Gastric Mucosal Injury Induced by Local Ischemia-Reperfusion in Rats (Role of Endogenous Endothelin-1 and Free Radical)

We investigated the role of an endogenousvasoconstrictor peptide endothelin-1 (ET-1) and freeradicals in local gastric ischemia-reperfusion injury inrats. Local gastric ischemia was induced by clamping the left gastric artery for 15 min andreperfusion was done for 10-30 min in the presence of150 mM exogenous HCl intragastrically. Local gastricischemia and reperfusion resulted in significantmacroscopic and microscopic gastric mucosal damage togetherwith elevation of gastric tissue ET-1 concentration.Gastric tissue ET-1 was found to increase after 15 minof ischemia alone and also with 30 min of reperfusion. A novel nonpeptide endothelin receptorantagonist, bosentan, or a combination of radicalscavengers (superoxide dismutase, catalase, anddeferoxamine) both attenuated gastric mucosal injury.However, the greater protection observed with bosentan thanwith radical scavengers might reflect a preferentialrole of endothelin-1 in this type of injury.     

Effect of treatment on ventricular function and troponin I proteolysis in reperfused myocardium

Effects of ischemia time and treatment interventions upon troponin I (TnI) proteolysis and function of reperfused myocardium were examined in isolated, perfused rabbit hearts. Hearts were randomized to 90 min aerobic perfusion, 15 min low-flow (1 ml/min) ischemia (I) and 60 min reperfusion (R) or 60 min low-flow I and 60 min R. Hearts subject to 60 min I and 60 min R received either no treatment, l -arginine treatment, or treatment with oxygen free radical (OFR) scavengers (mercapto-proponyl-glycine, catalase and superoxide dismutase). Hearts from cholesterol-fed rabbits were also studied after 60 min I and R. Isovolumic LV pressure and heart rate were recorded throughout and Western analysis of ventricular myocardium, using 3 specific antibodies, detected intact TnI (29 kDa) and TnI fragment (25 kDa). Hearts subject to 15 min I had minimal irreversible injury (TTC negative region=0.6+/-0.4% LV) but hearts subject to 60 min I had more extensive injury (TTC negative=40.7+/-5.8% LV). Recovery of rate-pressure product after 15 min I and 60 min R (56+/-9% of baseline) was better than after 60 min I and 60 min R (23+/-9%, P<0.01). Both l -arginine and OFR scavengers were associated with better recovery of function after 60 min I, (66+/-7% and 72+/-3% of baseline respectively, P<0.01 v no treatment) but cholesterol hearts had poor recovery after 60 min I (37+/-8%). The 25 kDa TnI (% total TnI immunoreactivity) was 8.7+/-0.9% in controls, 10.0+/-1.6% after 15 min I and 60 min R, and 17.4+/-2.4% after 60 min I and 60 min R (P<0.01 v controls and 15 min I). The proportion of 25 kDa TnI was increased in all hearts after 60 min I and did not change with treatment (l -arginine 16.8+/-1.8%, OFR scavengers 16.0+/-3.2%, cholesterol 14.0+/-1.9%). There was no relation between proportion of 25 kDa TnI and recovery of function. Samples from freshly excised rabbit hearts and human right atria also had 25 kDa TnI (relative intensities 8.5+/-2.3% and 5.1+/-2.6% respectively). Although TnI fragmentation increases after prolonged ischemia and reperfusion, the functional recovery of stunned myocardium is independent of degree of TnI fragmentation.     

