| Budget Amount *help |
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1992: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1991: ¥700,000 (Direct Cost: ¥700,000)
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| Research Abstract |
1) Acute pancreatitis is a disease of variable intensity, ranging a mild, self-limiting disease to a life-threating condition causing multiple organ failure. The important causes of morbidity and mortality in patients with acute pancreatitis include shock and cardiovascular dysfunction, respiratory and renalfailure etc. These effects may be caused by hypovolemia from fluid requestration around the pancreas, which may release a myocardial depressant factor vasoactive substances. Our recent work has shown that beta-emdorphin may play an important role in the complicated physiopathologic balance of hypotension and myocardial depression in acute pancreatitis. Although the mechanism of beta-endorphin release during acute pancreatitis is unknown, it has been reported that trypsin like enzyme and bradykinin, released by noxious stimuli, induces the production and the liberation of beta-endorphin. In addition, trypsin-like activity and serum bradykinin levels increase during acute pancreatitis
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Recently, various protease inhibitors have been developed and widely used for the treatment of acute pancreatitis, but been developed and widely used for the treatment of acute pancreatitis, but their efficacy is controversial. Protease inhibitors can inhibit serine protease such as trypsin, kallikrein etc. which suggests that beta-endorphin release during acute pancreatitis may be prevented by protease inhibitors through the inhibition of trypsin-like enzymes and bradykinin release. However, there are no reports of the effect of protease inhibitors on beta-endorphin release or on hemodynamic changes during acute pancreatitis.
Pancreatitis was induced by the injection of autologous bile mixed with trypsin into the main pancreatic duct after ligation of the accessory duct. Plasma beta-endorphin levels and cardiovascular function were measured. Control group was given 10 ml/kg/h of lactate Ringer s solution intravenously beginning 1 h before the induction of pancreatitis. Protease inhibitor received an intravenous infusion of 3 mg/kg/h of a synthetic protease inhibitor in lactate Ringers's solution soon after the induction of pancreatitis.
Plasma beta-endorphin levels in the control group increased significantly. However, plasma beta-endorphin levels in the protease inhibitor group did not increase as in the control group. The protease infusion improved hypotension, myocardial depression and plasma lactate, suggesting that the inhibitory effect of the protease inhibitor on beta-endorphin release contribute to the improvement. Furthermore, protease inhibitor infusion 30min after the indication of pancreatitis showed the same effect.
2) Submaximal administration of cholecystokinin (CCK) or analogs (cerulein) induces edematous acute pancreatitis. In addition, introvenous injection of these hormones has been shown to warsen the morbidity and mortality in experimental acute pancreatitis.
Creation of a closed duodenal loop produced edematous acute pancreatitis at 6 h later and hemorrhagic acute pancreatitis at 12 h later and the pancreatitis established tended to improve after releasing the loop.
We investigated the effect of a CCK-receptor antagonist on the healing process in edematous and hemorrhagic acute pancreatitis after releasing the loop. In the group treated with a CCK-receptor antagonist, serum amylase and lipase levels decreased markedsly upon release the loop in edematous acute pancreatitis compared with the control group.Further more, the histological changes in edematous acute pancreatitis improved more rapidly than in the control group. No such biochemical and histological evidence of improvement was observed in hemorrhagic acute pancreatitis. The CCK-receptor antagonist displayed a therapeutic effect in edematous acute pancreatitis. These findings suggests that endogenous CCK release induced by the closed cluodenal loop may have a contributory role in the development of edematous acute pancreatitis but not of hemorrhagic acute pancreatitis. Less
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