Gadano A C, Sogni P, Yang S, Cailmail S, Moreau R, Nepveux P, Couturier D, Lebrec D
INSERM U-24, Hopital Beaujon, Clichy, France.
J Hepatol. 1997 Mar;26(3):678-86. doi: 10.1016/s0168-8278(97)80435-7.
BACKGROUND/AIMS: Increased nitric oxide production has been implicated in impaired vascular responsiveness to vasoconstrictors in portal hypertension. However, there is no firm evidence concerning the involved nitric oxide synthase isoform. The present study investigated the possible contribution of one nitric oxide synthase isoform, the endothelial constitutive Ca2+-calmodulin dependent, in the overproduction of nitric oxide in portal hypertension.
Vascular responses to norepinephrine and acetylcholine were evaluated in isolated thoracic aortic rings from normal and portal vein stenosed rats.
An impaired concentration-dependent contraction to norepinephrine was observed in intact rings from portal hypertensive rats compared to controls. The hyporeactivity to norepinephrine was reversed after endothelium denudation, the inhibition of nitric oxide synthase with L-NOARG or the inhibition of calmodulin with W-7, but not after pre-incubation with indomethacin. Stimulation of intact rings with norepinephrine after the inhibition of calmodulin with calmidazolium was followed by a decreased vascular response in vessels from normal rats but not in those from portal hypertensive rats. Stimulation of intact rings with norepinephrine in a Ca2+-free medium was followed by a decreased vascular response in vessels from both portal hypertensive and normal rats. No difference in vasoconstrictive responses was observed between the two groups after calmidazolium or in a Ca2+-free medium. Relaxation induced by acetylcholine in norepinephrine-precontracted rings was more marked in rings from portal hypertensive rats than in controls. No differences in the vasodilator responses were observed after relaxations had been inhibited by the removal of the endothelium, pre-incubation with L-NOARG, indomethacin, W-7 or calmidazolium and in a Ca2+-free medium.
This study demonstrates the involvement of the endothelial constitutive Ca2+-calmodulin dependent nitric oxide synthase isoform in the overproduction of nitric oxide in portal hypertension.
背景/目的：一氧化氮生成增加与门静脉高压时血管对血管收缩剂反应性受损有关。然而，关于所涉及的一氧化氮合酶同工型尚无确凿证据。本研究探讨了一种一氧化氮合酶同工型，即内皮型组成性钙调蛋白依赖性一氧化氮合酶，在门静脉高压时一氧化氮过量生成中的可能作用。
评估正常大鼠和门静脉狭窄大鼠离体胸主动脉环对去甲肾上腺素和乙酰胆碱的血管反应。
与对照组相比，门静脉高压大鼠完整血管环对去甲肾上腺素的浓度依赖性收缩受损。去内皮、用L-NOARG抑制一氧化氮合酶或用W-7抑制钙调蛋白后，对去甲肾上腺素的低反应性得到逆转，但用吲哚美辛预孵育后未逆转。用氯米帕明抑制钙调蛋白后，正常大鼠血管对去甲肾上腺素刺激的反应性降低，而门静脉高压大鼠血管则未降低。在无钙培养基中用去甲肾上腺素刺激完整血管环后，门静脉高压大鼠和正常大鼠血管的反应性均降低。氯米帕明处理后或在无钙培养基中，两组间血管收缩反应无差异。在去甲肾上腺素预收缩的血管环中，门静脉高压大鼠血管环对乙酰胆碱诱导的舒张作用比对照组更明显。去除内皮、用L-NOARG、吲哚美辛、W-7或氯米帕明预孵育以及在无钙培养基中抑制舒张后，两组间血管舒张反应无差异。
本研究表明内皮型组成性钙调蛋白依赖性一氧化氮合酶同工型参与了门静脉高压时一氧化氮的过量生成。