Direct detection of oxygen free radicals produced by myocardial reperfusion using electron spin resonance spectroscopy

There is a growing evidence for the role of oxygen free radicals (OFR) in mediating myocardial tissue injury during myocardial ischemia and particularly during reperfusion. But almost all of the evidence was indirect, using electron spin resonance (ESR) spectroscopy, we have directly measured OFR generated in ischemic and reperfused isolated rabbit hearts. 17 hearts were rapidly frozen in liquid nitrogen after their arrest by cardioplegic solution and sampled after 150 min of sustained hypothermic global ischemia or after reperfusion. The ESR spectra obtained from experiment have directly demonstrated that OFR is produced in significant amounts in the isolated rabbit hearts during early stage of reperfusion but only small amount during ischemia. The mitochondrial electron transport chain appeared to be the main source of OFR. We found that superoxide dismutase scavenged OFR generated during reperfusion efficiently, but catalase did not. We believe that superoxide anion, not hydroxyl radical, is the main OFR which is responsible for myocardial reperfusion injury. We also found that Salvia, a traditional Chinese medicine, a very efficient OFR scavenger, had the similar effect as superoxide dismutase.     

Effects of free radical scavengers on indomethacin-induced aggravation of gastric ulcer in rats

Effects of treatment with free radical scavengers in the healing process of acetic acid-induced gastric ulcer on the ulcer aggravation induced by indomethacin were investigated. Gastric ulcers were produced on the anterior wall of the stomach of male Sprague-Dawley rats by submucosal injection of 20% acetic acid. To investigate the role of oxygen radicals, rats with gastric ulcer were treated with scavengers for six weeks and then treated with indomethacin (1 mg/kg/day). While superoxide dismutase (10,000 units/kg/day) did not affect the ulcer area after indomethacin treatment, allopurinol (50 mg/kg/day) slightly inhibited the increase in ulcer area. Dimethyl sulfoxide (1% solution,ad libitum) produced a significant decrease in size of the ulcer after indomethacin treatment. Increased lipid peroxides in the gastric mucosa after indomethacin treatment decreased significantly in the rats of the dimethyl sulfoxide and allopurinol groups. These results indicate that lipid peroxidation mediated by oxygen radicals plays an important role in the mechanism of ulcer aggravation induced by indomethacin.     

Role of active oxygen, lipid peroxidation, and antioxidants in the pathogenesis of gastric mucosal injury induced by indomethacin in rats.

The roles of active oxygen, lipid peroxidation, and the antioxidative defence mechanism in gastric mucosal injury induced by treatment with indomethacin in rats were investigated. The total area of gastric erosions and concentration of lipid peroxides in the gastric mucosa increased with time after administration of indomethacin (20 mg/kg, orally). The alpha-tocopherol:total cholesterol ratio in serum was significantly decreased and the activity of glutathione peroxidase, an important enzyme to scavenger of lipid peroxides, was inhibited by the administration of indomethacin. Treatments with superoxide dismutase and catalase inhibited the increases in gastric mucosal erosions and lipid peroxides in the gastric mucosa, and the reduction of serum alpha-tocopherol. Treatment with these scavengers did not improve the decreased glutathione peroxidase activity. These findings suggest that active oxygen species and lipid peroxidation play an important part in the pathogenesis of gastric mucosal injury induced by indomethacin, and that the decreased glutathione peroxidase activity aggravated the injury due to accelerated accumulation of hydrogen peroxide and lipid peroxides in the gastric mucosal cell.     

Impaired Adaptive Cytoprotection to Ethanol-Induced Damage in Gastric Mucosa of Portal Hypertensive Rats

Portal hypertension predisposes gastric mucosato increased damage by noxious agents. Adaptivecytoprotection has not been studied in portalhypertensive gastric mucosa. We evaluated adaptivecytoprotection in the gastric mucosa of portal hypertensiverats by exposure to ethanol. The injury index (percentgross lesions) was significantly higher in portalhypertensive rats than in sham-operated rats. The ratio of adaptive cytoprotection, calculated as thedegree of decrease in the injury index caused bypre-absolute-ethanol administration of 20% ethanol, wassignificantly impaired in portal hypertensive rats. Basal levels of gastric mucosal hexosamine werelower in portal hypertensive rats than in controls, anda blunted response to 20% ethanol was associated withportal hypertension. Nitric oxide inhibition (L-NAME, 5 mg/kg) reduced the ratio of adaptivecytoprotection in sham-operated but not in portalhypertensive rats. These results suggest that impairedadaptive cytoprotection in portal hypertensive gastric mucosa may be caused by blunted mucusproduction.     

