一氧化氮对急性肝功能衰竭大鼠脏器影响的实验研究

１．资料与方祛：选用雄性Ｗｉｓｔａｒ大鼠（湖南医科大学实验动物中心提供）５０只,体重２５０～３５０ｇ,随机分为５组：假手术（ＳＯ）组、急性肝功能衰竭（ＡＬＦ）组、左旋精氨酸（Ｌ－Ａｒｇ）组、左旋甲基精氨酸甲酯（Ｌ－ＮＡＭＥ）组及Ｌ－Ａｒｇ＋Ｌ－ＮＡＭＥ组,每组１０只。切除大鼠肝左叶和中叶,右叶和尾状叶热缺血ｌｈ建立ＡＬＦ模型,Ｌ－Ａｒｇ组、Ｌ－ＮＡＭＥ组手术前后３０ｍｉｎ经尾静脉注入用生理盐水稀释的Ｌ－Ａｒｇ或Ｌ－ＮＡＭＥ;Ｌ－Ａｒｇ＋Ｌ－ＮＡＭＥ组手术前３０ｍｉｎ经尾静脉注入Ｌ－Ａｒｇ,间隔３…     

一氧化氮在肝损伤中作用的实验研究

材料与方法：１．动物模型的复制及分组：雄性ｗｉｓｔａｒ大鼠,随机分成六组。除正常对照组外,各组均给予１０％Ｄ－半乳糖胺（Ｄ－Ｇａ１Ｎ）０．６ｇ／ｋｇ及大肠杆菌Ｏ１１１Ｂ４脂多糖（ＬＰＳ）０．１ｍｇ／ｋｇ腹腔注射,造成大鼠急性肝损伤模型。并分别于给Ｄ－ＧａｌＮ前２０分钟及后６小时、１１小时,精氨酸（Ａｒｓ）组给子Ｌ－Ａｒｇ０．５ｇ／ｋｇ腹腔注射;Ａｒｇ一硝基精氨酸甲酯（ＮＡＭＥ）组给予Ｌ－Ａｒｇ０．５ｇ／ｋｇ加Ｌ一ＮＡＭＥ５０ｍｇ／ｋｇ;ＮＡＭＥ组给予Ｌ－ＮＡＭＥ１０ｍｇ／ｋｇ;地塞米松（Ｄｅｘ）…     

内源性一氧化氮在哮喘大鼠气道高反应性中的作用

目的　利用一氧化氮合成前体Ｌ精氨酸（ＬＡｒｇ） 和一氧化氮合酶抑制剂亚硝基Ｌ精氨酸甲酯（ＬＮＡＭＥ）研究内源性一氧化氮在哮喘大鼠气道高反应性中的作用,探讨支气管哮喘的发病机制。方法　用卵白蛋白作为致敏原制备哮喘大鼠模型,建立大鼠离体气管环张力的测定方法,并用ＬＡｒｇ、ＬＮＡＭＥ和ＬＡｒｇ＋ ＬＮＡＭＥ孵育离体气管环,观察气管环乙酰胆碱浓度反应曲线和最大收缩反应的变化,同时观察去上皮对哮喘大鼠气道反应性的影响。结果　哮喘大鼠（１０ 只） 离体气管环经ＬＮＡＭＥ１０５ ｍｏｌ／Ｌ孵育后对乙酰胆碱的最大收缩反应从孵育前（１２４±３９） ｍｇ 上升到（１８７ ±５３） ｍｇ,孵育前、后最大收缩反应比较差异具有显著性（ Ｐ＜ ０．０１）,浓度反应曲线上移,而ＬＡｒｇ 可以逆转ＬＮＡＭＥ的作用,单用ＬＡｒｇ ２×１０５ ｍｏｌ／Ｌ和ＬＡｒｇ１０３ ｍｏｌ／Ｌ孵育气管环,对哮喘大鼠气管环的最大收缩反应和浓度反应曲线与对照组比较,差异无显著性（ Ｐ＞ ０．０５） 。去上皮哮喘大鼠气管环的反应性与上皮完整气管环比较差异有显著性（ Ｐ＜ ０．００５） ,而ＬＡｒｇ、ＬＮＡＭＥ＋ ＬＡｒｇ 和ＬＮＡＭＥ孵育去上     

L一精氨酸及L-NAME对大鼠胃粘膜保护因素影响的研究

Ｌ一精氨酸及Ｌ－ＮＡＭＥ对大鼠胃粘膜保护因素影响的研究侯晓华，刘劲松，钱伟ＮＯ（一氧化氮）具有广泛的生物活性。参与体内的多种生理和病理过程，１９８９年发现其与胃粘膜保护功能有关［１］。我们通过ＮＯ的前体Ｌ－精氨酸（Ｌ－Ａｒｇ）和抑制剂Ｌ－ＮＡＭＥ对鼠...     

