Departament de Farmacologia, Terapèutica i Toxicologia, Facultat de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Br J Pharmacol. 2012 Feb;165(4):937-50. doi: 10.1111/j.1476-5381.2011.01617.x.
Endothelin-1 (ET-1) plays an important role in the maintenance of vascular tone. We aimed to evaluate the influence of superior mesenteric artery (SMA) ischaemia-reperfusion (I/R) on mesenteric resistance artery vasomotor function and the mechanism involved in the changes in vascular responses to ET-1.
SMA from male Sprague-Dawley rats was occluded (90 min) and following reperfusion (24h), mesenteric resistance arteries were dissected. Vascular reactivity was studied using wire myography. Protein and mRNA expression, superoxide anion (O(2) (•-) ) production and ET-1 plasma concentration were evaluated by immunofluorescence, real-time quantitative PCR, ethidium fluorescence and elisa, respectively.
I/R increased ET-1 plasma concentration, ET-1-mediated vasoconstriction and ET(B) mRNA expression, and down-regulated ET(A) mRNA expression. Immunofluorescence confirmed mRNA results and revealed an increase in ET(B) receptors in the mesenteric resistance artery media layer after I/R. Therefore, the ET(B) receptor agonist sarafotoxin-6 induced a contraction that was inhibited by the ET(B) receptor antagonist BQ788 only in vessels, with and without endothelium, from I/R rats. Furthermore, BQ788 potentiated ET-1 vasoconstriction only in sham rats. Endothelium removal in rings from I/R rats unmasked the inhibition of ET-1 vasoconstriction by BQ788. Endothelium removal, N(ω) -nitro-L-arginine methyl ester and superoxide dismutase abolished the differences in ET-1 vasoconstriction between sham and I/R rats. We also found that I/R down-regulates endothelial NOS mRNA expression and concomitantly enhanced O(2) (•-) production by increasing NADPH oxidase 1 (NOX-1) and p(47phox) mRNA.
Mesenteric I/R potentiated the ET-1-mediated vasoconstriction by a mechanism that involves up-regulation of muscular ET(B) receptors and decrease in NO bioavailability.
内皮素-1（ET-1）在维持血管张力方面发挥着重要作用。本研究旨在评估肠系膜上动脉（SMA）缺血再灌注（I/R）对肠系膜阻力动脉血管舒缩功能的影响，以及血管对 ET-1反应变化的机制。
雄性 Sprague-Dawley 大鼠的 SMA 被阻断（90min），再灌注 24h 后，分离肠系膜阻力动脉。采用有线肌描记术研究血管反应性。通过免疫荧光、实时定量 PCR、荧光黄和 ELISA 分别评估蛋白和 mRNA 表达、超氧阴离子（O2（•-））产生和 ET-1 血浆浓度。
I/R 增加了 ET-1 血浆浓度、ET-1 介导的血管收缩和 ET（B）mRNA 表达，并下调了 ET（A）mRNA 表达。免疫荧光证实了 mRNA 的结果，并显示 I/R 后肠系膜阻力动脉中层 ET（B）受体增加。因此，ET（B）受体激动剂 sarafotoxin-6 引起的收缩仅在 I/R 大鼠有和无内皮的血管中被 ET（B）受体拮抗剂 BQ788 抑制。此外，BQ788 仅在假手术大鼠中增强了 ET-1 血管收缩。在 I/R 大鼠的血管环中去除内皮，揭示了 BQ788 对 ET-1 血管收缩的抑制作用。去除内皮、N（ω）-硝基-L-精氨酸甲酯和超氧化物歧化酶消除了 sham 和 I/R 大鼠之间 ET-1 血管收缩的差异。我们还发现，I/R 下调内皮型一氧化氮合酶 mRNA 表达，同时通过增加 NADPH 氧化酶 1（NOX-1）和 p（47phox）mRNA 增加 O2（•-）的产生，从而降低了 NO 的生物利用度。
肠系膜 I/R 通过上调肌肉 ET（B）受体和降低 NO 生物利用度的机制增强了 ET-1 介导的血管收缩。
