Endothelin Receptor Blockade Improves Fluid Sequestration, Pancreatic Capillary Blood Flow, and Survival in Severe Experimental Pancreatitis

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Abstract

Objective

To evaluate the effect of a new endothelin receptor antagonist (ET-RA) on the course of severe experimental pancreatitis.

Background

Endothelin-1 has been shown to reduce regional blood flow in various organs, including the pancreas, and to aggravate cerulein-induced mild pancreatitis.

Methods

Acute necrotizing pancreatitis (ANP) was induced in rats by standardized intraductal bile acid infusion and cerulein hyperstimulation. Serum trypsinogen activation peptides (TAP) were measured to verify comparable disease severity. Starting 6 hours after the onset of ANP, animals randomly received either saline or the new ET-RA LU-135252. Monitoring included cardiorespiratory parameters, urine output, hematocrit, and TAP levels. After 24 hours, animals were relaparotomized to determine pancreatic capillary blood flow and to assess the amount of free intraabdominal fluid and acinar cell necrosis. Survival was determined in a second set of experiments on 24 animals observed for 48 hours after pancreatitis induction and treatment with either normal saline or ET-RA.

Results

Comparable TAP increases confirmed equally severe ANP in both groups before treatment. Treatment with ET-RA significantly reduced the mortality rate, from 50% in untreated animals to 8%. Improved survival was associated with significantly decreased hematocrit, improved urinary output, decreased ascites, and increased pancreatic capillary blood flow. There were no significant differences in plasma TAP and acinar cell injury in the surviving animals of the two treatment groups.

Conclusion

Therapy with the new ET-RA reduces the early mortality rate in experimental ANP, probably by reducing fluid sequestration and improving microcirculation.

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