Brzozowski T, Konturek P C, Konturek S J, Kwiecién S, Pajdo R, Brzozowska I, Hahn E G
Department of Physiology, Jagiellonian University School of Medicine, Cracow, Poland.
J Clin Gastroenterol. 1998;27 Suppl 1:S125-37. doi: 10.1097/00004836-199800001-00020.
Duodenal fat such as oleate is known to influence gut functions by release of cholecystokinin (CCK), but the contribution of CCK endogenously released by duodenal fat or by diversion of pancreatic juice from the duodenum in the mechanism of mucosal integrity and gastroprotection has been little studied. This study was designed to compare the effect of CCK-8 and intraduodenal (i.d.) instillation of sodium oleate, or diversion of the pancreatic biliary secretions that are known to release CCK, on the gastric mucosal lesions induced by topical application of 100% ethanol or acidified aspirin (ASA) in rats with or without the pretreatment with a CCK-A receptor antagonist, loxiglumide, or with L-365,260 to block CCK-B receptors. In addition, the effect of suppression of prostaglandin (PG) biosynthesis by indomethacin (5 mg/kg i.p.), inhibition of nitric oxide (NO)-synthase by L-NAME (5 mg/kg i.v.), or blockade of sensory nerves by capsaicin (125 mg/kg s.c.) on the protective activity of sodium oleate was determined. Sodium oleate (50-200 mM i.d.), or diversion of pancreatic juice from the duodenum for 3 h that produced significant rise in plasma CCK levels, significantly reduced gastric lesions induced by 100% ethanol to an extent similar to that induced by exogenous CCK-8 (5 nmol/kg s.c.). The protective effect of oleate or diversion of pancreatic juice was accompanied by an increase in gastric blood flow (GBF). Both protection and accompanying hyperemia were completely abolished by blockade of CCK-A receptors with loxiglumide, whereas L-365,260, an antagonist of CCK-B receptors, had no effect. Oleate given i.d. significantly attenuated acidified ASA-induced gastric lesions and gastric secretion while increasing the luminal concentration of somatostatin. These effects were significantly reduced by loxiglumide but not by L-365,260. In contrast, CCK-8, which stimulated gastric acid secretion, failed to affect the lesions induced by acidified ASA and the decrease in the GBF produced by this ulcerogen. Indomethacin, which suppressed PG generation by approximately 90%, failed to influence the protective activity of oleate or CCK-8 against ethanol-induced lesions, whereas L-NAME, vagotomy, or sensory denervation significantly attenuated this protection and accompanying hyperemia. Addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of CCK-8 and duodenal oleate against gastric lesions induced by ethanol or acidified ASA. We conclude that endogenous CCK released by oleate or diversion of pancreatic secretion exerts a potent gastroprotective action on the stomach involving predominantly CCK-A receptors and depending on vagal activity, and hyperemia mediated by NO and sensory nerves but unrelated to acid secretory effects and endogenous PG.
已知十二指肠脂肪如油酸酯可通过释放胆囊收缩素（CCK）来影响肠道功能，但十二指肠脂肪内源性释放的CCK或十二指肠胰液改道在黏膜完整性和胃保护机制中的作用鲜有研究。本研究旨在比较CCK-8和十二指肠内（i.d.）滴注油酸钠，或已知可释放CCK的胰胆分泌物改道，对局部应用100%乙醇或酸化阿司匹林（ASA）诱导的大鼠胃黏膜损伤的影响，这些大鼠在预处理时使用了CCK-A受体拮抗剂洛西格列胺或L-365,260来阻断CCK-B受体。此外，还测定了吲哚美辛（5 mg/kg腹腔注射）抑制前列腺素（PG）生物合成、L-NAME（5 mg/kg静脉注射）抑制一氧化氮（NO）合酶或辣椒素（125 mg/kg皮下注射）阻断感觉神经对油酸钠保护活性的影响。十二指肠内注射油酸钠（50 - 200 mM）或十二指肠胰液改道3小时导致血浆CCK水平显著升高，可显著减轻100%乙醇诱导的胃损伤，其程度与外源性CCK-8（5 nmol/kg皮下注射）相似。油酸钠或胰液改道的保护作用伴随着胃血流量（GBF）增加。用洛西格列胺阻断CCK-A受体可完全消除保护作用和伴随的充血，而CCK-B受体拮抗剂L-365,260则无作用。十二指肠内给予油酸钠可显著减轻酸化ASA诱导的胃损伤和胃分泌，同时增加腔内生长抑素浓度。这些作用被洛西格列胺显著减弱，但未被L-365,260减弱。相比之下，刺激胃酸分泌的CCK-8未能影响酸化ASA诱导的损伤以及该致溃疡剂引起的GBF降低。吲哚美辛抑制PG生成约90%，但未能影响油酸钠或CCK-8对乙醇诱导损伤的保护活性，而L-NAME、迷走神经切断术或感觉神经去神经支配则显著减弱这种保护作用和伴随的充血。在L-NAME中加入L-精氨酸而非D-精氨酸可恢复CCK-8和十二指肠油酸钠对乙醇或酸化ASA诱导的胃损伤的保护和充血作用。我们得出结论，油酸钠或胰液改道释放的内源性CCK对胃具有强大的胃保护作用，主要涉及CCK-A受体，依赖迷走神经活动，以及由NO和感觉神经介导的充血，但与酸分泌作用和内源性PG无关。
