Endothelin 1 induces leukocyte adhesion in submucosal venules of the rat small intestine

Background & Aims: The release of endothelin 1 (ET-1) and the activation of leukocytes are Involved in the pathophysiology of gastrointestinal ischemia/reperfusion injuries. The aim of this study was to define the in vivo relation between ET-1 and endothelial cell-leukocyte interactions. Methods: Anesthetized rats were studied to characterize the microvascular effects of increasing doses of local and systemic infusions of ET-1 in all layers of an ileal segment. Leukocyte-endothelial interactions were monitored with intravital fluorescence videomicroscopy. The ETA receptor-selective antagonist BQ 610, the novel ETA-receptor antagonist ETR-Pl/fl peptide, and the ETA-receptor antagonist IRL 1038 were used to investigate the roles of receptor subtypes. Results: The functional capillary density of the mucosa was significantly decreased by 3 nmol/kg intravenous ET-1. After 30 minutes the rolling fraction of leukocytes reached 90% in the postcapillary venules, and the number of adherent leukocytes was significantly increased after 90 minutes. ETR-Pl/fl peptide inhibited leukocyte rolling by 88%, BQ 610 by 73%, and IRL 1038 by 30%. Both ETA-receptor antagonists prevented ET-l-induced firm adhesion. The ETA-receptor antagonists but not IRL 1038 inhibited the ET-1-induced lymphatic muscle and mucosal capillary perfusion failure. Conclusions: ET-1 induces leukocyte rolling and adherence through a predominantly ETA receptor-mediated mechanism in the submucosal venules of the intestinal microcirculation.