雨蛙肽中枢促胃酸分泌作用机制的初步分析

利用特异的受体阻断剂能够拮抗相应的受体激动剂的效应的原理,分析雨蛙肽中枢促胃酸分泌作用的受体机制。向大鼠侧脑室内注射微量雨蛙肽(67ng/鼠),可引起急性灌流大鼠胃酸分泌明显增加。预先向大鼠侧脑室内注射肾上腺素受体阻断剂酚妥拉明或心得安,20min后再向侧脑室内注射雨蛙肽,预处理对雨蛙肽的促胃酸分泌作用影响不大。但事先向侧脑室内注射乙酰胆碱受体阻断剂阿托品或胆囊收缩素(CCK)受体阻断剂二丁酰环化-磷酸鸟苷(Bt_2 cGMP)则可有效地阻断雨蛙肽的作用。以上结果提示,脑内雨蛙肽促胃酸分泌机制中,可能有 CCK 受体和胆碱能受体参与,而与肾上腺素能系统关系不大。     

吗啡和脑啡肽对大鼠基础胃酸分泌的影响

用大鼠作急性实验,腹腔注射乌拉坦麻醉。以恒定速度将37℃的生理盐水自食道插管灌流入胃,收集从幽门插管流出的灌流液,用0.01当量的 NaOH 滴定其酸度,并计算单位时间内的总酸排出量。结果表明:静脉注射吗啡(3mg/kg)后,胃酸分泌增加,在注射后的30分钟时总酸排出量达最高水平,90分钟恢复至基础水平。静脉注射亮啡肽(2mg/kg),胃酸分泌也增加,总酸排出量于注射后20分钟达最高水平,60分钟恢复至基础水平。纳洛酮在一定剂量范围内(1.2—2.6mg/kg)可完全阻断吗啡增加胃酸分泌的作用,如剂量过大,则反增强吗啡对胃酸分泌的作用。     

侧脑室注射雨蛙肽对应激性胃粘膜损伤的影响

本工作研究了向侧脑室注射雨蛙肽对束缚四肢再浸水引起大鼠应激性胃粘膜损伤的影响及机制。侧脑室注射雨蛙肽(1.0ng/rat)可显著减轻胃粘膜损伤,抑制胃酸分泌,促进胃壁结合粘液分泌并使胃液中PGE_2含量增加。电镜观察可见胃壁细胞分泌增强。预先侧脑室注射纳洛酮或皮下注射消炎痛可消除雨蛙肽抗胃粘膜损伤和抑制胃酸分泌的效应,但对胃壁结合粘液分泌无影响。侧脑室注射阿托品、酚妥拉明、心得安不影响雨蛙肽的抗损伤作用。上述结果提示:注射到侧脑室的雨蛙肽的抗胃粘膜损伤作用,部分是通过中枢的吗啡受体和促进内源性PGE_2合成而实现的。     

下丘脑室旁核注射神经降压素对大鼠胃酸分泌的影响及机制探讨

本实验用乌拉坦麻醉的大鼠,探讨了下丘脑室旁核（ＰＶＮ）注射神经降压素（ＮＴ）对胃酸分泌的影响及其机制。结果表明,ＰＶＮ注射微量ＮＴ后,胃酸排出量呈剂量依赖性减少,此效应可被侧脑室内预先注射酚妥拉明所阻断,但不能被螺哌啶酮阻断、双侧颈迷走神经切断后,ＰＶＮ注射ＮＴ对胃酸排出量无明显影响。这提示,ＰＶＮ注射ＮＴ对大鼠胃酸分泌的抑制作用,可能与该处α－受体的激活有关,并通过迷走神经所中介。     