一氧化氮在高脂饲养兔胸主动脉的变化和意义

观察高脂饲养兔胸主动脉血管环对去甲肾上腺素（ＮＥ）的反应性及环磷酸鸟苷（ｃＧＭＰ）含量的变化。结果表明其对ＮＥ的反应性降低，组织ｃＧＭＰ的含量减少。左旋精氨酸（Ｌ－Ａｒｇ）和硝普钠（ＳＮＰ）可恢复此反应性，而一氧化氮合成酶（ＮＯＳ）阻滞剂Ｌ－硝基精氨酸（Ｌ－ＮＮＡ）却加重其降低的反应性。提示高脂饲养兔血管环中的一氧化氮（ＮＯ）减少，Ｌ－Ａｒｇ及ＳＮＰ可以逆转之，暗示Ｌ－Ａｒｇ／ＮＯ通路障碍可能是动脉粥样硬化的又一机理。     

高血压病人血小板L—精氨酸／一氧化氮系统的改变

目的原发性高血压（ＥＨ）病人（２３例）与健康成年人（１４）例作对照，观察高血压时血小板（Ｐｔ）左旋精氨酸（Ｌ－Ａｒｇ）－一氧化氮（ＮＯ）系统的改变及Ｌ－Ａｒｇ转运的特征。方法微盘测定法测定血小板孵育液中亚硝酸盐（ＮＯ２－）的含量来反映ＮＯ产生量、ＡＤＰ刺激下ＮＯ的产生量；采用张新波等建立的一氧化氮合酶（ＮＯＳ）测定改良法测定血小板ＮＯＳ活性；放射性同位素标记测定血小板３Ｈ－Ｌ－Ａｒｇ转运的动力学特征。结果ＥＨ患者Ｐｔ的ＮＯ产生量及ＮＯＳ活性较对照组明显降低（Ｐ＜０．０１），用ＡＤＰ刺激后，ＥＨ患者Ｐｔ的ＮＯ增加量仅为正常对照组增加量的６０％，其Ｌ－Ａｒｇ转运能力亦显著低于正常人（各浓度点Ｐ均＜０．０１）。最大转运速率（Ｖｍａｘ）仅为正常人的７９％（Ｐ＜０．０１），而米氏常数（Ｋｍ）则无明显改变（Ｐ＞０．０５）。结论高血压时Ｐｔ的Ｌ－Ａｒｇ－ＮＯ系统存在明显异常，提示对ＥＨ患者，在降压的同时，联合应用改善Ｌ－Ａｒｇ－ＮＯ系统的药物，对预防和治疗高血压减少并发症可能会有更好的效果。     

胰岛素抵抗高血压大鼠血小板L—精氨酸／一氧化氮系统的改变

目的 观察胰岛素抵抗高血压大鼠血小板Ｌ－精氨酸／一氧化氮系统的改变。方法 自发性高血压大鼠（ＳＨＲ）自第５周至第１０周喂信果糖,制备胰岛素抵抗高血压大鼠（ＩＲ）模型。在此模型上,检测血小板一氧化氮合酶（ＮＯＳ）活性、一氧化氮（ＮＯ）产生量及Ｌ－精氨酸（Ｌ－Ａｒｇ）转运特征,同时观察了血浆Ｌ－Ａｒｇ水平、心纳素（ＮＡＰ）、ＮＯ水平及ｃＧＭＰ水平。结果 ＳＨＲ大鼠收缩压（ＳＢＰ）（Ｐ〈０．０１）,血浆     