Gastric injury induced by ethanol and ischemia-reperfusion in the rat

This study determined the role that oxygen-derived free radicals played in the production of gastric injury in rats challenged orally with concentrated ethanol or subjected to vascular compromise. In the ethanol study, rats were pretreated with a variety of free radical scavengers or enzyme inhibitors prior to exposing the stomach to 100% ethanol. At sacrifice, the degree of macroscopic damage to the glandular gastric mucosa was quantified. In separate studies, the effects of ethanol on gastric mucosal levels of enaldehydes (malondialdehyde and 4-hydroxynonenal) were examined as an index of lipid peroxidation. Superoxide dismutase and catalase pretreatment were without benefit in reducing injury in our ethanol model, excluding potential contributory roles for the superoxide anion or hydrogen peroxide, respectively. Dimethyl sulfoxide and desferoxamine were likewise without protective capabilities, eliminating a role for the hydroxyl radical. Allopurinol, a xanthine oxidase inhibitor, provided no protection under acute conditions, even though partial protection was noted when administered chronically. Further, enaldehyde levels were not increased over control levels in alcohol-exposed mucosa, indicating no enhanced lipid peroxide formation. In contrast, in animals in which ischemia to the stomach was induced followed by reperfusion, marked gastric injury was observed in combination with enhanced enaldehyde levels. Prevention of enaldehyde formation by a 21-aminosteroid concomitantly prevented injury induced by ischemia-reperfusion. These findings support the conclusion that ischemia-reperfusion injury to the stomach is an oxygen-derived free radical process whereas ethanol-induced injury clearly involved some other process. Although allopurinal was partially protective against ethanol damage when administered chronically, observations in other models of injury suggest that this action is independent of its inhibitory effect on xanthine oxidase.     

Role of oxygen radicals in ischemia-induced lesions in the cat stomach

Ischemia in a stomach that contains acid may produce severe gastric mucosal injury. The extent to which oxygen-derived free radicals are involved in the pathogenesis of this injury was investigated in the present study. Local gastric ischemia was achieved by reducing celiac artery pressure to 30 mmHg for 1 h. Ischemic injury was assessed by recording the loss of 125I-albumin and 51Cr-red cells across the gastric mucosa. Cats were treated with a xanthine oxidase inhibitor (allopurinol), a superoxide radical scavenging enzyme (superoxide dismutase), and a scavenger of hydroxyl radicals (dimethyl sulfoxide). The damage associated with ischemia only occurred during reperfusion of the stomach and was worst in the antrum. The level of xanthine oxidase in the antrum was twice that of the corpus. Treatment with allopurinol, superoxide dismutase, and dimethyl sulfoxide reduced 51Cr-red cell loss to 15%, 25%, and 21% of control (untreated) animals, respectively. The data indicate that oxygen-derived free radicals play a role in ischemic injury to the stomach and that the hydroxyl radical, a secondary radical produced from the superoxide anion, appears to be the major oxygen radical contributing to ischemic damage.     

Sequence of gastric mucosal injury following ischemia and reperfusion

The mechanisms of gastric mucosal injury following a period of ischemia remain unclear. The aim of this study was to determine the relative contributions of ischemia, reperfusion, and reactive oxygen metabolites to mucosal injury induced by temporary occlusion of the celiac artery. Rats were subjected to 30 min of gastric ischemia in the presence of 100 mM HCl. Reperfusion periods ranged from 1 min to 24 hr. Drug treatments included allopurinol (100 mg/kg) or a combination of superoxide dismutase (15,000 units/kg), catalase (90,000 units/kg), and desferrioxamine (50 mg/kg). Mucosal injury was assessed by quantitative histology and the extent of macroscopic hemorrhage. Approximately one third of the total injury to the volume of the mucosa (11.8 +/- 9.1%) was due to ischemia alone. Another third was blocked by allopurinol or superoxide dismutase, catalase, and desferrioxamine (22.1 +/- 6.9%, P less than 0.001; and 25.9 +/- 4.6%, P less than 0.01), respectively, compared with control (32.5 +/- 5.1%). In contrast, extensive surface mucosal injury (62.2 +/- 27.6%) occurred primarily during ischemia and was not affected by antioxidants. Macroscopic hemorrhage was halved by treatment with allopurinol (17.5 +/- 12.6%, P less than 0.01) or superoxide dismutase, catalase, and desferrioxamine (15.9 +/- 14.5%, P less than 0.01). We conclude that temporary celiac occlusion results in gastric mucosal damage that consists of both ischemic and reperfusion components. The majority of surface mucosal injury occurred during ischemia, whereas injury to the volume of the mucosa and the vasculature occurred equally during reperfusion and was associated with reactive oxygen metabolites.     