侧脑室注射胰高血糖素对兔血浆自由脂肪酸、血糖及胰岛素浓度的影响

胰高血糖素是一种脑-肠肽,但它在脑中的生理作用尚不清楚。本工作在家兔侧脑室埋藏慢性套管,并通过注射20μl含0.5—5μg的胰高血糖素溶液,在注射后的15、45、75、105分钟各取血样测定血糖、血浆自由脂肪酸(FFA)和胰岛素的浓度。结果发现:(1)对血糖及血浆胰岛素浓度无明显影响;(2)能引起血浆 FFA 浓度降低,且与剂量有依赖关系,在注射后的45分钟,FFA 降低最明显,以后逐渐恢复;(3)皮下注射阿托品(0.2mg/kg)或静脉注射酚妥拉明(5mg/kg)均不能消除侧脑室注射胰高血糖素降低 FFA 的作用;(4)静脉注射心得安(5mg/kg)能阻断侧脑室注射胰高血糖素的降低 FFA 的作用。这似表明脑中的胰高血糖素可能参与脂代谢的调节,并可能是通过肾上腺素β-受体起作用的。     

铃蟾肽(Bombesin)对离体灌流大鼠胃的胃泌素、生长抑素、胰升糖素及胃酸释放的影响

本研究用离体大鼠胃灌流技术来观察铃蟾肽对胃-肠激素及胃酸分泌的影响。2×10~(?)mol/L铃蟾肽以0.3ml/min速度作动脉内输注,可刺激胃酸的分泌,自2.50±0.05×10~(-1)增至5.50±1.50×10~(-1)mEq/min,但与外源性五肽胃泌素无协同作用。铃蟾肽引起两次性的门脉中胃泌索及生长抑素的释放,但抑制胰升糖素释放。这三种激素的基础释放率分别为:胃泌素62±8pg,生长抑素5.9±1.1ng,胰升糖素0.40±0.03ng/min;2×10~(-8)mol/L铃蟾肽以0.3ml/min作动脉内输注,胃泌素及生长抑素的峰值分别为1,000±20pg及12.2±2.0ng/min,胰升糖素的最低值为0.17±0.05ng/min,三种激素的反应均与铃蟾肽的浓度成正比。在胃腔流出液中也可测到上述三种激素,但量要少得多。     

兔侧脑室注射胰高血糖素对血清总胆固醇和甘油三酯浓度的影响

我们最近曾报道,向兔侧脑室内注射胰高血糖素有明显降低血浆自由脂肪酸的作用。本工作又进一步观察了它对空腹血清总胆固醇和甘油三酯浓度的影响。结果发现:(1)对血清总胆固醇浓度无明显作用;(2)能引起血清甘油三酯浓度的下降,且与剂量有依赖关系,在注射后的 75min降低最显著,以后则逐渐恢复;(3)皮下注射阿托品(0.2mg/kg)或静脉注射心得安(5mg/kg)均不能消除侧脑室注射胰高血糖素降低血清甘油三酯的作用;(4)静脉注射酚妥拉明(5mg/kg)能阻断侧脑室注射胰高血糖素的降低血清甘油三酯的作用。这些结果表明脑内的胰高血糖素对血清甘油三酯的影响可能是通过肾上腺素α-受体起作用的。     

迷走-胃泌素机制在胃液分泌神經反射期中的重要性

本工作利用具有食道瘘和新设计的胃肠四通瘘的狗进行慢性实验,以收集完整神经支配的全部胃底和胃体部的胃液分泌,观察切除胃窦前后假饲和胰岛素低血糖刺激所引起的胃酸分泌的变化,企图阐明迷走-胃泌素机制在胃液分泌神经反射期中的重要性,结果如下: (一)切除胃窦后,由于取消了迷走-胃泌素的作用,胃腺对假饲及胰岛素低血糖所引起的3.5小时总酸排出量分别较切窦前减少了86.6％及80.6％。 (二)给切除胃窦后的狗皮下注射一定量的胃泌素并与假饲同时作用,使其总酸排出量基本上恢复至切除胃窦前假饲的水平,然后分别测定单独假饲及单独注射该剂量胃泌素时的总酸排出量。结果指出,单独假饲与单独注射胃泌素的作用比例约为1∶4。这表明在胃液分泌神经反射期中迷走-胃泌素作用较迷走直接作用为强。 (三)注射胃泌素与假饲同时作用所引起的总酸排出量较两者单独作用时所引起的总酸排出量之机械总和高出约一倍。这表明迷走直接作用与迷走-胃泌素作用之间有相互加强效应。总结以上结果,可以认为:在胃液分泌的神经反射期中,确实存在有迷走直接作用和迷走-胃泌素作用两种机制,后者起着重要作用,而二者又有相互加强效应。     

