胃黏膜对阿司匹林适应性的实验研究

目的 探讨胃黏膜对阿司匹林的适应性及其发生机制。方法 连续数天经胃管给大鼠灌入酸化阿司区林（ａｃｉｄｉｆｉｅｄ ａｓｐｉｒｉｎ,ＡＳＡ）,计算胃黏膜损伤面积和损伤深度。用ＲＩＡ法检测胃黏膜组织内ＥＧＦ的含量。为观察一氧化氮（ＮＯ）在胃黏膜对ＡＳＡ适应性中的 应用ＡＳＡ前３０ｍｉｎ经大鼠性静脉分另注入Ｌ－精氨酸（Ａｒｇ）、Ｌ－ＮＡＭＥ及Ｌ－Ａｒｇ＋ＬＮＡＭＥ,观察胃黏膜损伤面积及深度。结果 初次应用     

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.     

Mucosal adaptation to aspirin induced gastric damage in humans. Studies on blood flow,gastric mucosal growth,and neutrophil activation.

The gastropathy associated with the ingestion of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin is a common side effect of this class of drugs, but the precise mechanisms by which they cause mucosal damage have not been fully explained. During continued use of an injurious substance, such as aspirin, the extent of gastric mucosal damage decreases and this phenomenon is named gastric adaptation. To assess the extent of mucosal damage by aspirin and subsequent adaptation the effects of 14 days of continuous, oral administration of aspirin (2 g per day) to eight healthy male volunteers was studied. To estimate the rate of mucosal damage, gastroscopy was performed before (day 0) and at days 3, 7, 14 of aspirin treatment. Gastric microbleeding and gastric mucosal blood flow were measured using laser Doppler flowmeter and mucosal biopsy specimens were taken for the estimation of tissue DNA synthesis and RNA and DNA concentration. In addition, the activation of neutrophils in peripheral blood was assessed by measuring their ability to associate with platelets. Aspirin induced acute damage mainly in gastric corpus, reaching at day 3 about 3.5 on the endoscopic Lanza score but lessened to about 1.5 at day 14 pointing to the occurrence of gastric adaptation. Mucosal blood flow increased at day 3 by about 50% in the gastric corpus and by 88% in the antrum. The in vitro DNA synthesis and RNA concentration, an index of mucosal growth, were reduced at day 3 but then increased to reach about 150% of initial value at the end of aspirin treatment. It is concluded that the treatment with aspirin in humans induces gastric adaptation to this agent, which entails the increase in mucosal blood flow, the rise in neutrophil activation, and the enhancement in mucosal growth.     

Gastric Mucosal Blood Flow and Neutrophil Activation in Aspirin-Induced Gastric Mucosal Damage in Man

Konturek JW, Dembinski A, Stoll R, Konturek M, Domschke W. Gastric mucosal blood flow and neutrophil activation in aspirin-induced gastric mucosal damage in man. Scand J Gastroenterol 1993; 28:767-771.

Gastric and intestinal injury induced by nonsteroidal anti-inflammatory agents (NSAIDs) such as aspirin (ASA) is a common side effect of this class of drugs, but the mechanism by which these drugs act is not fully explained. In this study the effects of 3 days of continuous oral ASA administration (1 g twice daily) to eight healthy male volunteers were studied. To estimate the extent of mucosal damage, gastroscopy was performed before and after 3 days of ASA treatment, during which the mucosal blood flow was measured by means of laser-Doppler flowmetry. Before each endoscopy gastric microbleeding was measured. Since neutrophil activation has recently been suggested to be involved in the pathogenesis of ASA-induced gastric mucosal damage, we examined the influence of ASA treatment on the activation of leukocytes by determining their association with platelets in the blood. Aspirin-induced acute gastric damage reached about 3.5 in the endoscopic Lanza score. Mucosal blood flow increased significantly after ASA treatment, by about 50% in the oxyntic gland area and by 87% in the antral area. Gastric microbleeding rose from about 0.38 ml/day in the intact stomach to about 7.7 ml/day after ASA treatment. The platelet/neutrophil adherence increased significantly in both thrombin-unstimulated and thrombin-stimulated platelets. We conclude that acute 3 days' administration of ASA in man produces well-defined areas of gastric damage accompanied by a significant increase in gastric microbleeding and gastric blood flow and that ASA promotes platelet/neutrophil adhesion that may resemble the neutrophil/ endothelium interaction in the gastric mucosa.     

