Further evidence for endothelin as an important mediator of pancreatic and intestinal ischemia in severe acute pancreatitis

Introduction: Severe acute pancreatitis is occasionally associated with pancreatic and intestinal necrosis. Mesenteric vasoconstriction is one of the most probable types of pathogenesis of these complications. Aim: To investigate the involvement of endothelin-1 (ET-1), a potent vasoconstrictor. Methodology and Results: Plasma ET-1 concentrations were extremely high in patients with pancreatic and/or diffuse intestinal necrosis. ET-1 mRNA was demonstrated in the rat pancreas, and the production of ET-1 protein by human umbilical vein endothelial cells was enhanced by tumor necrosis factor-a, thrombin, and protease-activated receptor-2-activating peptide. Administration of ET-1 in vivo induced mesenteric arterial spasm and decreased pancreatic and intestinal blood flow. Conclusion: These results suggest the following: ET-1 is produced in and around the pancreas, mainly by endothelial cells, in severe acute pancreatitis; in the inflammatory setting, cytokines, activated thrombin and trypsin, may stimulate ET-1 production in a paracrine fashion; produced ET-1 may exaggerate the splanchnic microcirculation; and progressive ischemia may lead to necrosis of the pancreas and intestine. Key Words: Acute pancreatitis-Endothelin-1-Vascular spasm-Nonocclusive mesenteric ischemia-Pancreatic necrosis-Intestinal necrosis.