Endothelin-A receptor antagonism improves small bowel graft perfusion and structure after ischemia and reperfusion

Background. We hypothesized that endothelin-A (ET-A) receptor activation pl ays a central role in intestinal ischemia-reperfusion-induced hemodynamic c hanges and may trigger the process of mucosal barrier destruction. Our aims were to investigate and compare the effects of systemic and intragraft ET- A receptor antagonist therapy during the early revascularization phase of s mall bowel transplants. Methods, In Groups 1, 2, and 3 orthotopic small bowel autotransplants were performed in anesthetized dogs. Group 4 served as sham-operated control. Gr oup 2 was treated i.v. with the ET-A receptor antagonist ETR-p1/fl peptide at the onset of reperfusion, In Group 3, intragraft infusion of the ETR-p1/ fl peptide was applied during cold ischemia, The mucosal myeloperoxidase ac tivity and the free radical-producing capacity of the granulocytes passing the intestinal graft were determined, and the systemic hemodynamic features were recorded. The extent of the mucosal injury was determined from tissue biopsies taken after 4 hr of reperfusion, Results. Reperfusion progressively decreased the mesenteric blood flow, inc reased the mesenteric vascular resistance, and enhanced the accumulation an d free radical production capacity of the leukocytes. These changes were si gnificantly inhibited in Group 2 with systemic (i.v.) administration of the ET-A receptor antagonist. The local, intragraft treatment improved the mes enteric hemodynamic changes and decreased the accumulation but not the acti vation of the circulating leukocytes, The structural injury of the graft wa s prevented in both treated groups. Conclusions. Endothelins are involved in the hemodynamic events leading to structural injury of the intestinal graft after ischemia-reperfusion. The a ntagonism of intestinal ET-A receptors by a combination of local and system ic drug delivery offers a rational treatment modality in these conditions.