Potentiation of aspirin-induced gastric lesions by exposure to cold in rats. Role of acid secretion, mucosal blood flow, and gastric mucosal prostanoid content

We investigated the mechanism by which exposure to cold sensitizes rats to the formation of gastric lesions after a low dose of aspirin (50 mg/kg). Six times more lesions were produced by aspirin plus cold than by aspirin alone. Three hypotheses were studied to explain the synergism of aspirin plus cold on lesion formation: gastric acid hypersecretion, reduced gastric mucosal blood flow, and decreased prostanoid synthesis by the stomach. Cold, and cold plus aspirin, stimulated gastric acid secretion (to a similar extent), whereas aspirin had no effect. Gastric mucosal blood flow, measured by the hydrogen gas clearance method, was decreased by cold, aspirin, and aspirin plus cold, and the extent of decrease was similar. Prostanoid generation [prostaglandin E2 (PGE2), PGF2 alpha, 6-keto PGF1 alpha, and thromboxane B2] by the gastric corpus mucosa was not affected by cold, but was reduced equally (by at least 90%) in animals receiving aspirin alone or aspirin plus cold. After oral administration of aspirin, the plasma contained mostly salicylic acid (98%), whereas the gastric mucosa contained mostly aspirin (80%-85%). We conclude that the synergism of aspirin plus cold on the formation of gastric lesions probably results from the combined effects of three factors: increased secretion of acid (because of exposure to cold) that is in contact with a gastric mucosa in which blood flow is reduced (because of exposure to cold or to aspirin), and in which the synthesis of cytoprotective prostaglandins is inhibited (by aspirin). Such mucosa may be particularly vulnerable to the damaging effect of hyperacidity.     

Rolipram, a Specific Type IV Phosphodiesterase Inhibitor, Ameliorates Aspirin-Induced Gastric Mucosal Injury in Rats

Inhibition of type IV phosphodiesterase (PDE IV) activity reduces the production of various proinflammatory cytokine and suppresses neutrophil activation. Nonsteroidal anti-inflammatory drugs such as aspirin induce gastric mucosal lesions. In the pathogenesis of aspirin-induced gastric mucosal lesion, the contributions, of activated inflammatory cells and proinflammatory cytokine production are critical. The specific PDE IV inhibitor rolipram is known to be a potent inhibitor of inflammation by increasing intracellular cyclic AMP in leukocytes. The aim of the present study was to determine whether rolipram can ameliorate aspirin-induced gastric mucosal lesions in rats and whether the agent can inhibit the inrease in neutrophil accumulation and the production of proinflammatory cytokines. Gastric lesions were produced by administration of aspirin (200 mg/kg) and HCl (0.15 N; 8.0 ml/kg). Rolipram was injected 30 min before aspirin administration. The tissue myeloperoxidase concentration in gastric mucosa was measured as an indicat or of neutrophil infiltration. The gastric mucosal concentrations of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined by ELISA. The intragastric administration of aspirin induced multiple hemorrhagic erosions in rat gastric mucosa. Gastric mucosal lesions induced by aspirin were significantly inhibited by treatment with rolipram. The mucosal myeloperoxidase concentration was also suppressed by rolipram. Increases in the gastric content of TNF-α and IL-1β after aspirin administration were inhibited by pretreatment with rolipram. We demonstrated that the specific type IV PDE inhibitor, rolipram, could have a potent antiulcer effect, presumably mediated by its anti-inflammatory properties.     

Uremia increases gastric mucosal permeability and acid back-diffusion injury in the rat.

