The cumulative effect of nuclear factor-B (NF-B) inhibition and endothelins in early cerulein-induced acute pancreatitis in rats

Długosz JW, Andrzejewska A, Nowak K, Wróblewski E, Dąbrowski A

Abstract

Purpose: To assess effects of NF- B activation inhibitor (pyrrolidine dithiocarbamate – PDTC) alone or with endothelins (ET-1, ET-2, ET-3) in early course of cerulein -induced acute pancreatitis (AP) in rats.
Material and methods: After 4 h of AP in Wistar rats, treated with PDTC 10 or 40 mg/kg or with PDTC 10 mg/kg and ET-1, ET-2 or ET-3, 0.5 or 1.0 nmol/kg twice i.p. in 1 h interval, free active trypsin (FAT), total potential trypsin (TPT) and lipase in 12 000 x g supernatants of pancreatic homogenates, plasma -amylase and histological changes were assayed. %FAT/TPT was an index of trypsinogen activation.
Results: %FAT/TPT significantly increased to 12.42± 2.14%, lipase to 5.51±0.84 U/mg protein and -amylase to 28.5±5.61 U/mL in AP vs 1.96±0.31%, 1.29±0.11 U/mg and 5.80±1.38 U/ml in healthy control. Higher dose PDTC attenuated trypsinogen activation to 3.01±0.53% and -amylase to 15.3±1.38. PDTC and ET-1 attenuated %FAT/TPT to 2.55±0.18% with lower and 2.34±0.44% with higher dose. ET-3 was less effective than ET-1: 6.76±0.46% with lower dose. Lower doses of ET-1 and ET-2 with PDTC, diminished lipase activity to 2.60±0.36 and 2.94±0.33.
Conclusions: Cumulative attenuation of trypsinogen activation after lower dose of PDTC and ET-1 approximated the effect of higher dose of PDTC. Additional effect of ET-3 was weaker than ET-1, and ET-2 was ineffective in this respect. The combination of this NF-B activation inhibitor and ET-1 could be beneficial in early course of edematous AP by attenuating of trypsinogen activation. However, it should be treated with caution because of some unfavorable effects on histological scores of pancreatic injury.

Key words:	cerulein acute pancreatitis, NF-B, pyrrolidine dithiocarbamate, ET-1, ET-2, ET-3, trypsinogen, rats.