NO,AngⅡ对大鼠主动脉内皮细胞功能及形态学影响的实验研究

目的：通过培养的大鼠主动脉内皮细胞,观察ＡｎｇⅡ对ＥＣ分泌ＮＯ,ＥＴ－１的影响及形态学变化和ＮＯ的前体物Ｌ－Ａｒｇ 对ＡｎｇⅡ的抵消作用及对ＥＣ的保护作用。结果：随ＡｎｇⅡ浓度增高ＥＣ生成ＮＯ减低,分泌ＥＴ－１ 增加,加入Ｌ－Ａｒｇ 及卡托普利后ＮＯ生成回升,ＥＴ－１ 分泌减低;高浓度ＡｎｇⅡ及ＬＤＬ胆固醇使ＥＣ释放ＬＤＨ增加,细胞收缩。适量Ｌ－Ａｒｇ 可改善之。结论：高浓度ＡｎｇⅡ,ＥＴ－１ 及ＮＯ生成量减低可能加速ＡＳ及高血压的发生发展     

静滴L—精氨酸对原发性高血压影响的研究

从血流动力学及神经内分泌学两方面探讨左旋精氨酸（Ｌ－Ａｒｇ）－一氧化氮（ｎｉｔｒｉｃｏｘｉｄｅ，ＮＯ）通路对原发性高血压的影响。方法２６例高血压病人分为两组，一组静滴Ｌ－Ａｒｇ，一组静滴生理盐水，观察其血压、心率及心功能的变化，同时检测血中ＮＯ、ｃＧＭＰ、肾上腺素（Ｅ）、去甲肾上腺素（ＮＥ）以探讨其降压机理。结果在Ｌ－Ａｒｇ静注期间，病人血压下降，心率增快，心输出量（ＣＯ）、每搏输出量（ＳＶ）、射血分数（ＥＦ）增加，总外周阻力（ＴＰＲ）降低，ＮＯ的标志物ｃＧＭＰ升高。而在滴注６０＇时，随着ｃＧＭＰ浓度的降低，ＣＯ、ＳＶ、ＥＦ也随之降低，而ＴＰＲ复又回升。Ｅ、ＮＥ、Ｎｉｔｒｉｔｅ及Ｎｉｔｒａｔｅ在静滴前后无显著性改变。结论Ｌ－Ａｒｇ通过使ｃＧＭＰ浓度升高，引起明显的血流动力学改变；Ｌ－Ａｒｇ可能抑制血压过低所致的反应性Ｅ及ＮＥ的升高作用。     

左旋精氨酸对家兔心肌缺血再灌注损伤的保护作用

目的探讨左旋精氨酸（Ｌ－Ａｒｇ）对心肌缺血再灌注损伤（ＭＩＲＩ）的保护作用。方法制备家兔ＭＩＲＩ模型,观察Ｌ－Ａｒｇ对血清中和心肌组织中一氧化氮代谢产物（ＮＯＰ）含量、乳酸脱氢酶（ＬＤＨ）活性及心肌细胞形态学变化的影响。结果Ｌ－Ａｒｇ保护组和非保护组比较,血清及心肌ＮＯＰ明显升高（Ｐ＜０．０５）;心肌ＬＤＨ显著增高（Ｐ＜０．０５）,而血清ＬＤＨ无明显变化;心肌细胞形态学异常改变明显减轻。结论Ｌ－Ａｒｇ通过提高机体一氧化氮水平而保护缺血再灌注损伤的心肌。     

Gastric adaptation to injury by repeated doses of aspirin strengthens mucosal defence against subsequent exposure to various strong irritants in rats.

