花生油及油酸对消炎痛引起的大鼠胃粘膜损伤的保护作用

本工作研究了花生油及油酸对由消炎痛所致的大鼠胃粘膜损伤的保护作用。用花生油1.0ml,油酸0.25、0.5和1.0ml 灌胃均能明显地减轻由消炎痛引起的胃粘膜损伤,其中油酸的作用还呈现明显的量-效关系。而30%甘油、油酸乙酯、5%葡萄糖或0.1%乙酸各1.0ml灌胃则无效。将油酸注入空肠,其作用与灌胃相似。阿托品、酚妥拉明和心得安不能阻断油酸的上述保护作用。这些结果表明,花生油及油酸具有明显的保护胃粘膜的作用。油酸这种作用主要不是通过提供能量,也不是通过副交感神经和交感神经传递,而可能是通过它作用于小肠刺激多种胃肠激素释放而产生的。     

油酸对消炎痛引起的胃粘膜损伤大鼠胃粘液分泌的影响

本工作研究油酸对消炎痛引起胃粘膜损伤大鼠胃粘液分泌的影响。胃粘液测定采用阿尔新蓝(Alcian blue)与胃液中糖蛋白结合的方法。将1.0ml 油酸注入到结扎幽门的大鼠空肠内,就可引起胃壁粘液及游离粘液分泌量的明显增加。以0.25、0.5和1.0ml 油酸注入到不结扎幽门的大鼠空肠内,也能显著增加胃壁粘液分泌,保护胃粘膜。这两种作用表现着剂量依赖关系。不论以油酸灌胃或注入空肠、回肠,都能明显增加胃壁粘液量,而灌胃的作用比注入肠内更明显。以1.0ml 30%甘油、0.1%乙酸及1/15N HCl 分别注入空肠,都不能刺激胃壁粘液的分泌。上述结果表明,油酸具有刺激胃粘液分泌的作用。因此,加强胃粘液分泌可能对粘膜起到屏障作用,这是油酸保护胃粘膜损伤的机制之一。     

生长抑素对胃粘膜的保护作用可能与清除自由基有关

本文观察到生长抑素对大鼠冷冻－束缚应激性胃粘膜损伤具有明显的保护作用,同时显著地抑制应激引起的胃粘膜丙二醛含量的升高。应激时大鼠胃粘膜内黄嘌呤氧化酶的生增高,同时谷胱甙肽过氧化物酶的活性降低,但超氧化物歧化酶的活性未见明显变化,生长抑素预处理可使应激时ＧＳＨ－ＰＸ活性的降低恢复到正常水平,但对ＸＯ和ＳＯＤ未见明显影响。上述结果提示,生长抑素对应激性胃粘膜损伤的保护作用似与增强胃粘膜对自由基的清除有     

氧自由基在应激性胃溃疡中的发病学意义

本工作研究了氧自由基在大鼠冷冻束缚应激性胃溃疡中的发病学意义。实验结果如下:(1)以超氧自由基清除剂超氧化物歧化酶(SOD)或羟自由基清除剂二甲亚砜和甘露醇预先处理大鼠,均可显著地减轻胃粘膜损伤;(2)应激时,胃粘膜内的脂质过氧化分解产物丙二醛的含量显著升高;(3)组织化学的研究显示,胃粘膜层含有丰富的黄嘌呤氧化酶,其活性在应激时明显升高,预先用别嘌呤醇处理大鼠以抑制黄嘌呤氧化酶的活性,可使胃粘膜损伤显著减轻。上述结果提示,氧自由基是应激性胃溃疡的重要致病因子,而黄嘌呤氧化酶活性的升高似可能为应激时氧自由基生成增加的重要原因。     

