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Involvement of tissue kallikrein but not plasma kallikrein in the development of symptoms mediated by endogenous kinins in acute pancreatitis in rats
Author(s) -
Griesbacher Thomas,
Rainer Irmgard,
Tiran Beate,
Evans D Michael
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704910
Subject(s) - kallikrein , endogeny , acute pancreatitis , pancreatitis , bradykinin , medicine , endocrinology , chemistry , biochemistry , enzyme , receptor
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, (2 S ,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 μmol 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 μmol 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 μmol kg −1 indicating improved enzyme removal from the tissue. Enzyme activities in the tissue and in the blood remained unaffected by FE999026. FE999024 (20 μmol 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 μmol 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.British Journal of Pharmacology (2002) 137 , 692–700. doi: 10.1038/sj.bjp.0704910