Role of superoxide dismutase in mechanism of diethyldithiocarbamate-induced gastric antral ulcer in rats: Protective effect of prostaglandin, cimetidine and pirenzepine

The role of superoxide radicals and the protective effects of superoxide dismutase (SOD), allopurinol, 16, 16-dimethyl-prostaglandin E₂ (dmPGE₂), cimetidine and pirenzepine in diethyldithiocarbamate (DDC)-treated rats were evaluated. Pretreatment with Cu,Zn-SOD (superoxide radical scavenger) 60 000 units/kg, allopurinol (competitive inhibitor of xanthine oxidase) 50 mg/kg, dmPGE₂ (prostaglandin analogue) 10 μg/kg, cimetidine (H₂-receptor antagonist) 10 mg/kg or pirenzepine (selective antimuscarinic drug) 10 mg/kg all significantly reduced the DDC-induced (800 mg/kg) gastric antral ulcer formation in rats. DDC treatment substantially decreases the gastric mucosal Cu, Zn-SOD activity. In this study treatment with DDC and SOD, DDC and dmPGE₂, DDC and cimetidine, and DDC and pirenzepine were demonstrated significantly to prevent the decrease of gastric mucosal Cu, Zn-SOD activity. However, allopurinol did not have this effect. The results suggest that SOD and/or superoxide radicals may play an important role in the mechanism of DDC-induced gastric antral ulcer. The protective property against ulcer formation of these drugs studied might be due to the action of SOD in the gastric mucosa.     

Effect of brief regional ischemia followed by reperfusion with or without superoxide dismutase and catalase administration on myocardial sarcoplasmic reticulum and contractile function

The effect of reperfusion with and without free radical scavengers on sarcoplasmic reticulum and contractile function was examined in a canine model of 15-minute coronary artery occlusion followed by reperfusion. Dogs were reperfused with (n = 13) or without (n = 16) superoxide dismutase and catalase or were killed at 15 minutes of ischemia (n = 17). Superoxide dismutase and catalase were administered as a bolus (20,000 and 12,500 U/kg, respectively) beginning 1.25 minutes before reperfusion followed by infusion of 16,000 and 12,500 U/kg/hr, respectively. Sarcoplasmic reticulum function was evaluated from the rate of calcium uptake of unfractionated subepicardial, subendocardial, and transmural homogenates determined with and without ruthenium red to close the calcium release channel. Mechanical function was evaluated by means of sonomicrometry. Fifteen minutes of ischemia significantly (p less than 0.05) depressed the sarcoplasmic reticulum calcium uptake rate only in the subendocardium (from 25 +/- 2 to 14 +/- 1 nmol/min/mg without ruthenium red and from 60 +/- 3 to 49 +/- 3 nmol/min/mg with ruthenium red). Reperfusion with or without superoxide dismutase and catalase restored homogenate calcium uptake rates to normal, although severe contractile dysfunction persisted. This indicates that damage to the sarcoplasmic reticulum may not be the major cause of postreperfusion contractile dysfunction. Ischemia-reperfusion caused a decrease in systolic shortening from 19 +/- 2% to 1 +/- 2% with and from 18 +/- 1% to 4 +/- 1% without free radical scavengers (p = NS between groups). Thus administration of superoxide dismutase and catalase beginning shortly before reperfusion had no effect on postreperfusion contractile dysfunction or sarcoplasmic reticulum function.     