Gastric adaptation to injury during repeated doses of acetyl salicylic acid (ASA) is a well documented finding but it is not known whether this adaptation affects the tolerance of the mucosa to other strong irritants. Gastric adaptation was induced by repeated daily doses of acidified ASA (100 mg/kg in 1.5 ml of 0.2 N HCl) given intragastrically (series A rats). Control rats with an intact stomach were given daily intragastric vehicle only (1.5 ml of 0.2 N HCl) (series B). After full adaptation to ASA (5 days), rats were challenged again with acidified ASA or, for comparison, with strong irritants such as 100% ethanol, 200 mM acidified taurocholate, or 25% NaCl for 1 hour or with water immersion and restraint for 3.5 hours. The first dose of ASA produced numerous gastric lesions and deep histological necrosis accompanied by a fall in the gastric blood flow, negligible expression of epidermal growth factor (EGF) and transforming growth factor alpha (TGF alpha) or their receptors, and no evidence of mucosal proliferation. As adaptation to ASA developed, however, the areas of gastric lesions were reduced by more than 80% and there was a noticeable decrease in deep necrosis, a partial restoration of gastric blood flow, an approximately four-fold increase in EGF expression (but not in TGF alpha) and its receptors, and an appreciable increase in mucosal cell proliferation compared with vehicle treated rats. Increases in the mucosal expression of EGF receptors and the luminal content of EGF were also found in ASA adapted animals. In ASA adapted rats subsequently challenged with 100% ethanol, 200 mM TC, 25% NaCl, or stress, the area of the gastric lesions and deep histological necrosis were appreciably reduced compared with values in vehicle treated rats. This increased mucosal tolerance to strong irritants was also accompanied by the return of the gastric blood flow towards control levels and further significant increases in the mucosal expression of EGF receptors and mucosal cell proliferation. Gastric adaptation to ASA enhances the mucosal resistance to injury by strong irritants probably as a result of the restoration of the gastric blood flow and increased cell proliferation that may result from increased mucosal expression of EGF and its receptors.     

Adaptation of the gastric mucosa to repeated administration of aspirin in the rat

The effects of single and repeated doses of aspirin on the gastric mucosa of the rat were compared to determine whether the mucosal response alters after repeated aspirin. Aspirin (120 mg/kg) was administered by esophageal intubation either as a single dose or daily for 3, 14, 28 and 56 days. Mucosal damage was present in all treated rats but, on histologic quantitation, there was a highly significant reduction in the numbers of acute erosions in the groups receiving repeated daily aspirin. This apparent adaptation did not persist when aspirin administration was interrupted for 3 days. Repeated aspirin administration was not associated with any reduction in aspirin absorption or excretion, nor was there any significant change in hydrochloric acid or pepsin secretion. The investigation has shown an adaptation to repeated aspirin in the rat which appears to result from an alteration in the gastric mucosa. The precise mechanism of the adaptation remains uncertain.Supported by the National Health and Medical Research Council and the Alfred Hospital.Presented, in part, to the Gastroenterological Society of Australia, May 1971.     

Role of gastric blood flow, neutrophil infiltration, and mucosal cell proliferation in gastric adaptation to aspirin in the rat.

Gastric mucosa exhibits the ability to adapt to ulcerogenic action of aspirin but the mechanism of this phenomenon is unknown. In this study, acute gastric lesions were produced by single or repeated doses of acidified aspirin in rats with intact or resected salivary glands and with intact or suppressed synthase of nitric oxide. A single oral dose of aspirin produced a dose dependent increase in gastric lesions accompanied by considerable blood neutrophilia and mucosal neutrophil infiltration, significant reduction in gastric blood flow, and almost complete suppression of biosynthesis of prostaglandins. After rechallenge with aspirin, the mucosal damage became smaller and progressively declined with repeated aspirin insults. Gastric adaptation to aspirin was accompanied by a significant rise in gastric blood flow, reduction in both blood neutrophilia and mucosal neutrophil infiltration, and a remarkable increase in mucosal cell regeneration and mucosal content of epidermal growth factor. Salivectomy, which reduced the mucosal content of epidermal growth factor, aggravated the initial mucosal damage induced by the first exposure to acidified aspirin but did not prevent the adaptation of this mucosa to repeated aspirin insults. Pretreatment with NG-nitro-L-arginine (L-NNA), a specific inhibitor of nitric oxide synthase, eliminated the hyperaemic response to repeated aspirin but did not abolish the development of adaptation to aspirin showing that the maintenance of the gastric blood flow plays little part in this adaptation. In conclusion, the stomach adapts readily to repeated aspirin insults and this is accompanied by a considerable reduction in blood neutrophilia and the severity of neutrophil infiltration and by an extensive proliferation of mucosal cells possibly involving epidermal growth factor.     

Do Infiltrating Leukocytes Contribute to the Adaptation of Human Gastric Mucosa to Continued Aspirin Administration?

Stachura J, Konturek JW. Dembinski A, Domschke W. Do infiltrating leukocytes contribute to the adaptation of human gastric mucosa to continued aspirin administration? Scand J Gastroenterol 1994:29:966-972.