白藜芦醇预处理对束缚应激大鼠胃溃疡的保护作用

采用水浸束缚应激(WRS)诱导大鼠急性胃粘膜损伤模型,观察胃粘膜氧化应激指标和胃液pH值的变化,探讨白藜芦醇对大鼠应激性胃溃疡的保护作用及机制。将30只wistar大鼠随机分为对照组,应激组,白藜芦醇低、中、高剂量组(30、60、120 mg/kg)。通过观察胃黏膜形态学改变,测定胃液pH值、胃溃疡指数(UI)、胃黏膜组织SOD活性及MDA含量的改变,研究不同剂量白藜芦醇对大鼠应激性胃溃疡的抑制作用及机制。结果显示白藜芦醇能明显减轻WRS大鼠胃黏膜的水肿、出血和溃疡面积,明显降低UI(P0.01);同时显著提高胃粘膜组织SOD的活性、胃液pH(P0.01)和降低MDA水平(P0.01),各指标均以白藜芦醇中剂量组作用显著。本实验结果表明白藜芦醇具有较强的抗溃疡作用,对束缚应激大鼠胃溃疡有明显保护作用,其机制主要与减少自由基产生和提高抗氧活酶活性有关。     

组蛋白去乙酰化酶抑制剂对大鼠应激性心肌损伤的保护作用

目的:观察组蛋白去乙酰化酶抑制剂在应激性心肌损伤发生过程中的作用。方法:健康雄性Wistar大鼠随机分为3组(n=6),用束缚应激方法建立慢性应激性心肌损伤模型,采用组蛋白去乙酰化酶抑制剂曲古抑菌素A(TSA)干预,观察TSA对应激性心肌损伤的保护作用。Western blot检测实验各组大鼠心肌的组蛋白乙酰化水平,采用分光光度法动态监测大鼠血清乳酸脱氢酶(LDH)和肌酸激酶同工酶-MB(CK-MB)活性以及心肌组织Caspase 3活性,Nagar Olsen染色观察心肌的早期损伤。结果:束缚应激可以显著降低大鼠心肌的组蛋白乙酰化水平(P0.05),而TSA干预可以抑制应激所致的心肌组蛋白乙酰化水平降低(P0.05);束缚应激可以引起大鼠血清LDH和CK-MB活性、心肌组织Caspase 3活性显著升高(P0.05),发生心肌早期损伤,而TSA干预可显著降低束缚应激引起的LDH(P0.05)、CK-MB活性(P0.05)、Caspase 3活性升高(P0.05)。结论:组蛋白去乙酰化酶抑制剂TSA对应激性心肌损伤具有一定的保护作用。     

白介素－1β对大鼠应激性胃粘膜损伤的保护作用

本工作观察了人重组白介素１β（ＩＬ－１β）对大鼠束缚冷冻应激造成的胃粘膜损伤的影响。外周给予ＩＬ－１β后能防止胃粘膜损伤的形成,呈剂量依从关系。ＩＬ－１片段１６３－１７１对应激性胃粘膜损伤无明显影响。但巯基物质耗竭剂Ｎ－乙烯顺丁烯二酰亚胺（Ｎ－ｅｔｈｙｌｍａｌｅｉｍｉｄｅ）能部分阻断ＩＬ－１β的作用。应激３ｈ后胃粘膜蛋白质和非蛋白质巯基含量明显降低,而ＩＬ－１β能防止巯基含量的下降。ＩＬ－１β也能减少应激造成的胃粘膜脂质过氧化产物丙二醛（ｍｏｌｏｎｄｉａｙｌｄｅｈｙｄｅ）的含量。提示ＩＬ－１β能明显减轻大鼠应激性胃粘膜损伤程度,其机制可能与胃粘膜内源性巯基物质有关。     

应激状态下NO的胃粘膜保护作用及其与壁细胞泌酸的关系

目的:探讨应激状态下一氧化氮(NO)的胃粘膜保护作用及其与壁细胞泌酸的关系.方法:采用水浸-束缚应激(WRS)方法制备应激性溃疡(SU)动物模型,检测胃粘膜溃疡指数(UI)、胃粘膜NO含量和壁细胞H ,K -ATPase活性,观察L-硝基精氨酸甲酯(L-NAME)和L-精氨酸(L-Arg)对应激后大鼠壁细胞H ,K -ATPase活性及胃粘膜损伤的影响.结果:L-NAME(20 mg·kg-1)可使胃粘膜NO含量减少(P＜0.01),壁细胞H ,K -AT-Pase活性增加(P＜0.05),并加重应激所致的胃粘膜损伤;L-Arg(300 mg·kg-1)则使胃粘膜NO含量增加(P＜0.01),壁细胞H ,K -ATPase活性下降(P＜0.05),减轻应激所致胃粘膜损伤.结论:NO对应激状态下大鼠胃粘膜具有保护作用,其机制与抑制壁细胞H ,K -ATPase活性有关.     

