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Endothelin-1 induces mucosal mast cell degranulation in the rat small intestine

机译：内皮素-1诱导大鼠小肠黏膜肥大细胞脱粒

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The enhanced production of endothelial cell-derived vasoactive mediators and the activation of mast cells (MCs) have been implicated in the pathogenesis of mucosal damage during ischemia and reperfusion injuries. The first objective of our study was to define the in vivo relation between endothelin-l (ET-1) and the MC system. Secondly, we determined whether pretreatment with ET receptor antagonists would attenuate MC responses to exogenous ET-1. In the first series of experiments, increasing doses of ET-1 (0.1, 1 and 3 nmol/kg i.v.) were administered to anesthetized rats. In the second series, the animals were pretreated with equimolar doses of the ET-A receptor antagonist BQ-610 or ETR-P1/fl peptide, and the ET-B receptor antagonist IRL-1038. Intestinal perfusion changes and macrohemodynamics were recorded, and the proportion of degranulated MCs was determined in ileal biopsies. The average mucosal thickness was recorded with an image analysis system. ET-I induced dose-dependent alterations in the hemodynamic and morphological parameters and caused pronounced mucosal injury, with a significant reduction in villus height. The ratio of degranulated MCs was similar in all ET-treated groups (77%, 82% and 86%) to that observed in animals subjected to 15-min ischemia and 60-min reperfusion (85% degranulation). Pretreatment with BQ-610 and ETR-P1/fl peptide attenuated the ET-1 induced alterations in the hemodynamic parameters and decreased structural injury to the mucosa. ET-induced MC degranulation was significantly inhibited by the ET-A receptor antagonists, but not by IRL-1038. These results indicate that elevated levels of circulating ET-1 might induce intestinal mucosal tissue injury and MC degranulation via activation of ET-A receptors, and raise the possibility that ET-A receptor antagonist administration could exert a potentially beneficial effect through a mechanism other than the blockade of vasoconstriction in pathologies associated with an increased ET-1 release. (C) 2000 Elsevier Science Inc. All rights reserved. [References: 28]
机译：内皮细胞衍生的血管活性介导物的生产增加和肥大细胞（MCs）的激活与缺血和再灌注损伤期间粘膜损伤的发病机制有关。我们研究的第一个目标是确定内皮素-1（ET-1）和MC系统之间的体内关系。其次，我们确定用ET受体拮抗剂预处理是否会减弱MC对外源ET-1的反应。在第一个系列的实验中，将麻醉剂量的ET-1（0.1、1和3 nmol / kg静脉内）增加剂量。在第二系列中，用等摩尔剂量的ET-A受体拮抗剂BQ-610或ETR-P1 / f1肽和ET-B受体拮抗剂IRL-1038进行预处理。记录肠道灌注变化和宏观血流动力学，并在回肠活检中确定脱颗粒MC的比例。用图像分析系统记录平均粘膜厚度。 ET-1引起血液动力学和形态学参数的剂量依赖性变化，并引起明显的粘膜损伤，绒毛高度显着降低。在所有经ET处理的组中，脱颗粒的MC的比例（77％，82％和86％）与经历15分钟局部缺血和60分钟再灌注（85％脱颗粒）的动物相似。用BQ-610和ETR-P1 / fl肽进行预处理可减弱ET-1诱导的血液动力学参数变化，并减少对粘膜的结构性损伤。 ET-A受体拮抗剂可显着抑制ET诱导的MC脱粒，但IRL-1038则不会。这些结果表明循环水平的ET-1水平升高可能通过激活ET-A受体而引起肠粘膜组织损伤和MC脱粒，并增加了ET-A受体拮抗剂给药可能通过除以下以外的其他机制发挥潜在有益作用的可能性。与增加的ET-1释放相关的病理中的血管收缩的阻滞。 （C）2000 Elsevier Science Inc.保留所有权利。 [参考：28]

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