下丘脑外侧区注入胃泌素对大鼠胃酸分泌的影响

本工作观察了下丘脑外侧区(LHA)、腹内侧核(VMH)或侧脑室(LCV)注射17肽胃泌素(G17)或五肽胃泌素(G5)对清醒大鼠胃酸分泌的影响。结果表明,将 G17或 G5注入 LHA可引起胃酸分泌明显增加,而将 G5注入 VMH、LCV 或静脉则不影响胃酸分泌;切断迷走神经可以阻断在 LHA 注入 G5引起胃酸分泌增加的效应;在阿托品背景下,将 G5注入 LHA仍能引起胃酸分泌明显增加;静脉注射酚妥拉明,心得安或纳洛酮均不影响 G5对 LHA 刺激胃酸分泌的作用。这些结果提示:LHA 是胃泌素作用的一个特异性部位,由 LHA 发出的冲动可能通过迷走神经内的两种传出纤维引起胃酸分泌,一为胆碱能纤维,另一为非胆碱能非肾上腺素能纤维。     

下丘脑腹内侧核Orexin-1及其受体对大鼠胃酸分泌的影响及其机制

目的:探讨下丘脑腹内侧核Orexin-1及其受体对大鼠胃酸分泌的影响及其机制。方法:大鼠麻醉后侧脑室及VMH置管,大鼠分组后分别VMH注射orexin-A、[Pro~(34)]-酪酪肽、[c PP1-7、NPY~(19-23)、Ala~(31)、Aib~(32)、Gln~(34)]胰多肽;腹腔注射SB-334867;皮下注射阿托品;侧脑室微量注射GR-231118、CGP-71683。给药结束后使用幽门结扎模型检测大鼠的胃酸分泌。结果:OXA能够促进胃酸分泌,且呈量效依赖关系。腹腔注射SB-334867能够抑制胃酸分泌,且呈量效依赖关系;SB-334867能够抑制orexin-A对胃酸分泌的促进作用;阿托品不但能够抑制胃酸分泌并且还能够完全阻断OXA的促胃酸分泌作用。侧脑室微量注射GR-231118或CGP-71683胃酸及胃液量减少,呈量效依赖关系,并且能够完全阻断OXA的促胃酸分泌作用。VMH内微量注射[cPP~(1-7),NPY~(19-23),Ala~(31),Aib~(32),Gln~(34)]胰多肽胃酸分泌增多,且呈量效依赖关系。结论:Orexin-A能够作用于下丘脑VMH促进胃酸分泌,orexin受体、Y1和Y5受体以及迷走神经系统均参与该过程。     

Inhibition of gastric and pancreatic secretions by cerebroventricular injections of gastrin-releasing peptide and bombesin in rats

It has been suggested that mammalian gastrin-releasing peptide (GRP) and bombesin (BBS) might inhibit gastric secretion by a central nervous system action. The present investigations were intended to define the gastric effect and to look for an effect on the exocrine pancreas. Wistar male rats were provided with a chronic cannula allowing cerebroventricular injections in the 3rd ventricle, and with chronic gastric and/or pancreatic fistulas allowing the collection of gastric and/or pancreatic secretions in conscious animals. Both basal secretions were studied. Gastric secretion was stimulated with a 75 mg/kg s.c. injection of 2-deoxyglucose (2-dGlc). The dose range of bombesin was 0.01–1 μg (6–600 pmol) and GRP was 0.01–10 μg/rat (3.5 pmol to 3.5 nmol). A significant dose related decrease of basal gastric secretion was observed with the two peptides. The gastric acid response to 2-dGlc was inhibited by both peptides in a dose-related fashion and the reduction of gastric acid output mainly resulted from a decrease in the volume of gastric juice. The exocrine pancreatic secretion was also decreased by 30–55% after GRP but the BBS inhibitory effect was poorly dose-related. No significant difference was found after removal of gastric secretion, indicating that most of the pancreatic inhibition was independent of gastric secretion.     