左金丸对实验性应激性胃溃疡的保护作用及其机制

目的探讨中药左金丸对因束缚-水浸应激引起的大鼠应激性胃溃疡胃黏膜损伤的保护作用的影响,并初步探讨其作用机制。方法将60只健康SD雄性大鼠随机分为6组,即空白对照组、模型对照组、阳性对照组、左金丸低剂量组、左金丸中剂量组和左金丸高剂量组。连续灌胃给药5 d,末次给药后禁食不禁水24 h,采用"束缚-水浸"应激法制备大鼠应激性胃溃疡模型。造模成功后进行胃体形态学观察,测量胃液p H值,计算胃溃疡指数(UI),并用酶联免疫法检测血清中前列腺素E2(PGE2)的含量。结果(1)与空白对照组比较,模型对照组大鼠胃液p H值明显降低、胃黏膜损伤指数(UI)显著升高(P0.01);与模型对照组比较,阳性对照组、左金丸中、高剂量组大鼠胃液p H值明显升高,UI明显下降(P0.01);与阳性对照组比较,左金丸高剂量组大鼠胃液p H值和UI差异无统计学意义(P0.05)。(2)与空白对照组比较,模型对照组大鼠血清中PGE2含量显著降低(P0.01);与模型对照组比较,阳性对照组和左金丸高、中剂量组大鼠血清中PGE2含量均显著升高(P0.01);与阳性对照组比较,左金丸中、高剂量组大鼠血清中PGE2的含量差异无统计学意义(P0.05)。结论 (1)左金丸对应激性胃溃疡大鼠胃黏膜具有保护作用。(2)左金丸通过升高大鼠胃液p H值和提高血清中PGE2含量,达到降低胃黏膜攻击因素和增强胃黏膜防御功能的作用,从而起到保护大鼠胃黏膜的作用。左金丸可以预防应激性胃溃疡的发生并能促进胃溃疡的愈合,其作用机制可能与提高胃液p H值从而降低胃黏膜攻击因素,促进PGE2释放从而增强胃黏膜防御功能等因素有关。(3)左金丸对应激性胃溃疡胃黏膜的保护作用在一定范围内与其浓度呈正相关关系。     

大鼠浸水应激性胃粘膜损伤机制的研究

本工作观察了室温下单纯束缚加生理盐水,浸水应激加生理盐水,浸水应激加阿托品(0.5mg/kg),浸水应激加酚苄明(10mg/kg),浸水应激加戊巴比妥钠(30mg/kg)5组大鼠的胃粘膜损伤程度,胃酸分泌,胃壁结合粘液分泌和胃运动的变化。结果表明:大鼠浸水应激后胃粘膜损伤严重,胃酸分泌增加,胃壁结合粘液分泌减少,胃运动亢进;预先应用阿托品再浸水应激可显著减轻胃粘膜损伤程度,抑制胃酸分泌和胃运动,但增加胃壁结合粘液的分泌;预先应用应巴比妥钠亦显著减轻胃粘膜损伤程度,抑制胃运动和增加胃壁结合粘液的分泌,但对胃酸分泌无影响;预先应用酚苄明对胃粘膜损伤程度、胃酸分泌、胃壁结合粘液分泌和胃运动均无明显影响。上述结果提示,胃运动亢进、胃壁结合粘液分泌减少及胃酸分泌增加均不同程度地参与了浸水应激性胃粘膜损伤的形成,但在胃运动受到抑制及胃壁结合粘液分泌增加的情况下,仅胃酸的存在不致引起胃粘膜严重损伤。     

N-acetyl-cysteine: protective agent or promoter of gastric damage?