Background: Aspirin (ASA)-induced gastropathy decreases with continued ASA ingestion due to the development of gastric mucosal tolerance. However, the mechanism of the gastric mucosal adaptation to repeated ASA challenge is unknown.

Methods: The aim of the present study was to determine the density of leukocytes infiltrating the gastric mucosa in healthy subjects during prolonged treatment with ASA. In eight healthy volunteers ASA treatment (2 g/day) was continued for 14 days. Endoscopy was performed before medication, on the 3rd, 7th. and 14th day of ASA treatment, and on the 16th and 18th day (2 and 4 days after medication was stopped). Gastric damage was scored (Lanza score), and gastric biopsy specimens were taken from both the oxyntic and antral mucosa.

Results: ASA administration resulted in the development of hemorrhagic erosions, which were most severe on the 3rd day of the medication; later significant reduction of severity of the damage was observed. ASA administration caused an increased mucosal infiltration of leukocytes; leukocyte margination and adherence to endothelia were commonly observed in the gastric mucosa, particularly on the 3rd day of ASA treatment but not later on. Mast cell density increased significantly on the 3rd day of ASA treatment. Density of mast cells later decreased in the antral mucosa but continued to be significantly increased in the oxyntic mucosa up to the 14th day. There was a striking correspondence between mast cell density and endoscopic score of the mucosal damage. Eosinophil density increased significantly during ASA treatment and remained high even alter medication was withdrawn.

Conclusions: 1) Initial mucosal damage by ASA is followed by gastric adaptation on continuous exposure to this agent; 2) infiltrating leukocytes appear to contribute to the development of gastric mucosal adaptation to ASA; and 3) mast cell density reflects the endoscopic score of gastric damage by ASA.     

Effect of sialoadenectomy on gastric mucosal integrity and growth in the rat

The effect of removal of the submandibular-sublingual salivary gland (sialoadenectomy) has been examined in terms of the effects on the susceptibility of the gastric mucosa to the inflammatory and damaging actions of ethanol. In addition, the effects of sialoadenectomy on cell turnover in the gastric mucosa has been examined. Animals were examined at one to five weeks after removal of the submandibular-sublingual salivary gland complex. In response to 100% w/v ethanol, sialoadenectomized rat displayed greater hemorrhagic damage to the gastric mucosa than sham-operated control rats. The difference between sialoadenectomized and sham control rats was significant at two to five weeks after surgery. The rate of [³H]thymidine incorporation into gastric mucosa was significantly reduced in sialoadenectomized rats at one and two weeks. Mucosal DNA concentration was significantly reduced in sialoadenectomized rats at four and five weeks after surgery. Mucosal myeloperoxidase activity was greater in sialoadenectomized rats treated with ethanol compared to control animals, but this difference was only significant at two weeks after surgery. Sialoadenectomy was also associated with a reduction in duodenal and gastric mucosal levels of immunoreactive epidermal growth factor (EGF). Differences between sialoadenectomized and control rats were not significant until three to four weeks after surgery. These data indicate that sialoadenectomy was associated with an increase in the susceptibility of rat gastric mucosa to ethanol-mediated damage. Sialoadenectomy also resulted in a reduction in gastric mucosal growth and gastroduodenal mucosal levels of EGF. However, the influence of sialoadenectomy on the susceptibility of the rat gastric mucosa to ethanol-mediated damage occurred prior to any significant effect on mucosal DNA concentration or EGF levels.This work was supported by a grant from the Medical Research Council of Canada, Grant No. MT6426.     

