[Endothelin receptor block in acute pancreatitis--improvement of microcirculation and decrease of capillary permeability also distant from the pancreas].

Abstract

We have previously demonstrated that therapy with a new specific endothelin-1 receptor antagonist (ET-RA) significantly reduced mortality in acute necrotizing pancreatitis (ANP) in the rat. Improved survival was not associated with decreased intrapancreatic trypsinogen activation or parenchymal necrosis but with reduced fluid sequestation into the third space suggesting that ET-RA counteracts systemic rather than local sequelae of severe pancreatitis. The present study further tests this hypothesis by evaluating the effect of the specific ET-1 antagonist LU-135252 on capillary blood flow, capillary density, and capillary permeability not only in the pancreas but also in the colon, and monitoring fluid losses and renal and respiratory function. The experiments demonstrate that therapy with the specific ET-RA started 6 hours after disease onset stabilizes increased capillary permeability in ANP not only in the pancreas but also in the colon. This is associated with reduced ascites and improved renal and respiratory function. Furthermore, ET-RA enhances decreased capillary blood flow and capillary density in the pancreas and colon. The present results are consistent with our previous observation that ET-RA improves outcome in ANP by counteracting systemic microcirculatory disorders (particularly capillary leakage) which are believed to contribute to organ failure in early pancreatitis in this model as well as in severe human pancreatitis.