N-acetyl-cysteine (NAC), when given orally, has been shown to prevent gastric damage induced by ethanol, but when administered intraperitoneally, it appears to potentiate such damage. In an effort to resolve these seemingly discordant findings, fasted rats (six per group) received 1 ml of saline or 20% NAC orally or intraperitoneally (ip). Two hours or 15 min later, they received 1 ml of 100% ethanol orally. At sacrifice 5 min later, rats receiving oral pretreatment with 20% NAC at both 15 and 120 min prior to ethanol exposure demonstrated a significant reduction in the magnitude of gastric injury when compared with saline controls. In contrast, actual promotion of ethanol damage was noted when NAC was given intraperitoneally, but was more pronounced when NAC was administered 15 min prior to exposing the mucosa to 100% ethanol. In all animals receiving intraperitoneal NAC, large amounts of peritoneal fluid (4-6 ml/rat) were recovered at the time of sacrifice, most of which occurred within 15 min of NAC administration; these more pronounced peritoneal effects at 15 min after NAC correlated with the more severe injury from ethanol at this time period compared to 120 min after intraperitoneal NAC. Saline controls had no peritoneal fluid. Mucosal glutathione (GSH) levels generally paralleled these results in that a significant decrease in tissue GSH occurred at 15 min following intraperitoneal NAC when compared with controls; at 120 min after intraperitoneal NAC, GSH levels were similar to control values. Additional experiments demonstrated that within 15 min following NAC administration, systemic blood pressure dropped by approximately 20% and basically remained unchanged over the next 2 hr; intraperitoneal saline had no sustained adverse effects on blood pressure. It was concluded that the inability of NAC to prevent ethanol injury when given intraperitoneally in contrast to orally is related to the drop in blood pressure secondary to NAC's peritoneal irritant effects, which presumably altered gastric mucosal blood flow, thus obivating its ability to prevent ethanol damage under these conditions. Furthermore, the decreased levels in mucosal GSH following the hypotension induced by intraperitoneal NAC suggest that perturbations in GSH metabolism may also have contributed to the decreased resistance to ethanol injury.     

Differences in action of topical and systemic cysteamine on gastric blood flow,gastric acid secretion and gastric ulceration in the rat

The effect of cysteamine on gastric blood flow and on the indomethacin-induced gastric mucosal damage was studied. In anesthetized rats, cysteamine (280 mg/kg) given subcutaneously (sc) decreased gastric blood flow measured by the laser Doppler flowmetry technique. In contrast, cysteamine (1–60 mg/ml) applied topically to the serosal surface of the stomach evoked a concentration-dependent and long-lasting increase in gastric blood flow. At 60 mg/ml, cysteamine increased blood flow by 166.8 ± 26.1% of predrug control value. Pretreatment with indomethacin (20 mg/kg, sc), intravenous (iv) atropine (1 mg/kg), propranolol (1 mg/kg, iv), combined H₁ and H₂-blockade or bilateral cervical vagotomy alone or combined with iv guanethidine (8 mg/kg), or pretreatment with the capsaicin analogue resiniferatoxin did not reduce the vasodilator response to cysteamine. The vasodilator response to topical capsaicin, was not reduced after sc cysteamine (280 mg/kg) pretreatment. In conscious pylorus-ligated rats, sc cysteamine (100 or 280 mg/kg) given simultaneously with indomethacin inhibited gastric acid output but had variable effects on the indomethacin-induced gastric mucosal damage. Cysteamine (100 or 280 mg/kg) administered sc 4 h prior to indomethacin enhanced gastric injury by sc indomethacin, but did not prevent the gastroprotective action of capsaicin. In contrast, orally administered cysteamine (60 mg/ml) reduced gastric injury induced by sc indomethacin plus intragastric HCl. These data provide the first evidence for the effect of cysteamine on gastric microcirculation in the rat and suggest a direct vasodilator effect for topical cysteamine. The microvascular effects of cysteamine are largely responsible for the different effects of this agent on experimental gastric injury.     