The possibility that chronic uremia renders the gastric mucosa more susceptible to acid injury was investigated. A rat model of chronic renal failure was induced by subtotal nephrectomy. [H+] back-diffusion across the mucosa, following intragastric perfusion of 0.15N HCl or 15% ethanol in 0.15N HCl, was significantly greater in uremic than in sham-operated rats. Gastric mucous gel thickness and transmural potential difference were significantly lower in rats with renal insufficiency. Furthermore, a significantly greater acidification rate of the surface epithelial cells was found in uremic rats than in sham-operated rats during superfusion with pH 1.7 buffer. Intragastric administration of acidified ethanol or aspirin solutions markedly increased gastric mucosal blood flow (68% and 89% respectively) in the sham-operated group producing mild injury, in contrast to uremic rats, where a lesser increase in mucosal blood flow (7% and 14% respectively) was associated with more pronounced mucosal injury. It was concluded that enhanced susceptibility to acid injury in uremia is due to a reduction of function of pre-epithelial, epithelial, and postepithelial elements of the gastric mucosal barrier.     

Attenuation of gastric mucosal inflammation induced by aspirin through activation of A2A adenosine receptor in rats

AIM:To determine whether a specific adenosine A_(2A) re-ceptor agonist(ATL-146e)can ameliorate aspirin-inducedgastric mucosal lesions in rats,and reduce neutrophil ac-cumulation and production of pro-inflammatory cytokines.METHODS:Gastric lesions were produced by oralgarage of aspirin(200 mg/kg)and HCl(0.15 mol/L,8.0 mL/kg).4-{3-[6-Amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl}-cyclohexanecarboxylic acid methyl ester(ATL-146e,2.5-5 μg/kg,IP)was injected 30 min before the admin-istration of aspirin.Tissue myeloperoxidase(MPO)con-centration in gastric mucosa was measured as an indexof neutrophil infiltration.Gastric mucosal concentrationsof tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)were determined by ELISA.Also,we examinedthe effect of ATL-146e on tissue prostaglandin E2(PGE2)production and gastric secretion.RESULTS:Intragastric administration of aspirin inducedmultiple hemorrhagic erosions in rat gastric mucosa.Thetotal length of gastric erosions(ulcer index)in controlrats was 29.8±7.75 mm and was reduced to 3.8±1.42mm after pretreatment with 5.0 g/kg ATL-146e(P<0.01).The gastric contents of MPO and pro-inflammatory cy-tokines were all increased after the administration ofaspirin and reduced to nearly normal levels by ATL-146e.Gastric mucosal PGE2 concentration was not affected byintraperitoneal injection of ATL-146e.CONCLUSION:The specific adenosine A_(2A) receptor ago-nist,ATL-146e,has potent anti-ulcer effects presumablymediated by its anti-inflammatory properties.     

Role of neutrophil-mediated inflammation in aspirin-induced gastric mucosal injury

The objectives of this study were to determine the roles of neutrophil-endothelial cell interactions and oxygen-derived free radicals in the pathogenesis of aspirin-induced gastric mucosal injury in rats. Oral administration of acidified aspirin (200 mg/kg) resulted in linear hemorrhagic erosions and an increase in myeloperoxidase activity, an index of neutrophil infiltration, in the gastric mucosa. Aspirin-induced gastric damage and the increase in myeloperoxidase activity were significantly inhibited by the injection of anti-CD11a, anti-CD11b, anti-intercellular adhesion molecule-1 monoclonal antibodies, and the combination of superoxide dismutase and catalase, which are scavengers of active oxygen species. These results suggest that neutrophil-endothelial adhesive interactions, which occur via CD11a/CD18-and CD11b/CD18-dependent interactions with intercellular adhesion molecule-1, and oxygen-derived free radicals produced by neutrophils are implicated in the production of aspirin-induced gastric mucosal injury.     

