Inhibition of kinin action and kinin generation compared to dexamethasone pretreatment with respect to vascular effects and pancreatic enzymes in experimental acute pancreatitis

It was determined earlier that inhibition of the action of endogenous kinin s by the bradykinin B-2 antagonist, icatibant (Hoe-140; D-Arg-[Hyp(3), Thi( 5), D-Tic(7), Oic(8)]-bradykinin), prevents pancreatic oedema formation dur ing caerulein-induced acute pancreatitis, and simultaneously improves the e gress of activated pancreatic enzymes from the pancreas. We have now invest igated whether inhibition of increases in vascular permeability by another approach, i.e., pretreatment with dexamethasone, would have comparable effe cts. In addition, preliminary data are presented on the effects of the sele ctive low molecular weight inhibitor of tis sue kallikrein, H-(4-Cl)-D-Phe- 1Nal-(3-aminopropyl)-guanidine (CH-2856). Icatibant abolished plasma extrav asation into the pancreatic tissue and prevented the development of hypovol aemia. Caerulein-induced increases of amylase activity in the pancreas were significantly reduced by icatibant, while amylase activity in blood was au gmented. Inhibition of kinin generation by CH-2856 had similar effects, as oedema formation was inhibited and enzyme activities were reduced in the pa ncreas and augmented in the blood serum. Dexamethasone completely abolished oedema formation, but only partially inhibited the development of hypovola emia and haemoconcentration. Amylase activities in the pancreas and in bloo d remained completely unaffected by dexamethasone. The results suggest that retention of activated enzymes in the pancreatic tissue during acute pancr eatitis involves a Bz receptor-mediated, but glucocorticoid-insensitive mec hanism. (C) 1999 Elsevier Science B.V. All rights reserved.