Effect of Lonicerae Flos extracts on reflux esophagitis with antioxidant activity

AIM： To observe the effects of traditional antiinflammatory medicine Lonicerae FIos （LF） on rat reflux esophagitis （RE） induced by pylorus and forestomach ligation compared with the well-known proton antioxidant, α-tocopherol. METHODS： Rats were pretreated with three different dosages of LF （500, 250 and 125 mg/kg） orally, once a day for 14 d before pylorus and forestomach ligation. Nine hours after pylorus and forestomach ligation, changes to the stomach and esophagus lesion areas, gastric volumes, acid and pepsin outputs, antioxidant effects, esophageal lipid peroxidation, superoxide dismutase （SOD）, catalase （CAT）, malondialdehyde （MDA）, myeloperoxidase and glutathione （GSH） levels, and collagen contents （marker of flexibility） were observed on the esophageal and fundic histopathology. The results were compared with an α-tocopherol （once orally, 1 h before operation, 30 mg/kg） treated group in which the effects on RE were already confirmed.RESULTS： Pylorus and forestomach ligations caused marked increases of gross esophageal and gastric mucosa lesion areas, which corresponded with histopathological changes. In addition, increases of esophageal lipid peroxidation, decreases of SOD, CAT, and GSH-free radical scavengers, increases of collagen were observed. However, these pylorus and forestomach ligation induced RE were dose-dependently inhibited by treatment of 500, 250 and 125 mg/kg of LF extract, mediated by antioxidant effects. RE at 250 mg/kg showed similar effects α-tocopherol. CONCLUSION： The results suggest that antioxidant effects of LF could attenuate the severity of RE and prevent the esophageal mucosal damage, and validate its therapeutic use in esophageal reflux disease.     

Mechanism of Gastroprotection by Bismuth Subsalicylate Against Chemically Induced Oxidative Stress in Cultured Human Gastric Mucosal Cells

Reactive oxygen species (ROS) are implicated inthe pathogenesis of chemically induced gastric mucosalinjury. We have investigated the effects of ethanol,hydrochloric acid (HCl), and sodium hydroxide (NaOH) on: (1) enhanced production of ROSincluding superoxide anion and hydroxyl radicals, (2)modulation of intracellular oxidized states by laserscanning confocal microscopy, and (3) DNA fragmentation, indices of oxidative tissue, and DNA damage ina primary culture of normal human gastric mucosal cells(GC), which were isolated and cultured from Helicobacterpylori-negative endoscopic biopsies from human subjects. The induction of ROS and DNAdamage in these cells following exposure to ethanol(15%), HCl (150 mM) and NaOH (150 mM) were assessed bycytochrome c reduction (superoxide anion production), HPLC detection for enhanced production ofhydroxyl radicals, changes in intracellular oxidizedstates by laser scanning confocal microscopy, and DNAdamage by quantitating DNA fragmentation. Furthermore, the protective ability of bismuth subsalicylate(BSS) was assessed at concentrations of 25, 50, and 100mg/liter. Incubation of GC with ethanol, HCl, and NaOHincreased superoxide anion production by approximately 8.0-, 6.1- and 7.1-fold and increased hydroxylradical production by 13.3-, 9.6-, and 8.9-fold,respectively, compared to the untreated gastric cells.Incubation of GC with ethanol, HCl, and NaOH increased DNA fragmentation by approximately 6.7-, 4.3-,and 4.8-fold, respectively. Approximately 20.3-, 17.5-,and 13.1-fold increases in fluorescence intensities wereobserved following incubation of gastric cells with ethanol, HCl, and NaOH, respectively,demonstrating dramatic changes in the intracellularoxidized states of GC following exposure to thesenecrotizing agents. Preincubation of GC with 25, 50, and 100 mg/liter of BSS decreased ethanol-inducedincreases in intracellular oxidized states in thesecells by 36%, 56%, and 66%, respectively, demonstratinga concentration-dependent protective ability by BSS. Similar results were observed withrespect to BSS in terms of superoxide anion and hydroxylradical production, and DNA damage. The present studydemonstrates that ethanol, HCl, and NaOH induce oxidative stress and DNA damage in GC and thatBSS can significantly attenuate gastric injury byscavenging these ROS.     

