Pathological events in experimental acute pancreatitis prevented by the bradykinin antagonist, Hoe 140.
1. In a previous investigation, Hoe 140, a specific and potent bradykinin B2 receptor antagonist, prevented the pancreatic oedema and the hypotension observed during acute experimental pancreatitis; however, it augmented the associated rises in the serum activities of pancreatic enzymes. Therefore, we have now investigated the consequences of the pancreatic oedema for the fate of activated enzymes released into the tissue during the course of acute pancreatitis. 2. Acute oedematous pancreatitis was induced in rats, pretreated with captopril (50 mumol kg-1, i.p.), by hyperstimulation of the exocrine function of the pancreas with the cholecystokinin analogue, caerulein (4 nmol kg-1 h-1, i.v.), for up to 120 min. 3. Pancreatic oedema began to develop 10 min after the start of the caerulein infusion, reached a maximum within about 45 min, and then declined slightly. The development of the oedema parallelled the second phase of the caerulein-induced fall in blood pressure found in earlier experiments. No further extravasation of plasma proteins occurred during the 2nd hour of the caerulein infusion. The oedema formation was completely blocked in animals pretreated with the bradykinin receptor antagonist, Hoe 140 (100 nmol kg-1, s.c.). Pretreatment with aprotinin or soy bean trypsin inhibitor did not result in a significant inhibition of the oedema. 4. The haematocrit of animals with experimental pancreatitis showed a pronounced increase which started 10 min after the start of the caerulein infusion and reached maximal values at 60 min. The changes in haematocrit showed a reduction in total blood volume of 28% due to a 48% loss of plasma. This effect was completely blocked by Hoe 140. 5. In rats with caerulein-induced pancreatitis, there was a time-dependent increase in the activities of amylase and lipase in blood serum as well as in the pancreas. Pretreatment with Hoe 140 greatly augmented the caerulein-induced rise in enzyme activities in blood serum but potently attenuated it in the pancreas. The activities of trypsin in both the blood serum and the pancreas were below or near the limit of detection in all experimental groups.6. It is concluded that the second phase of hypotension in this model of acute pancreatitis is due to the liberation of kinins which cause a massive loss of blood plasma into the pancreas and into the retroperitoneal space. Activated enzymes are trapped in the pancreas, at least in part, by the oedema of the gland. Treatment with Hoe 140 prevents the oedema formation and greatly facilitates the egress of activated enzymes from the pancreas.
Griesbacher
T
T
Department of Experimental and Clinical Pharmacology, University of Graz, Austria.
Tiran
B
B
Lembeck
F
F
D000208:Acute Disease; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D004487:Edema / Q000503:physiopathology*; D005260:Female; D006400:Hematocrit; D007022:Hypotension / Q000503:physiopathology*; D010179:Pancreas / Q000201:enzymology; D010195:Pancreatitis / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D011480:Protease Inhibitors; C065679:icatibant; D001920:Bradykinin