Endothelin is involved in pancreatic and intestinal ischemia during severe acute pancreatitis

Abstract Introduction : Severe acute pancreatitis is occasionally associated with pancreatic and intestinal necrosis. Vasoconstriction of the abdominal artery is one of the most probable pathogeneses of these complications. Hence, we investigated the involvement of endothelin-1 (ET-1), a potent vasoconstrictor, in the pathogenesis of acute pancreatitis. Materials and methods : (1) Plasma samples from patients with acute pancreatitis were analyzed. (2) Production of ET-1 mRNA in rat pancreas and ET-1 protein by human umbilical vein endothelial cells (HUVECs) in vitro was analyzed. (3) After the administration of ET-1, pancreatic and intestinal blood flow was analyzed in rat. Results : (1) Plasma ET-1 concentrations were extremely high in patients with pancreatic and diffuse intestinal necrosis. (2) ET-1 mRNA was demonstrated in rat pancreas after the induction of pancreatitis, and the production of ET-1 protein by HUVECs was enhanced by TNF-α, thrombin, and trypsin receptor-activating peptide. (3) Administration of ET-1 induced mesenteric arterial spasm and resultant decreased splanchnic blood flow. Conclusions : These results suggest that (1) ET-1 is produced in and around the pancreas, mainly by endothelial cells, in severe acute pancreatitis; (2) in the inflammatory setting, cytokines, thrombin, and trypsin may stimulate ET-1 production through paracrine fashion; (3) produced ET-1 may exaggerate the splanchnic microcirculation; and (4) progressive ischemia may lead to necrosis of the pancreas and intestine.