The endothelin-1 receptor antagonists ameliorate histology and ultrastructural alterations in the pancreas and decrease trypsinogen activation in severe taurocholate pancreatitis in rats

The role of potent vasoconstrictor endothelin-1 (ET-1) in acute pancreatitis (AP) remains controversial. The aim was to compare the effect of nonselective ET R-A/B (LU-302872) and selective ET R-A (LU-302146) antagonists on pancreatic histology, ultrastructure and trypsinogen activation in severe taurocholate AP in rats. Male Wistar rats with AP were treated with an intraperitoneous injection of 1, 5 and 10 mg/kg of body weight of each antagonist at 0, 6, 12 and 18 h after taurocholate administration. After 24 h, the samples of pancreases were taken for histological and ultrastructural examinations and for assessment of trypsinogen activation. Both antagonists, at all investigated doses, decreased the damage to the acinar cells detected in the light microscope and ultrastructurally. Trypsinogen activation increased to 29.7 +/- 3.9% in the AP untreated in comparison to the control group [12.7 +/- 1.4% (P < 0.001)]. This increase was attenuated to 13.8 +/- 2.2% in AP treated with a high dose of the nonselective antagonist and to 8.4 +/- 1.7% with low dose of selective antagonist. The obtained results indicate that ET-1 could participate in the damage to the pancreas during AP. Both antagonists of ET-1 receptors exerted a similar beneficial effect on the morphological changes of the pancreas in AP. One of the probable mechanism could be the attenuation of trypsinogen activation.