Aggravation of gastric mucosal lesions in rat stomach by tobacco cigarette smoke

In the model of gastric mucosal injury induced by 2 mol/liter hypertonic saline in rats, we tested the hypothesis that tobacco cigarette smoke aggravates gastric mucosal lesions by inhibition of injury-induced gastric mucosal hyperemia. Experimental rats were treated with tobacco cigarette smoke or nicotine-free smoke from nontobacco cigarettes, and controls breathed room air. Gastric mucosal blood flow was measured by hydrogen gas clearance before and during the intragastric administration of hypertonic saline. Tobacco cigarette smoke 3 and 18 ml/min, but not nicotine-free smoke, significantly attenuated the hyperemia and aggravated the hypertonic saline-induced lesion in a dose-dependent manner. We then tested the hypothesis that 18 ml/min of tobacco cigarette smoke, and the dose of intravenous nicotine previously shown to block injury-induced hyperemia and aggravate 2 mol/liter saline-induced gastric damage, will also adversely affect gastric lesions induced by acidified aspirin or acidified ethanol. The results confirm that tobacco cigarette smoke and intravenous nicotine indeed aggravate gastric mucosal damage in these two models. Taken together, the data suggest that the inhibition of injury-induced hyperemia by nicotine and tobacco cigarette smoke is an important predictor of their ability to increase the susceptibility of the gastric mucosa to noxious damage. Although limited in their experimental nature, these data provide one plausible explanation for the adverse effect of tobacco cigarette smoke on peptic ulcer disease.     

Asynchrony in circadian rhythms of gastric function in the rat

A model for gastric mucosal injury is proposed in which a key pathogenetic event is the disruption in the normal relationships among several circadian rhythms of gastric function. In the rat a circadian rhythm in acid secretion was found to be out of phase with a circadian rhythm in gastric pepsin secretion, another aggressive factor, and several mucosal defensive factors (mucus and bicarbonate efflux and tissue prostacyclin content). Gastric corpus mucosal blood flow circadian patterns paralleled the rhythmicity in acid secretion and, therefore, was out of phase with the other measured mucosal defensive factors. Thus, gastric mucosal defense was maintained by different mechanisms over the 24-hr cycle. During the dark phase, when this species was active and when acid secretion was highest, enhanced damage by topical acidified aspirin was documented, despite increased mucosal blood flow. Natural asynchrony in circadian rhythms of gastric function can be protective of gastric mucosal integrity but disruption of this circadian interplay of gastric aggressive and defensive factors could theoretically lead to greater vulnerability to damage. In the human, a circadian rhythm in basal gastric acidity has been described but no information exists as to the possibility of similar rhythmic variation in other gastric factors (aggressive and defensive) and possible disruption of these rhythms in disease.     

阿司匹林对大鼠胃溃疡愈合的影响和机制

目的 探讨阿司匹林对胃溃疡愈合的影响和机制.方法 用乙酸诱导大鼠胃溃疡,8 d后随机分为模型组、盐水组、阿司匹林组.用组织学方法检测溃疡形态、肉芽组织中毛细血管数;用氢气清除法检测溃疡边缘胃黏膜血流;用免疫组化方法检测表皮生长因子(EGF)、血管内皮生长因子(VEGF)在胃黏膜中的表达并检测其积分光密度.结果 阿司匹林组的溃疡面积高于模型和盐水对照组(P<0.05);阿司匹林组的毛细血管数和胃黏膜血流低于模型和盐水组(P<0.01);阿司匹林组的EGF和VEGF积分光密度低于模型和盐水组(P<0.01).结论 阿司匹林通过抑制EGF和VEGF的表达抑制溃疡愈合.     

Aspirin damage to ischemic gastric mucosa in shocked cats.

Cardiac output and blood flow to different regions and layers of the stomach were determined by the microsphere distribution technique. Aspirin tablets were placed in the stomach of anesthetized cats by gastrotomy. In some animals the arterial pressure was reduced to about 60 mmHg for 30 min by bleeding. The gastric mucosal blood flow decreased markedly during the bleeding. Three hours after reinfusion of the blood gastric mucosal erosions were present at the site of contact of the tablet with the mucosa. In most of the non-bled animals no mucosal lesions were found 4 1/2 after aspirin application. No mucosal damage occurred in animals subjected to bleeding without aspirin treatment. It is concluded that the aspirin damage to the gastric mucosa increases under hemorrhagic shock because of mucosal ischemia in the shocked animals.     

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.     

