The effect of endothelin-1, endothelin-2 and endothelin-3 in early cerulein-induced acute pancreatitis in rats
Dlugosz JW, Nowak K, Andrzejewska A, Wroblewski E, Dabrowski A

Purpose: To assess the effect of endothelins: ET-1, ET-2 and ET-3 on trypsinogen activation, lipase activity and histological changes in the pancreas in early (4 hrs) cerulein acute pancreatitis (AP) in rats.
Material and methods: In 45 Wistar rats with cerulein induced AP (2x40 g/kg i.p. at 1 hour interval, the effect of endothelins at the dose 2x0.5 or 2x1.0 nmol/kg i.p. was assessed vs untreated AP; 6 healthy rats were control (C). Free active trypsin (FAT), total potential trypsin after activation with enterokinase (TPT), lipase in 12000 xg supernatants of pancreatic homogenates and the plasma -amylase were assayed. The %FAT/TPT was an index of trypsinogen activation. 
Results: %FAT/TPT increased from 3.0±0.6 in C to 16.2±3.1 in AP (p<0.01). ET-1 decreased this index to 4.8±1.1 after higher dose (p<0.01); the effect of lower dose was insignificant. Attenuating effect of ET-2 was significant: 7.3±1.7 after higher dose (p<0.05) and 6.1±0.9 after lower dose (p<0.01). ET-3 diminished this index to 4.5±1.5 (p<0.01) and to 6.3±2.2 (p<0.05) respectively. Lipase activity in supernatant increased from 4.1±0.6 in C to 6.3±0.7 U/mg protein in untreated AP (p<0.05) and plasma -amylase from 7.0±0.6 in C to 25.9±4.3 U/ml in AP (p<0.001), without essential changes in treated groups vs untreated AP. Higher doses of endothelins decreased inflammatory cell infiltration score in AP.
Conclusions: The exogenous endothelins, especially ET-2 and ET-3 and to lesser extent ET-1 exerted some protective effect in early, edematous acute pancreatitis by the attenuation of trypsinogen activation and inflammatory cell infiltration in the pancreas.

Key words:   cerulein acute pancreatitis, endothelins, trypsin, lipase, -amylase, histology.