Piqueras Laura, Martínez Vicente
Department of Physiology, Pharmacology and Toxicology, Cardenal Herrera CEU University, Valencia, Spain.
Naunyn Schmiedebergs Arch Pharmacol. 2004 Dec;370(6):510-20. doi: 10.1007/s00210-004-0992-8. Epub 2004 Nov 20.
Somatostatin, probably acting through somatostatin type 2 receptors (SSTR2), is the main inhibitor of gastric acid secretion. We characterized gastric acid secretion in SSTR2 knockout mice, and used preferential somatostatin receptor agonists to assess the relative role of SSTR1, 2, 3, 4, and 5 on gastric acid secretion. Basal gastric acid secretion and the secretory response to a meal were similar in conscious wild-type and knockout mice. However, under urethane anesthesia, which releases endogenous somatostatin, SSTR2 knockout mice had a basal secretion 11-15-fold higher than wild-type animals (micromol/10 min:1.40+/-0.09 vs. 0.10+/-0.01, p<0.05). Gastrin immunoneutralization or H(2) receptors blockade (cimetidine), but not cholinergic blockade (atropine), reduced the high basal secretion in SSTR2 knockout mice. In SSTR2 knockout mice, gastrin and histamine stimulated acid secretion with similar efficacy, while in wild-type mice histamine was more effective than gastrin. SSTR2 knockout mice showed also a hypersecretory response to pylorus ligation compared with wild-type animals. In wild-type mice, somatostatin-14, SMS 201-995, and the SSTR2-preferential agonist, DC 32-87, inhibited gastrin-stimulated acid secretion with an order of potency SMS 201-995>DC 32-87>somatostatin-14. Preferential agonists for the SSTR1, 3, 4, and 5 were devoid of any effect. None of the compounds tested affected the high basal secretion observed under urethane anesthesia in SSTR2 knockout mice. These results show that gastric antisecretory effects of peripheral somatostatin are mediated solely through SSTR2. In the absence of functional SSTR2 other somatostatin receptors do not compensate for the lack somatostatin-SSTR2-mediated inhibition. Basal acid secretion and the response to a meal are normal in conscious SSTR2 knockout mice, suggesting the presence of somatostatin-independent mechanisms that compensate for the lack of somatostatin-SSTR2-mediated inhibitory responses.
生长抑素可能通过2型生长抑素受体（SSTR2）发挥作用，是胃酸分泌的主要抑制剂。我们对SSTR2基因敲除小鼠的胃酸分泌进行了表征，并使用选择性生长抑素受体激动剂来评估SSTR1、2、3、4和5在胃酸分泌中的相对作用。清醒的野生型和基因敲除小鼠的基础胃酸分泌以及对进食的分泌反应相似。然而，在释放内源性生长抑素的氨基甲酸乙酯麻醉下，SSTR2基因敲除小鼠的基础分泌比野生型动物高11 - 15倍（微摩尔/10分钟：1.40±0.09对0.10±0.01，p<0.05）。胃泌素免疫中和或H₂受体阻断（西咪替丁），但不是胆碱能阻断（阿托品），可降低SSTR2基因敲除小鼠的高基础分泌。在SSTR2基因敲除小鼠中，胃泌素和组胺刺激胃酸分泌的效力相似，而在野生型小鼠中组胺比胃泌素更有效。与野生型动物相比，SSTR2基因敲除小鼠对幽门结扎也表现出高分泌反应。在野生型小鼠中，生长抑素 - 14、SMS 201 - 995和SSTR2选择性激动剂DC 32 - 87抑制胃泌素刺激的胃酸分泌，其效力顺序为SMS 201 - 995>DC 32 - 87>生长抑素 - 14。SSTR1、3、4和5的选择性激动剂没有任何作用。所测试的化合物均未影响在氨基甲酸乙酯麻醉下SSTR2基因敲除小鼠中观察到的高基础分泌。这些结果表明，外周生长抑素的胃抗分泌作用仅通过SSTR2介导。在缺乏功能性SSTR2的情况下，其他生长抑素受体不能补偿生长抑素 - SSTR2介导的抑制作用的缺乏。清醒的SSTR2基因敲除小鼠的基础胃酸分泌和对进食反应正常，表明存在不依赖生长抑素的机制来补偿生长抑素 - SSTR2介导的抑制反应的缺乏。
