑制和PGH(2)/TXA(2)受体阻断，而不是TXA2合成酶抑制，显著减弱了肝硬化肝的PP对AA的反应。此外，肝硬化肝脏显示cPLA2活性显著增加。结论：SEC增强了血管收缩剂前列腺素（可能是PGH2）的产生，有助于增加肝硬化肝脏的血管张力。(C) 2007年欧洲肝脏研究协会。Elsevier B.V.版权所有。
Baekground/Aims: Cyclooxygenase-1 (COX-1) is overexpressed in sinusoidal endothelial cells (SEC) of cirrhotic rat livers, and through an enhanced production of vasoconstrictor prostanoids contributes to increase intrahepatic resistance. Our study was aimed at investigating the role of enhanced AA bioavailability modulating the hepatic vascular tone of cirrhotic livers and identifying which prostanoid is involved.Methods: SEC isolated from control and cirrhotic rat livers were incubated with AA, methoxamine or vehicle. TXA(2) was quantified. In addition, portal perfusion pressure (PP) response curves to AA were performed in rat livers pre-incubated with vehicle, SC-560 (COX-1 inhibitor), Furegrelate (inhibitor of TXA2 synthesis) and SQ-29548 (PGH(2)/TXA(2) receptor blocker). cPLA2 activity was determined in control and cirrhotic livers.Results: AA and methoxamine incubation promoted a significant increase in TXA2 release by Cirrhotic-SEC, but not in Control-SEC. AA produced a dose-dependent increase in the PP, associated with increased TXA2 release. These responses were significantly greater in cirrhotic livers. COX-1 inhibition and PGH(2)/TXA(2) receptor blockade, but not TXA2 synthase inhibition, markedly attenuated the PP response to AA of cirrhotic livers. Additionally, cirrhotic livers exhibited significantly increased cPLA2 activity.Conclusions:An enhanced production of vasoconstrictor prostanoids, probably PGH2, by SEC contributes to increase vascular tone of cirrhotic livers. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.