Protection against necrotizing agents-induced gastric lesions in rats

Effects of necrotizing agents, blockers of gastric motility, and mild irritants on gastric mucosa and gastric motility were investigated in conscious rats. Gastric motor activity was recorded using a miniature balloon placed in the glandular part of the stomach, which was connected to a pressure transducer and polygraph. Necrotizing agents, such as 96% ethanol, 0.6 N hydrochloric acid, 0.2 N sodium hydroxide, or 4 M sodium chloride, were given intragastrically through a fistula on the forestomach. One milliliter of these agents produced hemorrhagic bandlike lesions in the corpus mucosa along the long axis of the stomach with the occurrence of a complete inhibition of gastric motility (smooth muscle relaxation). Blockers of gastric motility alone, such as subcutaneous papaverine HCl (50 mg/kg), and intraperitoneal verapamil (20 mg/kg), or mild irritants (1 ml/rat, orally) such as 20% ethanol or 1 M NaCl, which by themselves suppressed gastric motility, have no effect on gastric mucosa and on the inhibited gastric motility induced by necrotizing agents. Bandlike lesions were significantly prevented by pretreatment with 20% ethanol or 1 M NaCl but not with papaverine HCl or verapamil administered 30 min before necrotizing agents. The gastroprotection offered by 20% ethanol or 1 M NaCl was significantly diminished by pretreatment with subcutaneous indomethacin (30 mg/kg), but the inhibited gastric motility was not reversed by indomethacin. These results indicate that it seems unlikely that gastric contractile activity would play a major role in the development and prevention of gastric lesions after the administration of necrotizing agents.     

Participation of Phosphoinositides in Gastric Mucosal Protection by Colloidal Bismuth Subcitrate against Ethanol-Induced Injury

The mechanism of gastric mucosal protection by an antiulcer agent, colloidal bismuth subcitrate (CBS), against ethanol-induced injury was investigated using in vivo and in vitro systems. The experiments in vivo were conducted with groups of rats with and without indomethacin pretreatment, and the animals received either a dose of CBS (100 mg/kg) or a vehicle (saline), followed 30 min later by ethanol. In the in vitro studies, gastric mucosa segments were cultured in the presence of CBS, ethanol, or both. The results of in vivo experiments revealed that in the absence of CBS, ethanol caused extensive gastric hemorrhagic lesions which were significantly reduced following CBS pretreatment and this effect of CBS was not prevented by indomethacin. The data obtained with gastric mucosal culture established that in comparison to the controls, ethanol caused a 27% decrease in mucin synthesis, while mucin synthesis in the presence of CBS increased by 48%. The increase in mucin synthesis evoked by CBS was accompanied by the enhanced metabolism of mucosal phosphoinositides, as reflected by a decrease in PI (15%) and PIP2 (30%), and an increase in IP1 (26%) and IP3 (67%). In contrast, ethanol, which exhibited detrimental effect on mucin synthesis, caused a decrease in PIP (35%), IP2 (47%) and IP3 (38%), and an increase in PIP2 (80%), and IP1 (51%). However, when the mucosal culture was carried out in the presence of both CBS and ethanol, the detrimental changes evoked by ethanol on mucin synthesis were prevented, and the phosphoinositide and inositide phosphate distribution patterns were quite similar to those in the mucosa cultured in the presence of CBS only.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gastroprotection by 4-Methylpyrazole Against Ethanol in Humans

