Griesbacher T, Kolbitsch C, Tiran B, Lembeck F
Institut für Experimentelle und Klinische Pharmakologie, Karl-Franzens-Universität Graz, Austria.
Naunyn Schmiedebergs Arch Pharmacol. 1995 Nov;352(5):557-64. doi: 10.1007/BF00169391.
It has been found earlier that the bradykinin antagonist, icatibant (Hoe 140), prevents the pancreatic oedema and the ensuing hypotension and haemoconcentration, and facilitates the removal of activated enzymes form the tissue during caerulein-induced acute pancreatitis. For a potential therapeutic use of the compound in clinical situations it is essential to investigate whether the associated increase in enzyme activities in the blood serum has any adverse effects on the pancreas itself or on other organs. Normal amylase secretion into the biliopancreatic duct stimulated by a low dose of caerulein (0.4 nmol kg-1 h-1, i.v.) was not affect by icatibant (100 nmol kg-1, s.c.) Acute pancreatitis, induced by a high dose of caerulein (4 nmol kg-1 h-1 for 2 h, i.v.), resulted in elevations in the activities of amylase and lipase in the pancreatic tissue and in the blood serum lasting for at least 4 h after the end of the caerulein infusion. While the rise in enzyme activities in the blood serum was augmented in icatibant-treated rats only at the end of the caerulein-infusion, the enzyme accumulation in the pancreas was significantly reduced by icatibant for at least 4 h after the end of the caerulein infusion. The secretion of amylase and lipase into the biliopancreatic duct was significantly increased only during the first 20 min of acute pancreatitis; in rats pre-treated with icatibant, no significant increase could be observed. Twenty-four hours after induction of pancreatitis, a low-dose caerulein stimulation of the exocrine function of the pancreas led to a reduced but sustained secretion of amylase regardless of whether the animals had received icatibant or not. During the first 45 min of pancreatitis, blood glucose concentrations were significantly reduced, but returned to values not different from those obtained in saline-infused controls. This effect was not affected by icatibant. No changes in the response to an i.v. glucose tolerance test were found on the day after induction of acute pancreatitis. The serum activities of glutamic pyruvic transaminase and gamma-glutamyl transpeptidase determined up to 24 h after induction of pancreatitis were not different from saline controls. icatibant had no effect on the activities of these enzymes. It is concluded that during caerulein-induced acute pancreatitis normal exocrine secretion of pancreatic enzymes into the pancreatic duct ceases almost immediately. Pre-treatment with icatibant significantly reduces the accumulation of activated enzymes in the pancreatic tissue for several hours after induction of pancreatitis while a concomitant augmentation in enzyme activities in the blood serum lasts much shorter. There is no indication of adverse effects on the function of the endocrine or exocrine pancreas and that of the liver, either during the acute stages of pancreatitis or during the recovery period.
此前已发现，缓激肽拮抗剂艾替班特（icatibant，Hoe 140）可预防胰腺水肿以及随之而来的低血压和血液浓缩，并有助于在雨蛙肽诱导的急性胰腺炎期间从组织中清除活化酶。对于该化合物在临床情况中的潜在治疗用途而言，研究血清中酶活性的相关增加是否会对胰腺本身或其他器官产生任何不良影响至关重要。低剂量雨蛙肽（0.4 nmol kg-1 h-1，静脉注射）刺激胰胆管正常分泌淀粉酶不受艾替班特（100 nmol kg-1，皮下注射）影响。高剂量雨蛙肽（4 nmol kg-1 h-1，静脉注射2小时）诱导的急性胰腺炎导致胰腺组织和血清中淀粉酶和脂肪酶活性升高，在雨蛙肽输注结束后至少持续4小时。虽然仅在雨蛙肽输注结束时，艾替班特治疗的大鼠血清中酶活性的升高有所增强，但在雨蛙肽输注结束后至少4小时，艾替班特可显著降低胰腺中酶的积累。仅在急性胰腺炎的前20分钟内，淀粉酶和脂肪酶向胰胆管的分泌显著增加；在预先用艾替班特治疗的大鼠中，未观察到显著增加。胰腺炎诱导24小时后，低剂量雨蛙肽刺激胰腺外分泌功能导致淀粉酶分泌减少但持续存在，无论动物是否接受过艾替班特治疗。在胰腺炎的前45分钟内，血糖浓度显著降低，但恢复到与输注生理盐水的对照组无差异的值。这种效应不受艾替班特影响。在急性胰腺炎诱导后的第二天，静脉注射葡萄糖耐量试验的反应未发现变化。在胰腺炎诱导后长达24小时测定的谷丙转氨酶和γ-谷氨酰转肽酶的血清活性与生理盐水对照组无差异。艾替班特对这些酶的活性没有影响。结论是，在雨蛙肽诱导的急性胰腺炎期间，胰腺酶向胰管的正常外分泌几乎立即停止。在胰腺炎诱导后数小时，预先用艾替班特治疗可显著减少胰腺组织中活化酶的积累，而血清中酶活性的相应增加持续时间则短得多。无论是在胰腺炎的急性期还是恢复期，均未显示对胰腺内分泌或外分泌功能以及肝脏功能有不良影响。