Correlation of gastric mucosal damage with sialic acid profile in rats: effect of hydrochloric acid, pepsin and hypertonic saline

Sialic acids occupy terminal positions on gastric mucus glycoprotein where they contribute to the high viscosity of mucin. Desialylation of mucus may lead to degradation of the mucus and eventually to the breakdown of the gastric mucus barrier. The effect of a variety of damaging agents (0.1 M HCl, 2 mg ml(-1) pepsin and 2 M NaCl) on sialic acid profile was determined in pylorus-ligated rats. The relationship between sialic acid, galactose, pyruvate and the extent of gastric mucosal damage were studied. Instillation of pepsin significantly increased total sialic acid, galactose and macroscopic mucosal lesions in the stomach. Instillation of 0.1 M HCl reduced the total sialic acid but this decrease was not significant. Acidity led to a significant increase in the amount of free sialic acid in the gastric instillates and the macroscopic lesions induced by acid was not significantly different from the control animals (0.15 M NaCl). 2 M NaCl induced the macroscopic lesions in the stomach and also free sialic acid in the instillates. Pepsin potentiates the action of 2 M NaCl. In all the agents examined with the exception of acid, it was observed that an increase in free sialic acid and galactose was accompanied by gastric mucosal erosion and elevation of pyruvate concentration. It is concluded that gastric acidity alone is not inherently damaging and that resistance of gastric mucosa to destructive agents may be dependent on the integrity of the sialic acids.     

Close arterial infusion of calcitonin gene-related peptide into the rat stomach inhibits aspirin- and ethanol-induced hemorrhagic damage

Afferent neuron-mediated gastric mucosal protection has been suggested to result from the local release of vasodilator peptides such as calcitonin gene-related peptide (CGRP) from afferent nerve endings within the stomach. The present study, therefore, examined whether rat alpha-CGRP, administered via different routes, is able to protect against mucosal injury induced by gastric perfusion with 25% ethanol or acidified aspirin (25 mM, pH 1.5) in urethane-anesthetized rats. Close arterial infusion of CGRP (15 pmol/min) to the stomach, via a catheter placed in the abdominal aorta proximal to the celiac artery, significantly reduced gross mucosal damage caused by ethanol and aspirin whereas mean arterial blood pressure (BP) was not altered. Intravenous infusion of CGRP (50 pmol/min) did not affect aspirin-induced mucosal injury but significantly enhanced ethanol-induced lesion formation. Intravenous CGRP (50 pmol/min) also lowered BP and increased the gastric clearance of [14C]aminopyrine, an indirect measure of gastric mucosal blood flow while basal gastric output of acid and bicarbonate was not altered. Intragastric administration of CGRP (260 nM) significantly inhibited aspirin-induced mucosal damage but did not influence damage in response to ethanol. BP, gastric clearance of [14C]aminopyrine, and gastric output of acid and bicarbonate remained unaltered by intragastric CGRP. These data indicate that only close arterial administration of CGRP to the rat stomach, at doses devoid of a systemic hypotensive effect, is able to protect against both ethanol- and aspirin-induced mucosal damage. As this route of administration closely resembles local release of the peptide in the stomach, CGRP may be considered as a candidate mediator of afferent nerve-induced gastric mucosal protection.     

Mucosal damage induced by preferential COX-1 and COX-2 inhibitors: role of prostaglandins and inflammatory response

Nonsteroidal anti-inflammatory drugs (NSAID) are well known to induce gastric mucosal damage including bleeding, ulceration and perforation in humans and animals too. These effects are related with the inhibition of the enzyme cyclooxygenase, which is the main established mechanism of action for these drugs. Fasted rats were given piroxicam, preferential COX-1 inhibitor (10-20 mg/kg) or meloxicam, preferential COX-2 inhibitor (7.5-15 mg/kg) orally. Six or nine hours (h) later, respectively, the stomach was excised, the severity of the damage assessed and myeloperoxidase (MPO) activity measured, as well as prostaglandin PGE(2) content. Furthermore, in order to assess the effects of these oxicams over previously damaged gastric mucosa, 1 ml of 0.6 N HCl was administered p.o. followed, 1 h after, of the correspondent dose of each NSAID, and the same parameters were determined. Oral administration of both drugs dose-dependently caused acute gastric haemorrhage erosions. Myeloperoxidase activity was significantly increased by piroxicam administration. In addition, PGE(2) content was significantly reduced. The association between the administration of the acid and NSAID caused a worsening of the damage and, while myeloperoxidase activity did not modify by both piroxicam and meloxicam, PGE(2) levels were reduced. These results suggest that the PG derived from both COX-1 and COX-2 pathway plays a beneficial role in the gastroprotection, and thus caution should be exercise in the clinical use of preferential COX-2 inhibitors.     