Gastric effects of thyrotropin-releasing hormone microinjected into the dorsal vagal nucleus in cats

We investigated the gastric acid secretory and motility responses to microinjection of thyrotropin-releasing hormone (TRH) into the dorsal motor nucleus of the vagus (DMV) in anesthetized cats. Gastric acid output was collected every 15 min through a gastric cannula after saline flush and titrated to pH 7.0. Antral and corpus contractions were continuously recorded by extraluminal force transducers. TRH dissolved in 200 nl of saline and microinjected unilaterally into the DMV induced a dose-dependent (50-200 ng) increase in gastric acid secretion. The acid secretory response began in the first 15 min collection and lasted 45 min. TRH frequently increased the force of contractions of the antrum and corpus within one minute of microinjection. The minimal effective dose for eliciting increased motility was lower than for inducing acid secretion. These results demonstrate that TRH acts in the DMV of cats to stimulate gastric acid secretion and contractions.     

Experimental neurosis and gastric secretion in dogs

In four dogs (2 males and 2 females from one litter) with established gastric cannula gastric secretion was studied in control experiments and in induced experimental neurosis. Gastric secretion was stimulated by insulin. We monitored in individual 15 min. portions the amount of gastric juice, total HCl output, output of acid gastric proteinases, mucoproteins and some ions. The gastric juice was dialyzed and freeze dried. 50 mg of the lyophilisate was separated on Sephadex G 100. Macromolecular substances were fractionated into glycoproteins (peak I), acid gastric proteinases (peak II) and glycopeptides and polypeptides (peak III). The ratio of these individual macromolecular substances remainded constant in the same dog in all control experiments. However, there were significant differences between individual animals. Induction of experimental neurosis (by collision of the alimentary and avoidance reflex) gave rise to changes not only in the output of HCl and gastric proteinases, but also in the ratio of macromolecular substances. In the series of observed parameters these changes were of a different nature in males and females.     

Central action of somatostatin analog, SMS 201-995, to stimulate gastric acid secretion in rats

The effects of intracisternal and intravenous injections of the somatostatin analog, SMS 201-995, on gastric acid secretion were investigated in rats with pylorus ligation or gastric cannula. Intracisternal injection of SMS 201-995 induced a dose-related (0.1-0.3 microgram) and long-lasting stimulation of gastric acid output with a peak response at 3 h postinjection in conscious, pylorus-ligated rats. Intracisternal SMS 201-995 increased histamine levels in the portal blood, whereas plasma gastrin levels were not modified. Atropine, cimetidine and adrenalectomy abolished the stimulatory effect of intracisternal SMS 201-995 (0.3 microgram). SMS 201-995 (0.03 microgram), microinjected unilaterally into the dorsal vagal complex, increased gastric acid output in urethane anesthetized rats. SMS 201-995, injected intravenously at 0.5 microgram, did not alter gastric secretion, whereas higher doses (5-20 micrograms) resulted in a dose-related inhibition of gastric acid secretion in conscious pylorus-ligated rats. These data indicate that SMS 201-995, a selective ligand for somatostatin-1 receptor subtype, induces a centrally mediated stimulatory effect on gastric acid secretion in rats. The central action involves the parasympathetic system, muscarinic and H2 receptors as well as adrenal-dependent pathways.     

Phytohaemagglutinin inhibits gastric acid but not pepsin secretion in conscious rats

Phytohaemagglutinin (PHA), a kidney bean lectin, is known for its binding capability to the small intestinal surface. There has been no data available, however, on the biological activity of PHA in the stomach. Recent observations indicate that PHA is able to attach to gastric mucosal and parietal cells. Therefore, we examined whether PHA affects gastric acid and pepsin secretion in rats. Rats were surgically prepared with chronic stainless steel gastric cannula and with indwelling polyethylene jugular vein catheter. During experiments, animals were slightly restrained. Gastric acid secretion was collected in 30 min periods. Acid secretion was determined by titration of the collected gastric juice with 0.02 N NaOH to pH 7.0. Pepsin activity was estimated by measuring enzymatic activity. Saline, pentagastrin and histamine were infused intravenously. PHA or bovine serum albumin (BSA) were dissolved in saline and given intragastrically through the gastric cannula. PHA significantly inhibited basal acid secretion. Inhibition of acid output reached 72% during the first collection period following PHA administration when compared, then gradually disappeared. Pentagastrin-stimulated acid secretion was repressed dose-dependently by PHA as well. Maximal inhibition was observed during the first 30 min following application of PHA. Histamine-stimulated acid secretion was inhibited by PHA in a similar manner. Pepsin secretion was not affected by PHA under either basal or stimulated conditions. These results provide evidence that PHA is a potent inhibitor of gastric acid secretion in conscious rats, but it does not affect pepsin output from the stomach.     

