In order to investigate the mechanism of
kinin release leading to vascular symptoms in acute interstitial-oedematous
pancreatitis, the novel, selective inhibitors of
tissue kallikrein, (2S,2'R)-2-(2'-amino-3'-(4'-chlorophenyl)propanoylamino)-N-(3-guanidinopropyl)-3-(1-naphthyl)propanoamide (FE999024, CH-2856), and of
plasma kallikrein, (2'S,2"R)-4-(2'-(2"(carboxymethylamino)-3"-cyclohexyl-propanoylamino)-3'-phenyl-propanoylamino)
piperidine-1-carboxamidin (FE999026, CH-4215), were used in experimental
caerulein-induced
pancreatitis in rats. Oedema formation and
plasma protein extravasation during the 2 h infusion of
caerulein were inhibited in a dose-dependent manner by i.p. pretreatment with
FE999024 (7-60 micromol kg(-1)) while FE999026 had no effect at the same doses. Haemoconcentration and hypovolaemia associated with the pancreatic oedema formation during
pancreatitis were significantly attenuated by
FE999024 at a dose of 20 micro mol kg(-1). The reduction in circulating plasma volume was not affected by FE999026. Accumulation of
amylase and
lipase in the pancreas was dose-dependently reduced by
FE999024 while
enzyme activities in the blood serum were increased by
FE999024 at 60 micromol kg(-1) indicating improved
enzyme removal from the tissue.
Enzyme activities in the tissue and in the blood remained unaffected by FE999026.
FE999024 (20 micromol kg(-1)) largely inhibited increased
tissue kallikrein-like activity in the pancreas during
acute pancreatitis and also strongly attenuated influx of
plasma kallikrein into the tissue. FE999026 (20 micromol kg(-1)) significantly inhibited
plasma kallikrein-like activity in the pancreas but had no effect on
tissue kallikrein-like activity. In conclusion, vascular
kinin-mediated symptoms observed during oedematous
pancreatitis in the rat are caused by the action of
tissue kallikrein in the pancreas whereas an involvement of
plasma kallikrein seems to be unlikely.