4-Methylpyrazole (4-MP), a specific inhibitor ofalcohol dehydrogenase, exerts gastroprotection ofunusually long duration in rats. We tested thehypothesis that pretreatment with 4-MP might protect the human gastric mucosa against alcohol-inducedacute injury. Fourteen healthy volunteers receivedpretreatment with either 4-MP, 15 mg/kg body weightdissolved in 50 ml of orange juice, or placebo and 2 hr later 100 ml of 40% ethanol. The endoscopicappearance of the gastric mucosa was evaluated andscored (scale 0-5) and mucosal biopsies were obtainedjust before pretreatment and 30 min after ethanol for histologic examination and prostaglandinE₂ measurement. In the 4-MP group the meanendoscopic injury score was significantly lower thanthat in placebo group, in both the body and the antrum.Histologically, 4-MP significantly reduced disruption ofsurface epithelium and completely prevented the deephemorrhagic mucosal lesions. In the 4-MP group nochanges in gastric mucosal PGE₂ levels weredetected. In rats, 4-MP did not inhibit gastric acid output,whereas it markedly increased the adherent gastric mucusevaluated by the alcian blue recovery method. When lipidperoxidation was induced by carbon tetrachloride in hepatic microsomes, 4-MP caused significantinhibition of malondialdehyde generation. We concludethat 4-MP provides significant protection of the humanstomach against alcohol-induced acute mucosal injury. 4-MP, besides inhibiting the conversionof alcohol to acetaldehyde, might protect the gastricmucosa by increasing adherent gastric mucus and byscavenging free radicals.     

胶态次枸橼酸铋对大鼠急性胃粘膜损伤的预防作用

本文以无水乙醇灌胃诱发大鼠急性胃粘膜损伤为模型,观察胃粘膜损伤前后以及应用木同剂量胶态次枸橼酸铋(De-Nol)后胃粘膜损伤指数计分和胃粘膜病理组织学改变,并测定胃酸分泌量、胃粘液分泌量、胃粘膜Na~ ,K~ ATP酶活力以及不同组动物血浆6-keto-PGF_(l1)内皮素(ET)含量的变化,试图从多方面探讨胶态次枸橼酸铋在抗粘膜损伤中的作用及机制。结果:次枸橼酸铋能有效减轻由无水乙醇造成的胃粘膜病理组织学改变,使损伤指数计分降低,粘膜分泌增加,胃牯膜Na~ .K~ .ATP酶活力上升,并可抑制由于牯膜损伤造成的血浆PGI_2的下降和ET水平的升高,但其对胃酸分泌无明显影响。由此推断,次枸橼酸铋的抗损伤机制与提高血浆PGI_2水平、降低ET、激活Na~ .K~ .ATP酶活力和促进粘液分泌有关,而与抑酸作用无关。     

Protective effect of dimethylthiourea against mucosal injury in rat stomach

The present study was undertaken to determine whether dimethylthiourea (DMTU), a hydroxyl radical scavenger, could prevent gastric injury in the rat stomach induced by various noxious agents. Fasted rats (N=6–8/group) were given a 1-ml oral bolus of saline or DMTU over the dose range 10–500 mg/kg. After 30 min, animals received 1 ml of 100% ethanol orally and were sacrificed 5 min later. At sacrifice, stomachs were harvested and the degree of macroscopic damage was assessed by planimetry. In selected animals, specimens of gastric mucosa were also processed for histology. Saline pretreatment prior to ethanol exposure resulted in 22.5% injury to the glandular epithelium when assessed macroscopically. DMTU pretreatment prevented such injury in a dose-related fashion with only 2% of the mucosa showing injury with a 500 mg/kg dose (P<0.01 vs control). Although the superficial injury involving surface mucous cells induced by ethanol was not altered by DMTU, the deep damage to gastric glands was almost completely prevented. Other experiments in which DMTU was given intraperitoneally demonstrated similar protective effects against ethanol injury. Additional studies showed that indomethacin did not prevent the protective effects of oral or intraperitoneal DMTU, excluding a role for endogenous prostaglandins, and that DMTU was equally protective when administered within minutes or as long as 2 hr prior to ethanol exposure. Furthermore, DMTU was also shown to be protective against gastric injury induced by concentrated acid or base. Inin vitro studies in which hydroxyl radicals were actually generated, DMTU was noted to scavenge the hydroxyl radical in a dose-related fashion. The ability of DMTU to prevent gastric injury by three different damaging agents suggests that the hydroxyl radical may play a major role in the pathogenesis of such injury and that DMTU mediated its protective action by scavenging this radical species.This work was supported by Research Grant DK 25838 awarded to Dr. Miller from the National Institutes of Health.     

