胃泌素、生长抑素和多巴胺受体配体对大鼠胃肠嗜铬样细胞分泌和增殖影响的比较
A comparison of the effects of gastrin, somatostatin and dopamine receptor ligands on rat gastric enterochromaffin-like cell secretion and proliferation.
作者信息
Kidd M, Modlin I M, Black J W, Boyce M, Culler M
机构信息
Department of Surgery, Yale University School of Medicine New Haven, Connecticut 06520-8062, United Sates.
出版信息
Regul Pept. 2007 Oct 4;143(1-3):109-17. doi: 10.1016/j.regpep.2007.04.002. Epub 2007 Apr 29.
Gastrin regulates ECL cell histamine release and is a critical determinant of acid secretion. ECL cell secretion and proliferation is inhibited by gastrin antagonists and somatostatin but little is known about the role of dopamine agonists in this process. Since the ECL cell exhibits all three classes of receptor we evaluated and compared the effects of the gastrin receptor antagonist, (YF476), lanreotide (SST agonist) and novel dopaminergic agents (BIM53061 and BIM27A760) on ECL cell histamine secretion and proliferation. Highly enriched (>98%) ECL cell preparations prepared from rat gastric mucosa using a FACS approach were studied. Real-time PCR confirmed presence of the CCK2, SS2 and SS5 and D1 receptors on ECL cells. YF476 inhibited histamine secretion and proliferation with IC(50)s of 1.25 nM and 1.3 x 10(-11) M respectively, values 10-1000x more potent than L365,260. Lanreotide inhibited secretion and proliferation (2.2 nM, 1.9 x 10(-10) M) and increased YF476-inhibited proliferation a further 5-fold. The dopamine agonist, BIM53061, inhibited gastrin-mediated ECL cell secretion and proliferation (17 nM, 6 x 10(-10) M) as did the novel dopamine/somatostatin chimera BIM23A760 (22 nM, 4.9 x 10(-10) M). Our studies demonstrate that the gastrin receptor antagonist, YF476, is the most potent inhibitor of ECL cell histamine secretion and proliferation. Lanreotide, a dopamine agonist and a dopamine/somatostatin chimera inhibited ECL cell function but were 10-1000x less potent than YF476. Agents that selectively target the CCK2 receptor may provide alternative therapeutic strategies for gastrin-mediated gastrointestinal cell secretion and proliferation such as evident in the hypergastrinemic gastric carcinoids associated with low acid states.
胃泌素调节肠嗜铬样（ECL）细胞组胺释放，是胃酸分泌的关键决定因素。胃泌素拮抗剂和生长抑素可抑制ECL细胞分泌和增殖，但多巴胺激动剂在此过程中的作用知之甚少。由于ECL细胞表达所有三类受体，我们评估并比较了胃泌素受体拮抗剂（YF476）、兰瑞肽（生长抑素激动剂）和新型多巴胺能药物（BIM53061和BIM27A760）对ECL细胞组胺分泌和增殖的影响。使用荧光激活细胞分选（FACS）方法从大鼠胃黏膜制备的高度富集（>98%）的ECL细胞制剂进行了研究。实时聚合酶链反应（PCR）证实ECL细胞上存在胆囊收缩素2（CCK2）、生长抑素2（SS2）、生长抑素5（SS5）和多巴胺D1受体。YF476抑制组胺分泌和增殖，其半数抑制浓度（IC50）分别为1.25 nM和1.3×10−11 M，比L365,260的效力高10 - 1000倍。兰瑞肽抑制分泌和增殖（2.2 nM，1.9×10−10 M），并使YF476抑制的增殖进一步增加5倍。多巴胺激动剂BIM53061抑制胃泌素介导的ECL细胞分泌和增殖（17 nM，6×10−10 M），新型多巴胺/生长抑素嵌合体BIM23A760也有此作用（22 nM，4.9×10−10 M）。我们的研究表明，胃泌素受体拮抗剂YF476是ECL细胞组胺分泌和增殖的最有效抑制剂。兰瑞肽、一种多巴胺激动剂和一种多巴胺/生长抑素嵌合体抑制了ECL细胞功能，但效力比YF476低10 - 1000倍。选择性靶向CCK2受体的药物可能为胃泌素介导的胃肠细胞分泌和增殖提供替代治疗策略，如在与低酸状态相关的高胃泌素血症性胃类癌中所见。
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