正加速度暴露对大鼠应激性胃黏膜损伤和血浆EGF、CGRP的影响

目的 观察不同正加速度暴露值对大鼠胃黏膜的损伤和胃液EGF含量及降钙素基因相关肽（CGRP）水平的影响,探讨高正加速度值暴露后大鼠胃黏膜损伤的可能发生机制.方法 40只雄性Wistar大鼠随机分成4组：对照组（＋1Gz值,n=10）、＋5Gz值组（n=10）、＋10 Gz值组（n=10）、重复暴露组（n=10）.＋5 Gz值暴露组、＋10 Gz值组均连续暴露5 min;重复暴露组：＋5Gz值下暴露1.5 min,＋10 Gz值连续暴露2 min,＋5 Gz值连续暴露1.5 min.大鼠上机前每只大鼠专用一个固定盒,保证加速度作用的方向.大鼠头朝向离心机轴心,仰面固定于离心机转臂远端,每组10只同时上机.采用梯形正加速度作用曲线,G值增长率1 G/s,由计算机进行加速度程序控制.每组下离心机后,光镜下用游标卡尺检测胃黏膜损伤指数,生化比色法检测血浆EGF和CGRP含量并分析其相互关系.结果 各组胃黏膜损伤指数：重复暴露组＞＋10Gz值组＞＋5Gz值组＞对照组.＋5Gz值组与对照组相比胃黏膜损伤指数差异无统计学意义（P＞0.05）,＋ 10Gz值组、重复暴露组与对照组比较,差异均具有显著统计学意义（P＜0.01）.各组大鼠血浆EGF含量：重复暴露组＜＋10Gz值组＜＋5Gz值组＜对照组.＋5Gz值组与对照组相比血浆EGF含量差异无统计学意义（P＞0.05）,＋ 10Gz值组、重复暴露组与对照组比较,差异具有显著统计学意义（P＜0.01）.各组大鼠血浆CGRP含量：重复暴露组＜＋ 10Gz值组＜＋5Gz值组＜对照组.各实验组与对照组相比血浆CGRP含量差异均具有统计学意义（P＜0.05）.结论 正加速度值暴露对大鼠胃黏膜有损伤作用,在越高正加速度值暴露和正加速度重复暴露下,胃黏膜受损程度越重,血浆EGF和CGRP含量越低.高正加速度值暴露和重复加速度暴露造成大鼠的急性胃黏膜病变与胃黏膜的保护因子EGF和CGRP表达有关.     

Influence of L-NAME and L-Arg on ischaemia-reperfusion induced gastric mucosa damage

OBJECTIVE: The aim of this study was to investigate effects of L-NAME and L-Arginine on gastric mucosal injury induced by ischaemia-reperfusion. METHODS: In the experiment, 20 New Zealand rabbits were used (2700-3000 g). Celiac artery was clamped for 30 min for ischaemia and then 60 min of reperfusion followed this after all rabbits were anaesthetized. In the Sham-control group (G 1, n = 5), laparotomy was performed, and the celiac artery was prepared without clipping. Group 2 (Untreated, n = 5) rabbits were only subjected to ischaemia-reperfusion. Group 3 (n = 5) rabbits had L-Arginine Methyl Ester (L-Arg) 3 mg/kg/min as i.v. infusion during the first 15 min of the reperfusion. Group 4 (n = 5) rabbits had a nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME) 100 micrograms/kg/min i.v. during the first 15 min of the reperfusion. After 60 min of reperfusion, the rabbits were killed, and their stomachs were removed for histopathologic evaluation and determination of malondialdehyde (MDA) level. RESULTS: After ischaemia-reperfusion, Untreated group had macroscopic necrosis involving 50 +/- 6% of total gastric mucosa area and deep mucosal necrosis involving 10 +/- 5% of mucosal strips. In the group treated with L-NAME, macroscopic mucosal necrosis involved 52 +/- 6% of total gastric mucosa area and deep mucosal necrosis involved 11 +/- 3% of mucosal strips (both p > 0.05 versus Untreated group). L-Arg treatment significantly reduced macroscopic mucosal necrosis area to 20 +/- 6% and deep mucosal necrosis to 3 +/- 1% (both p < 0.05 versus Untreated group and L-NAME group). MDA level in the L-Arg group was significantly lower when compared to control and L-NAME group MDA level (p < 0.05). CONCLUSION: These results suggest that NO increase induced by L-Arginine injection is involved in the protection of gastric mucosa after ischaemia-reperfusion.     

