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 kinins by the bradykinin B2 antagonist, icatibant (Hoe-140; D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin), prevents pancreatic oedema formation during caerulein-induced acute pancreatitis, and simultaneously improves the egress of activated pancreatic enzymes from the pancreas. We have now investigated whether inhibition of increases in vascular permeability by another approach, i.e., pretreatment with dexamethasone, would have comparable effects. In addition, preliminary data are presented on the effects of the selective low molecular weight inhibitor of tissue kallikrein, H-(4-Cl)-D-Phe-1Nal-(3-aminopropyl)-guanidine (CH-2856). Icatibant abolished plasma extravasation into the pancreatic tissue and prevented the development of hypovolaemia. Caerulein-induced increases of amylase activity in the pancreas were significantly reduced by icatibant, while amylase activity in blood was augmented. Inhibition of kinin generation by CH-2856 had similar effects, as oedema formation was inhibited and enzyme activities were reduced in the pancreas and augmented in the blood serum. Dexamethasone completely abolished oedema formation, but only partially inhibited the development of hypovolaemia and haemoconcentration. Amylase activities in the pancreas and in blood remained completely unaffected by dexamethasone. The results suggest that retention of activated enzymes in the pancreatic tissue during acute pancreatitis involves a B2 receptor-mediated, but glucocorticoid-insensitive mechanism.
Griesbacher
T
T
Department of Experimental and Clinical Pharmacology, University of Graz, Austria. thomas.griesbacher@kfunigraz.ac.at
Rainer
I
I
Evans
D M
DM
D000208:Acute Disease; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects*; D003907:Dexamethasone / Q000494:pharmacology*; D004487:Edema / Q000517:prevention & control; D005260:Female; D007705:Kinins / Q000037:antagonists & inhibitors*; D010179:Pancreas / Q000201:enzymology*; D010195:Pancreatitis / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D007705:Kinins; C065679:icatibant; D003907:Dexamethasone; D000681:Amylases; D001920:Bradykinin