Effects of prostaglandin E2, 16,16-dimethyl prostaglandin E2 and a prostaglandin endoperoxide analogue (U-46619) on gastric secretory volume, [H+] and mucus synthesis and secretion in the rat

The effects of orally administered prostaglandin E2, 16,16-dimethyl prostaglandin E2 and U-46619, an analogue of the prostaglandin endoperoxide PGH2, on gastric secretory volume, acid and mucus were studied in the rat. All of the compounds significantly increased the volume of gastric secretion, mucus secretion, measured as N-acetylneuraminic acid and mucus synthesis measured as the incorporation of [3H]-glucosamine into mucosal glycoprotein; however, only PGE2 and 16,16-dimethyl PGE2 inhibited acid secretion. U-46619, 1.5 mg/kg provided significant protection against ethanol-induced gastric ulcers, an effect that has been previously shown for the other two compounds. These studies provide additional evidence that prostaglandin induced mucosal protection may be related to an effect on mucus and on stimulation of nonparietal cell gastric secretion. Further study of these parameters may be important in the development of antiulcer drugs for long term clinical use.     

Vegetable oils used as vitamin E vehicle affect the electrical activity of the rat heart

The aim of this study is to define the possible effects of vegetable oils used as vitamin E vehicle on the electrical activity of the rat heart. To test the possible effects of vitamin E vehicles we studied the effect of i.p. injected corn oil, hazelnut oil or peanut oil on the action potential parameters recorded in both papillary and left atrial muscle strips. Four experimental groups were used. The control group was injected (i.p.) with distilled water, while the three remaining groups received injections of corn oil, hazelnut oil, or peanut oil for five weeks (in a dose of 0.4 ml/kg/day--minimum amount of oil in which vitamin E could be dissolved). We used borosilicated (15-20 megaohms) capillary electrodes and intracellular action potentials (AP) were recorded in isolated papillary and left atrium muscle strips. While administration of three different types of vegetable oil had no significant effect on AP parameters of papillary muscle, they significantly prolonged the repolarization phase of AP in atrial strips. These results show that vegetable oils used as vitamin E vehicles may alter the electrical activity of the heart in a tissue-dependent manner. The present data indicate that the possible effect of vegetable oil vehicles should be kept in mind while evaluating the possible effects of in vivo vitamin E administration.     

Preventive Effects of Tocotrienol on Stress-Induced Gastric Mucosal Lesions and Its Relation to Oxidative and Inflammatory Biomarkers

This study aimed to investigate the possible gastroprotective effect of tocotrienol against water-immersion restraint stress (WIRS) induced gastric ulcers in rats by measuring its effect on gastric mucosal nitric oxide (NO), oxidative stress, and inflammatory biomarkers. Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) orally. After 28 days, rats from one control group and both treated groups were subjected to WIRS for 3.5 hours once. Malondialdehyde (MDA), NO content, and superoxide dismutase (SOD) activity were assayed in gastric tissue homogenates. Gastric tissue SOD, iNOS, TNF-α and IL1-β expression were measured. WIRS increased the gastric MDA, NO, and pro-inflammatory cytokines levels significantly when compared to the non-stressed control group. Administration of tocotrienol and omeprazole displayed significant protection against gastric ulcers induced by exposure to WIRS by correction of both ulcer score and MDA content. Tissue content of TNF-α and SOD activity were markedly reduced by the treatment with tocotrienol but not omeprazole. Tocotrienol significantly corrected nitrite to near normal levels and attenuated iNOS gene expression, which was upregulated in this ulcer model. In conclusion, oral supplementation with tocotrienol provides a gastroprotective effect in WIRS-induced ulcers. Gastroprotection is mediated through 1) free radical scavenging activity, 2) the increase in gastric mucosal antioxidant enzyme activity, 3) normalisation of gastric mucosal NO through reduction of iNOS expression, and 4) attenuation of inflammatory cytokines. In comparison to omeprazole, it exerts similar effectiveness but has a more diverse mechanism of protection, particularly through its effect on NO, SOD activity, and TNF-α.