Robert A, Lum J T, Lancaster C, Olafsson A S, Kolbasa K P, Nezamis J E
Drug Metabolism Research, Upjohn Company, Kalamazoo, Michigan.
Lab Invest. 1989 May;60(5):677-91.
Acute edematous pancreatitis was produced in rats by subcutaneous administration of caerulein. Pancreas weight, pancreas histology and plasma amylase were used as endpoints to quantitate the severity of the syndrome. A caerulein dose of 10 micrograms/kg.hour produced the most severe pancreatitis, whereas at 5 micrograms/kg.hour the values were half-maximal. The pancreatic lesions were characterized by edema, formation of cytoplasmic vacuoles, leukocytic infiltration, necrosis, and with time (12-hour caerulein infusion) dilated acini. Cholecystokinin octapeptide also produced pancreatitis when given at ten times the dose required for caerulein (50 micrograms/kg.hour instead of 5 micrograms/kg.hour). Carbachol did not induce pancreatitis. Two prostaglandins, 16,16-dimethyl prostaglandin E2 injected subcutaneously and prostaglandin E2 infused subcutaneously, dose dependently prevented caerulein-induced pancreatitis (pancreatic edema, leukocytic infiltration, and necrosis) and reduced the number and size of intracellular vacuoles. The ED50 were 15 to 25 micrograms/kg for 16,16-dimethyl prostaglandin E2 and 90 micrograms/kg.hour for prostaglandin E2. Neither prostaglandin, given at doses inhibiting the development of pancreatitis, prevented the retardation of gastric emptying caused by caerulein, a finding suggesting that the prostaglandins may act specifically on the effect of caerulein on the pancreas but not on caerulein receptors in gastric smooth muscle. Indomethacin, an inhibitor of prostaglandin synthesis, and methscopolamine bromide, an anticholinergic agent, had no effect on caerulein-induced pancreatitis. We concluded that prostaglandins of the E type prevent the development of caerulein-induced pancreatitis. The mechanism by which prostaglandins protect the pancreas may involve stabilization of lysosomes within the acinar cells and inhibition of intracellular activation of pancreatic digestive enzymes.
通过皮下注射蛙皮素在大鼠中诱发急性水肿性胰腺炎。胰腺重量、胰腺组织学和血浆淀粉酶被用作量化该综合征严重程度的终点指标。蛙皮素剂量为10微克/千克·小时时产生最严重的胰腺炎，而在5微克/千克·小时时，各项指标值为最大值的一半。胰腺病变的特征为水肿、细胞质空泡形成、白细胞浸润、坏死，并且随着时间推移（蛙皮素输注12小时）腺泡扩张。当以蛙皮素所需剂量的10倍给药时（50微克/千克·小时而非5微克/千克·小时），八肽胆囊收缩素也会引发胰腺炎。卡巴胆碱不会诱发胰腺炎。两种前列腺素，即皮下注射的16,16 - 二甲基前列腺素E2和皮下输注的前列腺素E2，剂量依赖性地预防了蛙皮素诱发的胰腺炎（胰腺水肿、白细胞浸润和坏死），并减少了细胞内空泡的数量和大小。16,16 - 二甲基前列腺素E2的半数有效剂量为15至25微克/千克，前列腺素E2为90微克/千克·小时。给予抑制胰腺炎发展剂量的这两种前列腺素，均未预防蛙皮素引起的胃排空延迟，这一发现表明前列腺素可能特异性作用于蛙皮素对胰腺的影响，而不是作用于胃平滑肌中的蛙皮素受体。前列腺素合成抑制剂吲哚美辛和抗胆碱能药物溴甲东莨菪碱对蛙皮素诱发的胰腺炎没有影响。我们得出结论，E型前列腺素可预防蛙皮素诱发的胰腺炎。前列腺素保护胰腺的机制可能涉及稳定腺泡细胞内的溶酶体以及抑制胰腺消化酶的细胞内激活。