Recovery of mucin content in surface layer of rat gastric mucosa after HCl-aspirin-induced mucosal damage

Quantitative changes in mucin (mucus glyco-protein) in different layers of rat gastric mucosa after mucosal damage induced by acidified acetylsalicylic acid (HCl-aspirin; 0.15N HCl, 20–200 mg acetylsalicylic acid/kg body weight) were studied. More than 50 mg/kg HCl-aspirin led to a significant increase in macroscopic gastric injury (expressed as ulcer index) at 3h, compared with control (no aspirin) and there was a significant recoverly at 7h. Three h after dosing with 50 mg/kg acidified aspirin, there was superficial mucosal damage and decreased mucin content in the surface mucosal layer. Mucin production recovered 7h after the administration of 50 mg/kg acidified aspirin. Doses of acidified aspirin higher than 100 mg/kg decreased mucin content in the surface and deep corpus mucosal layers and no recovery was seen 7h after the administration. Physiological damage after the administration of 50 mg/kg HCl-aspirin was limited mainly to surface epithelial mucus cells. An experimental model in which superficial erosion was induced in rat gastric mucosa was established with low-dose HCl-aspirin.     

Role of polymorphonuclear leukocytes and oxygen-derived free radicals in the formation of gastric mucosal lesions induced by platelet-activating factor

Gastric hemorrhagic erosions were induced by the administration of platelet-activating factor (PAF). Gastric wall blood flow was decreased and thiobarbituric acid (TBA) reactants in the gastric mucosa were increased 10 min after PAF injection. SOD and catalase reduced gastric mucosal lesions and TBA reactants, but had no influence on gastric blood flow. In polymorphonuclear leukocytes (PMN)-depleted rats, gastric mucosal lesions and TBA reactants in the gastric mucosa were reduced and gastric blood flow were increased. PAF induced the superoxide production from rat PMN in a dose dependent manner. These results suggest that oxygen-derived free radicals produced by PMN and lipid peroxidation may play an important role in the pathogenesis of gastric mucosal injury induced by PAF.     

Role of TFF in healing of stress-induced gastric lesions

AIM: To determine the changes of pS2 and ITF of TFF expression in gastric mucosa and the effect on ulcer healing of pS2, ITF to Water-immersion and restraint stress (WRS)in rats.METHODS: Wistar rats were exposed to single or repeated WRS for 4 h every other day for up to 6 days. Gastric mucosal blood flow (GMBF) was measured by LDF-3 flowmeter and the extent of gastric mucosal lesions were evaluated grossly and histologically. Expression of pS2 and ITF mRNA was determined by RT-PCR. Immunohistochemistry was used to further detect the expression of pS2 and ITF.RESULTS: WRS applied once produced numerous gastric mucosal erosions, but the number of these lesions gradually declined and GMBF restored at 2, 4, 8 h after stress. The area of gastric mucosal lesion was reduced by 64.9 % and GMBF was increased by 89.8 % at 8 h. The healing of stress-induced ulcerations was accompanied by increased expression of pS2 (0.51±0.14 vs0.77±0.11, P＜0.01) and ITF (0.022±0.001 vs 0.177±0.010, P＜0.01). The results were demonstrated further by immunohistochemistry of pS2(0.95±0.11 vs1.41±0.04, P＜0.01) and ITF (0.134±0.001 vs 0.253±0.01,P＜0.01). With repeated WRS, adaptation to this WRS developed, the area of gastric mucosal lesions was reduced by 22.0 % after four consecutive WRS. This adaptation to WRS was accompanied by increased GMBF (being increased by 94.2 %), active cell proliferation in the neck region of gastric glands, and increased expression of pS2 (0.37±0.02 vs 0.77±0.01, P＜0.01) and ITF (0.040±0.001 vs0.372±0.010, P＜0.01). The result was demonstrated further by immunohistochemistry of pS2 (0.55±0.04 vs 2.46±0.08, P＜0.01) and ITF (0.134±0.001 vs0.354±0.070,P＜0.01).CONCLUSION: TFF may not only participate in the early phase of epithelial repair known as restitution(maked by increased cell migration),but also play an important role in the subsequent, protracted phase of glandular renewal(made by cell proliferation).     