Gastric cytoprotection by prostaglandins, ranitidine, and probanthine in rats. Role of endogenous prostaglandins

Intragastric administration of aspirin (ASA) plus 0.15 M HCl to fasted rats produced typical gastric ulcers accompanied by almost complete disappearance of mucosal prostaglandins (PGs). Pretreatment with various exogenous PGs that were biologically inactive (e.g. 6-keto-PGF1 alpha or PGF2 beta) or active (PGE2 and PGI2) but used in non-antisecretory doses prevented the formation of these gastric lesions ('cytoprotection'). Besides PGs, antisecretory compounds such as ranitidine, a new H2-receptor antagonist, and probanthine were also found to be cytoprotective, even when given in non-antisecretory doses. Mucosal generation of PGs in animals treated with ASA and HCl plus ranitidine or probanthine was very low and not significantly different from those receiving only ASA and HCl. Thus, the cytoprotection appears to be the property not only of PGs but also of conventional gastric antisecretory compounds such as H2-receptor antagonists or anticholinergics. This cytoprotection can be demonstrated under conditions excluding any role of gastric secretory inhibition and in the absence of endogenous PGs.     

Parenteral aspirin and sodium salicylate are equally injurious to the rat gastric mucosa

The effects of parenteral aspirin (ASA) or sodium salicylate (SA) on the gastric mucosa were investigated in anesthetized pylorus-ligated rats 3 h after a bolus intravenous injection of ASA or SA, 150 mg/kg, or NaCl (control). Aspirin or SA produced similar extensive gross mucosal hemorrhagic lesions and similar microscopic damage in the presence of luminal acid (luminal pH 1.3 +/- 0.05). Neither ASA nor SA produced gastric mucosal injury with intragastric instillation of saline (luminal pH 3.7 +/- 0.5). Pretreatment for 1 h with luminal or subcutaneous 16,16-dimethyl prostaglandin E2 completely prevented the formation of red streaks in ASA-treated rats but not in SA-treated rats, although prostaglandin E2 pretreatment significantly reduced the gross lesion area in SA-treated rats (p less than 0.05). We conclude the following: (a) Intravenous SA is as damaging as intravenous ASA as long as luminal acid is present. (b) 16,16-Dimethyl prostaglandin E2 completely protected the gastric mucosa from injury by intravenous ASA, and to a lesser extent by intravenous SA. (c) In view of the damaging effects of SA on the gastric mucosa and the rapid conversion of ASA to SA, the mechanism of the gastric mucosal injury by intravenous ASA is much more complex than simple inhibition of endogenous prostaglandin synthesis.     

Low gastric toxicity of nitric oxide-releasing aspirin, NCX-4016, in rats with cirrhosis and arthritis

The gastric toxic effects of aspirin (ASA) and NCX-4016, a nitric oxide (NO)-releasing ASA, were compared in normal, cirrhotic, and arthritic rats. Oral administration of ASA (100 mg/kg) produced hemorrhagic lesions on the gastric mucosa in normal rats. The gastric ulcerogenic response to ASA was significantly worsened in both cirrhotic rats induced by N-nitrosodiethylamine and in arthritic rats induced by Freund's complete adjuvant. By contrast, NCX-4016 at 190 mg/kg (a dose equimolar to 100 mg/kg of ASA) did not induce damage in normal rat stomachs but caused slight lesions in the gastric mucosa of both cirrhotic and arthritic rats. Plasma salicylate levels following administration of ASA or NCX-4016 were not different between normal, cirrhotic, and arthritic rats, although the latter drug gave significantly lower values in any group of rats as compared to the former. Acid secretion was significantly increased in both cirrhotic and arthritic rats. ASA with 150 mM HCl caused severe gastric lesions in normal rats, the degree of damage being significantly greater than that induced by ASA alone. Coadministration of NOR-3, a NO donor, significantly prevented the development of gastric lesions induced by ASA, irrespective of whether or not ASA was given together with HCl. Gastric mucosal application of ASA (100 mg/kg) for 30 min caused a marked reduction of transmucosal potential difference (PD) with a minimal effect on gastric mucosal blood flow in both normal and cirrhotic rats, while that of NCX-4016 did not cause a PD reduction and produced a marked increase in the mucosal blood flow in both groups of rats. These results suggest that gastric mucosal susceptibility to ASA-induced damage is increased in both cirrhotic and arthritic rats (the process being partly accounted for by acid hypersecretion in these animals), NCX-4016 has even less gastric toxicity in both cirrhotic and arthritic rats, and the gastric-sparing effect of NCX-4016 is due, at least partly, to an increase of gastric mucosal blood flow, mediated by NO released from this drug.