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

The enhanced production of endothelial cell-derived vasoactive mediators an d the activation of mast cells (MCs) have been implicated in the pathogenes is of mucosal damage during ischemia and reperfusion injuries. The first ob jective of our study was to define the in vivo relation between endothelin- l (ET-1) and the MC system. Secondly, we determined whether pretreatment wi th 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 anta gonist BQ-610 or ETR-P1/fl peptide, and the ET-B receptor antagonist IRL-10 38. Intestinal perfusion changes and macrohemodynamics were recorded, and t he proportion of degranulated MCs was determined in ileal biopsies. The ave rage mucosal thickness was recorded with an image analysis system. ET-I ind uced dose-dependent alterations in the hemodynamic and morphological parame ters 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 i schemia and 60-min reperfusion (85% degranulation). Pretreatment with BQ-61 0 and ETR-P1/fl peptide attenuated the ET-1 induced alterations in the hemo dynamic parameters and decreased structural injury to the mucosa. ET-induce d MC degranulation was significantly inhibited by the ET-A receptor antagon ists, but not by IRL-1038. These results indicate that elevated levels of c irculating ET-1 might induce intestinal mucosal tissue injury and MC degran ulation 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 p athologies associated with an increased ET-1 release. (C) 2000 Elsevier Sci ence Inc. All rights reserved.