Effects of antioxidants and free radical scavengers in three different models of acute pancreatitis.

The present studies were done to evaluate the therapeutic potential of several antioxidants and free radical scavengers in three different models of acute pancreatitis. (a) Edematous pancreatitis with acinar cells necrosis was induced by seven hourly intraperitoneal injections of 50 micrograms of caerulein per kg in mice. (b) Hemorrhagic pancreatitis was induced by feeding a choline-deficient, ethionine-supplemented (CDE) diet in mice. (c) Hemorrhagic pancreatitis was induced by retrograde infusion of 0.6 ml of 5% sodium taurocholate into the pancreatic duct in rats. The following antioxidants and free radical scavengers were given at various doses intravenously, subcutaneously, or intraperitoneally before the onset of pancreatitis: Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], superoxide dismutase, catalase, deferoxamine (Desferal), dimethyl sulfoxide, or allopurinol. The severity of pancreatitis was assessed at various times after its onset by determination of serum amylase and pancreatic weight (edema), by grading of histological alterations, and by determination of survival (survival determined in models of hemorrhagic pancreatitis). In general, free radical scavengers and antioxidants ameliorated edema and inflammation to a greater degree than necrosis and the increase in serum amylase. Superoxide dismutase (as did Ebselen in previous studies) exerted beneficial effects on survival in diet-induced pancreatitis in the absence of marked effects on pancreatic necrosis, suggesting that these beneficial effects are due to amelioration of extrapancreatic complications that often contribute to mortality in acute pancreatitis. None of the antioxidants had major beneficial effects in taurocholate-induced hemorrhagic pancreatitis. Thus, formation of free radicals may be important for progression and outcome in diet-induced and, to a lesser degree, in caerulein-induced pancreatitis but not at all in taurocholate-induced pancreatitis. Different models of pancreatitis may, therefore, involve different degrees and mechanisms of free radical formation. Despite the amelioration of edema and the beneficial effects on mortality seen for some antioxidants in some of the models, antioxidants and free radical scavengers appear to have only a limited potential for treatment of acute pancreatitis.     

The effect of the oral iron chelator deferiprone on the liver damage induced by tamoxifen in female rats

Tamoxifen (TAM) is a non-steroidal antiestrogen used in the treatment and prevention of hormone-dependent breast cancer. Tamoxifen therapy may be accompanied with hepatic injury and iron accumulation in this organ. The present study investigates the influence of the effective oral iron chelator, deferiprone (L1), in TAM-induced acute liver injury. Four groups of female Wistar rats were used: I, control; II, TAM; III, TAM+L1; IV, L1. Tamoxifen (75 mg/kg) was administered orally on the first and second day; L1 (50 mg/kg) was administered orally on the first, second and third day of the experiment. On the fourth day, parameters of oxidative state: lipid peroxidation (LP), glutathione (GSH) and catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities were estimated in liver homogenates. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamate dehydrogenase (GLDH) levels and iron hepatic content were also evaluated. The TAM-induced oxidative damage was demonstrated by increased LP (52% above controls) and decreased GPx activity (to 92% of controls). The protective effect of L1 was manifested by attenuation of LP (p <0.05) and preserving of GPx activity. The TAM-induced increase of serum ALT and AST activity remained unchanged by L1 treatment. Significant increase of hepatic iron (Fe) level (41% above controls) was found in TAM-treated rats. Hepatic Fe accumulation was completely prevented by L1 treatment.