Aspirin can inhibit gastric mucosal cyclo-oxygenase without causing lesions in rat

Dose-response relationships between aspirin-induced cyclo-oxygenase inhibition and gastric mucosal injury were studied in rats. Oral or parenteral aspirin, 25 mg/kg, inhibited prostaglandin generation by 87%-95% at 1, 3, and 6 h with no lesion formation. Aspirin, 100 mg/kg, inhibited prostaglandin generation by 95%-98% at 1, 3, and 6 h, but lesions were observed only when aspirin was given orally. Three-hour pretreatment with intraperitoneal aspirin, 12.5 mg/kg, did not enhance the mucosal injury caused by 10 mM acidified taurocholate, although prostaglandin generation was inhibited by 80%. Pretreatment with 25 mg/kg aspirin inhibited prostaglandin generation by 89% and was associated with significant mucosal injury by acidified taurocholate. We conclude that aspirin-induced 95% inhibition of gastric mucosal cyclo-oxygenase is not, by itself, sufficient to produce lesions and inhibition by greater than 80% is required to predispose the gastric mucosa to injury by otherwise mild irritants.     

Bosentan, a novel synthetic mixed-type endothelin receptor antagonist, attenuates acute gastric mucosal lesions induced by indomethacin and HCl in the rat: Role of endogenous endothelin-1

Endothelin-1 has been reported to be responsible for gastric mucosal damage in various experimental models. We evaluated the role of endogenous endothelin-1 in the pathogenesis of gastric mucosal damage induced by indomethacin and HCl in the rat. Rats were given indomethacin (25 mg/kg) subcutaneously, and 15 min later, 0.2N HCl intragastrically. Gastric mucosal damage, gastric endogenous endothelin-1, and gastric mucosal hemodynamics were measured. The effects of bosentan, a mixed endothelin receptor antagonist, on gastric mucosal integrity and hemodynamics were assessed. Gastric endogenous endothelin-1 was significantly elevated at 20min, gastric mucosal blood flow began to decrease significantly at 25 min, and gastric damage occupied 52.2% of the total glandular mucosa at 135 min after injection of indomethacin. Intragastric pretreatment with bosenthan (5, 10, 30, and 60 mg/kg) significantly attenuated gastric damage, to 26.1%, 7.7%, 3.6%, and 1.6%, respectively, of the total glandular mucosa. Bosentan (60 mg/kg) prevented the initial decrease of blood flow and, even at 135 min, improved blood flow and hemoglobin oxygen saturation significantly. We suggest that indomethacin-induced endogenous endothelin-1 diminishes gastric mucosal blood flow and tissue oxygenation and ultimately causes gastric damage. Endogenous endothelin-1 may play an important role in the pathogenesis of the acute gastric mucosal lesions induced by indomethacin and HCl.     

Protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats

Objective:To observe the protective effect of omeprazole on gastric mucosal of cirrhotic portal hypertension rats.Methods:All rats were randomly divided into normal control group,cirrhosis and treatment group.Thioacetamide was used to establish rat model of cirrhotic portal hypertension.The necrotic tissue of gastric mucosa ulcer focus,degree of neutrophils infiltration at the ulcer margin,portal pressure,portal venous flow,abdominal aortic pressure,abdominal aortic blood flow at front end,gastric mucosal blood flow(GMBF),glycoprotein(GP)of gastric mucosa,basal acid secretion,H' back-diffusion,gastric mucosal damage index,NO,prostaglandin E_2(PGE_2) and tumor necrosis factor-α(TNF-α) were determined respectively,and the pathological changes of gastric mucosa were also observed by microscope.Results:Compared with cirrhosis group and the control group,the ulcer bottom necrotic material,gastric neutrophil infiltration and UI of the treatment group were all decreased significantly(P0.01),GMBF value,GP values,serum NO,PGE_2,TNF- a were all significantly increased.Conclusions:Omeprazole has an important protective effect on gastric mucosal and it can increase gastric mucosal blood flow and related to many factors.