Background and 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 ET(A) receptor-selective antagonist BQ 610, the novel ET(A)-receptor antagonist ETR-Pl/fl peptide, and the ET(B)-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 ET(A)- receptor antagonists prevented ET-1-induced firm adhesion. The ET(A)-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 ET(A) receptor-mediated mechanism in the submucosal venules of the intestinal microcirculation.
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