Endothelin mediates local and systemic disease sequelae in severe experimental pancreatitis

Endothelin-1 has been shown to reduce pancreatic blood flow and cause focal acinar cell necrosis similar to those seen in acute pancreatitis (AP), whe reas therapy with endothelin receptor antagonists enhanced pancreatic capil lary blood flow (PCBF) and decreased mortality rates. The current study eva luated the role of endothelin in the development of severe AP. Trypsinogen activation peptides, acinar cell necrosis, and PCBF were used as local indi cators of disease severity, fluid sequestration, cardiorespiratory and rena l parameters, and colonic capillary blood flow as systemic disease indicato rs. The following groups of animals were examined: 1)rats with mild edemato us AP and 2) severe necrotizing AP treated with and without endothelin. 3) transgenic rats overexpressing endothelin with severe AP, and 4) rats with severe AP prophylactically treated with endothelin receptor antagonists. Th e following observations were made: endothelin superimposed on mild AP caus ed hemoconcentration, a decrease in PCBF, and necrosis and ascites not seen in this model without endothelin exposure. Endothelin superimposed on seve re AP had no significant effects. After induction of severe AP, less PCBF a nd more acinar cell necrosis were observed in transgenic rats than in their normal littermates. Prophylactic endothelin receptor antagonists improved local (acinar necrosis, PCBF) and systemic parameters (ascites, urine produ ction, colonic capillary blood flow) of disease severity in animals with se vere AP. These observations underscore the role of endothelin as a mediator of disease severity in AP and suggest that endothelin receptor blockade ma y become a promising therapeutic tool in this disease.