Effects of the bradykinin antagonist, HOE 140, in experimental acute pancreatitis.
1. The novel bradykinin antagonist, HOE 140, completely blocked the fall in rabbit blood pressure caused, not only by i.v. bradykinin, but also by i.v. kallikrein. This shows that both the effects of exogenously administered bradykinin and those of endogenously released kinins are antagonized by HOE 140. 2. Acute pancreatitis was induced in rats by i.v. infusion of the cholecystokinin analogue, caerulein. This treatment resulted in massive oedema of the pancreas, increased activities of amylase and lipase in serum and a characteristic, biphasic fall in blood pressure. 3. HOE 140 prevented the caerulein-induced pancreatic oedema and the second phase of hypotension whereas NPC 349, a widely used, but short-acting, bradykinin antagonist did not show a significant inhibition. HOE 140, in contrast to its inhibitory effects on caerulein-induced pancreatic oedema and hypotension, significantly augmented the increases in amylase and lipase activities in serum. 4. It is concluded that in this model of acute pancreatitis, the release of kinins induces pancreatic oedema and hypotension. Prevention by HOE 140 of the kinin-induced oedema allows the pancreatic enzymes to leave the tissue without hindrance and thus will diminish subsequent pathological events. It is suggested that the results obtained with the highly potent and long-acting bradykinin antagonist, HOE 140, provide a pharmacological basis for a clinical trial in acute pancreatitis.
Griesbacher
T
T
Department of Experimental and Clinical Pharmacology, University of Graz, Austria.
Lembeck
F
F
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000031:analogs & derivatives; D002108:Ceruletide / Q000494:pharmacology; D005260:Female; D007610:Kallikreins / Q000494:pharmacology; D008049:Lipase / Q000097:blood; D009842:Oligopeptides / Q000494:pharmacology*; D010195:Pancreatitis / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000894:Anti-Inflammatory Agents, Non-Steroidal; D009842:Oligopeptides; C065679:icatibant; D002108:Ceruletide; D008049:Lipase; D000681:Amylases; D007610:Kallikreins; D001920:Bradykinin