Katz L B, Schoof R A, Shriver D A
Research Laboratories, Ortho Pharmaceutical Corporation, Raritan, NJ 08869-0602.
J Pharmacol Methods. 1987 Dec;18(4):275-82. doi: 10.1016/0160-5402(87)90059-3.
It has been hypothesized that prolonged achlorhydria causes compensatory elevation of serum gastrin, and that there is an association in rats between sustained hypergastrinemia, hyperplasia of gastric enterochromaffin-like cells, and subsequent formation of gastric carcinoids in 2-year carcinogenicity studies. The present study examined whether daily administration of gastric antisecretory drugs in rats for 4 days could cause hypergastrinemia associated with inhibition of acid output. Rats were dosed orally for 4 days with the histamine H2-receptor antagonist ranitidine or the H+,K+-sensitive ATPase inhibitor omeprazole, and examined on day 5 for effects on gastric acid secretion and serum gastrin. Omeprazole (138 mg/kg/day significantly inhibited gastric acid secretion and increased serum gastrin levels. Large, single daily doses of ranitidine (1000-2000 mg/kg/day) had no effect on 24-hr acid or gastrin secretion; however, ranitidine did inhibit next-day acid secretion with associated increases in serum gastrin when administered in three divided doses. These results with ranitidine support the hypothesis that a sustained gastric antisecretory action will cause a compensatory hypergastrinemia, regardless of the antisecretory agent used. The ability to detect increased serum gastrin levels associated with inhibition of acid secretion, after administration of antisecretory agents for only 4 days, suggest that this short 5-day test may be useful for determining the potential of antisecretory agents to cause hypergastrinemia due to 24-hr inhibition of acid secretion and may be predictive of long-term hyperplastic changes.
据推测，长期胃酸缺乏会导致血清胃泌素代偿性升高，并且在大鼠两年致癌性研究中发现，持续性高胃泌素血症、胃嗜铬样细胞增生以及随后胃类癌的形成之间存在关联。本研究探讨了大鼠连续4天每日给予胃分泌抑制剂是否会导致与胃酸分泌抑制相关的高胃泌素血症。给大鼠口服组胺H2受体拮抗剂雷尼替丁或H⁺，K⁺ - 敏感ATP酶抑制剂奥美拉唑4天，并在第5天检测对胃酸分泌和血清胃泌素的影响。奥美拉唑（138毫克/千克/天）显著抑制胃酸分泌并提高血清胃泌素水平。大剂量单次每日给予雷尼替丁（1000 - 2000毫克/千克/天）对24小时胃酸或胃泌素分泌无影响；然而，雷尼替丁分三次给药时确实抑制了次日胃酸分泌并伴有血清胃泌素升高。雷尼替丁的这些结果支持了这样的假设，即持续的胃分泌抑制作用会导致代偿性高胃泌素血症，无论使用何种分泌抑制剂。仅在给予分泌抑制剂4天后就能检测到与胃酸分泌抑制相关的血清胃泌素水平升高，这表明这个为期5天的短期试验可能有助于确定分泌抑制剂因24小时胃酸分泌抑制而导致高胃泌素血症的可能性，并且可能预测长期的增生性变化。
