Szalay L, Kaszaki J, Nagy S, Boros M
Institute of Experimental Surgery, Szent-Györgyi Albert Medical University, Szeged, Hungary.
Life Sci. 2000 Sep 8;67(16):1947-58. doi: 10.1016/s0024-3205(00)00783-9.
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-1 (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-1 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.
内皮细胞衍生的血管活性介质的产生增加以及肥大细胞（MCs）的激活与缺血再灌注损伤期间的粘膜损伤发病机制有关。我们研究的首要目标是确定内皮素-1（ET-1）与MC系统之间的体内关系。其次，我们确定ET受体拮抗剂预处理是否会减弱MC对外源性ET-1的反应。在第一系列实验中，向麻醉的大鼠静脉注射递增剂量的ET-1（0.1、1和3 nmol/kg）。在第二系列实验中，动物用等摩尔剂量的ET-A受体拮抗剂BQ-610或ETR-P1/fl肽以及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MCs的比例。用图像分析系统记录平均粘膜厚度。ET-1引起血流动力学和形态学参数的剂量依赖性改变，并导致明显的粘膜损伤，绒毛高度显著降低。所有ET治疗组中脱颗粒MCs的比例（77%、82%和86%）与经历15分钟缺血和60分钟再灌注的动物中观察到的比例（85%脱颗粒）相似。用BQ-610和ETR-P1/fl肽预处理减弱了ET-1诱导的血流动力学参数改变，并减少了对粘膜的结构损伤。ET-A受体拮抗剂显著抑制ET诱导的MC脱颗粒，但IRL-1038没有。这些结果表明，循环中ET-1水平升高可能通过激活ET-A受体诱导肠粘膜组织损伤和MC脱颗粒，并增加了在与ET-1释放增加相关的病理状态下，给予ET-A受体拮抗剂可能通过除阻断血管收缩以外的机制发挥潜在有益作用的可能性。