Effects of nitric oxide synthase inhibitor on the digestive system measured by simultaneous monitoring of gastric motility, gastric emptying activity and postprandial pancreaticobiliary secretion in dogs.

Relationships between the NO synthase inhibitor and gastric and pancreaticobiliary functions measured simultaneously in the digestive state have been little studied. The aim of this study was to estimate the effect of NO synthase inhibitor on integrated digestive function in conscious dogs. A strain gauge force transducer was implanted on the gastric antrum of 6 mongrel dogs to measure gastric contractile activity and two duodenal cannulas were inserted into the proximal and distal sites to measure the gastric emptying rate and the pancreaticobiliary output into the duodenum using our novel method. Postprandial pancreatic and biliary secretion were presented as amylase and bile acid activity, respectively. Furthermore, a cervical cannula was placed into the superior vena cava as a route for the administration of NO synthase inhibitor, N omega-nitro-L-arginine (L-NNA), at a dose of 2.5 mg/kg-h. In a group given L-NNA, gastric contractile activity after ingestion was significantly enhanced, but the emptying rates of gastric solids and liquids were significantly suppressed in comparison with the control. The mean 0-1 h amylase integrated output was significantly (P < 0.05) decreased in comparison with the control, and the mean bile acid integration of 0-1 h output was also significantly (P < 0.01) decreased. A possible explanation for this observation is that smaller volumes of nutrient are delivered into the duodenum; however, it could also be that postprandial pancreaticobiliary secretion is inhibited by an alteration of blood flow or by a change in contractions of the sphincter of Oddi after the administration of L-NNA.     

吗啡和纳洛酮对损毁下丘脑诱致的大鼠胃粘膜损伤之影响

本实验观察了静注吗啡和纳洛酮对电解损毁后部下丘脑诱致的大鼠胃粘膜损伤的影响并观察了在静注吗啡、纳洛酮后和侧脑室注射纳洛酮后其胃酸分泌和血清胃泌素水平之变化。实验揭示,吗啡仅略为降低该神经源性胃粘膜损伤程度,而纳洛酮则明显地减少其胃粘膜损伤;静注吗啡能抑制后部下丘脑损毁后大鼠的胃酸分泌,增加其血清胃泌素水平,而静注纳络酮后,这种大鼠的胃酸分泌增加,但血清胃泌素水平无明显变化;侧脑室注射纳洛酮对后部下丘脑损毁后大鼠胃酸分泌和血清胃泌素水平无明显影响。本结果表明,胃酸可能是导致这种消化道损伤的条件之一,而不是最重要因素;静注纳洛酮对后部下丘脑损毀后大鼠胃粘膜变化有保护作用。后者提示,内源性阿片样肽可能参与这种神经源性胃粘膜损伤的形成。     

Effect of 16,16-dimethyl prostaglandin-E2 given intra-arterially or intra-gastrically, on acid secretion by canine stomachs perfused ex vivo

Isolated whole canine stomachs, perfused ex vivo with homologous blood, were used for studying the effect of 16,16-dimethyl prostaglandin-E₂ (dmPGE₂) on gastric secretion. DmPGE₂ was administered either into the gastric artery or instilled intra-gastrically through an esophageal cannula. Histamine, infused intra-arterially, induced acid secretion of all ex vivo stomachs and this was significantly inhibited by intra-arterially or intra-gastrically administered dmPGE₂; volume of secretion, output of HCl and concentration of H⁺ were decreased and gastric peripheral vascular resistance was significantly reduced. The inhibitory action of dmPGE₂ continued after its administration was stopped.