Fung L, Pokol-Daniel S, Greenberg G R
Department of Medicine, University of Toronto, Ontario, Canada.
Endocrinology. 1994 Jun;134(6):2376-82. doi: 10.1210/endo.134.6.7910794.
This study was designed to examine whether one or both principle molecular forms of somatostatin (SLI), somatostatin-28 (S-28) and somatostatin-14 (S-14), mediate inhibition of stimulated gastric acid by intestinal fat and to determine whether the mode of action includes activation of type A cholecystokinin (CCK) receptors in conscious dogs. SLI molecular forms were separated by gel filtration chromatography after extraction of acidified plasma on octadecyl silyl cartridges and quantified by RIA. Basal plasma levels of S-28 and S-14 were 4.1 +/- 0.6 and 3.6 +/- 0.3 fmol/ml, respectively. Intraduodenal perfusion with a 10% fat emulsion increased plasma S-28 by 6.3 +/- 1.2 fmol/ml (P < 0.01) and S-14 by 17.8 +/- 2.6 fmol/ml (P < 0.001), and suppressed by 76 +/- 3% (P < 0.001) gastrin (150 pmol/kg.h)-stimulated gastric acid. Blockade of type A CCK receptors with MK-329 (75 micrograms/kg, i.v.) abolished S-28 and S-14 responses (both P < 0.001) and completely reversed the inhibitory effect of gastric acid produced by intraduodenal fat. Intravenous infusions of S-14 dose-dependently inhibited gastrin-stimulated secretion with an estimated 50% inhibitory dose of 125 pmol/kg.h that achieved an incremental plasma S-14 rise of 40 +/- 2 fmol/ml; infusions of S-28 at 30 pmol/kg.h increased plasma S-28 by 47 +/- 3 fmol/ml without altering acid output. The SLI antagonist cyclo-[7-aminoheptanoly-Phe-D-Trp-Lys-Thr(BZL)] (CyCam) reversed by 89 +/- 4% (P < 0.001) exogenous S-14-induced inhibition of gastrin-stimulated acid secretion, but did not influence gastric acid output after the infusion of S-28. CyCam also reversed by 139 +/- 9% (P < 0.001) the early phase of fat-induced acid inhibition; in the late phase, CyCam treatment was associated with a further 2-fold elevation of plasma peptide-YY (PYY) to 102 +/- 6 fmol/ml (P < 0.001) and a 75 +/- 5% suppression of gastric acid. Simulation of this plasma PYY increment with infusions of PYY at 50 pmol/kg.h inhibited by 44 +/- 5% gastrin-stimulated acid secretion. These results indicate that in conscious dogs, endogenous CCK mediation of intraintestinal fat-induced inhibition of stimulated acid secretion occurs in part through CCK type A receptor activation of S-14 secretion. Modulation of gastric acid by S-14 includes both inhibition and attenuation of further suppression via counterregulation of PYY secretion.
本研究旨在探讨生长抑素（SLI）的一种或两种主要分子形式，即生长抑素 - 28（S - 28）和生长抑素 - 14（S - 14），是否介导肠道脂肪对胃酸分泌的抑制作用，并确定其作用方式是否包括激活清醒犬的A 型胆囊收缩素（CCK）受体。在十八烷基硅烷柱上提取酸化血浆后，通过凝胶过滤色谱法分离SLI分子形式，并采用放射免疫分析法进行定量。S - 28和S - 14的基础血浆水平分别为4.1±0.6和3.6±0.3 fmol/ml。十二指肠内灌注10%脂肪乳剂可使血浆S - 28升高6.3±1.2 fmol/ml（P < 0.01），使S - 14升高17.8±2.6 fmol/ml（P < 0.001），并使胃泌素（150 pmol/kg·h）刺激的胃酸分泌抑制76±3%（P < 0.001）。用MK - 329（75微克/千克，静脉注射）阻断A 型CCK受体可消除S - 28和S - 14的反应（均为P < 0.001），并完全逆转十二指肠内脂肪对胃酸产生的抑制作用。静脉输注S - 14剂量依赖性地抑制胃泌素刺激的分泌，估计50%抑制剂量为125 pmol/kg·h，此时血浆S - 14增量为40±2 fmol/ml；以30 pmol/kg·h输注S - 28可使血浆S - 28升高47±3 fmol/ml，而不改变酸分泌量。生长抑素类似物拮抗剂环[7 - 氨基庚酰 - Phe - D - Trp - Lys - Thr（BZL）]（CyCam）可使外源性S - 14诱导的胃泌素刺激的酸分泌抑制作用逆转89±4%（P < 0.001），但在输注S - 28后不影响胃酸分泌量。CyCam还可使脂肪诱导的酸抑制早期阶段逆转作用增强139±9%（P < 0.001）；在后期，CyCam治疗使血浆肽YY（PYY）进一步升高2倍，达到102±6 fmol/ml（P < 0.001），胃酸分泌抑制75±5%。以50 pmol/kg·h输注PYY模拟这种血浆PYY增量可使胃泌素刺激的酸分泌抑制44±5%。这些结果表明，在清醒犬中，肠道脂肪诱导的刺激酸分泌抑制作用的内源性CCK介导部分是通过CCK A 型受体激活S - 14分泌实现的。S - 14对胃酸的调节包括抑制作用以及通过PYY分泌的反调节作用减轻进一步的抑制作用。
