左旋精氨酸甲酯及左旋精氨酸对应激状态下胃黏膜耐受性细胞保护作用的影响

目的：探讨内源性一氧化氮（NO）在应激状态下胃黏膜耐受性细胞保护中的作用及其可能的机制。方法：以重复浸水束缚应激（WRS）制作动物模型,以左旋精氨酸甲酯（L－NAME）或左旋精氨酸（L－Arg）抑制或促进内源性NO的合成,动态检测胃黏膜血流量（GMBF）、溃疡指数（UI）、黏膜一化氮含量的变化。结果：重复应激后,实验对照组大鼠UI明显下降,同时GMBF上升,黏膜内NO含量增高;L－NAME使WWRS引起的胃黏膜损伤加重,消除了GMBF的递增趋势,黏膜NO含量下降;而L－Arg可减轻WRS造成的黏膜损伤,GMBF、黏膜NO含量增相应增加;GMBF、UI、黏膜NO含量变化之间有相关关系。结论：内源性NO通过调节GMBF而介导耐受性细胞保护作用,L－NAME抑制其合成,延缓这一作用,L－Arg增加其合成,促进该作用。     

Epalrestat prevents the decrease in gastric mucosal blood flow and protects the gastric mucosa in streptozotocin diabetic rats

We have recently reported that steady-state gastric mucosal blood flow (GMBF) is decreased in streptozotocin (STZ) diabetic rats, and that their GMBF response to burn-stress is impaired, probably via a nitric oxide (NO)-mediated mechanism. Accordingly, this study was designed to investigate the relation of aldose reductase (AR) and NO synthase to the regulation of GMBF during chronic hyperglycemia. STZ rats were treated with or without chronic oral administration of an AR inhibitor, epalrestat (EPA) and/or an NO synthase inhibitor, N-nitro-L-arginine methyl ester (L-NAME). GMBF was measured by laser-Doppler velocimetry (LDV). In the STZ rats, GMBF after a 24-h fasting period was decreased significantly 4 weeks after the onset of diabetes and this was accompanied by an increase in the gastric ulcer index (UI) (a measure of the length of gastric erosions and ulcers). Chronic oral administration of EPA to the STZ rats dose-dependently inhibited the increased UI and the decreased GMBF after the fasting stress, whereas chronic oral administration of L-NAME further increased the UI and further decreased the GMBF. EPA administered in combination with L-NAME to the STZ rats reduced the effects of L-NAME, but the effects did not reach significance. These results suggest that EPA protects the gastric mucosa of diabetic rats, by preventing the decrease in GMBF that is, at least in part, caused by NO-related mechanisms. (Received Mar. 3, 1998; accepted Aug. 28, 1998)     

Relationship between gastric mucosal hemodynamics and gastric motility

Continuous measurement of gastric mucosal hemodynamics (the index of mucosal hemoglobin concentration, the index of oxygen saturation and blood flow) in rats showed oscillatory changes. The mechanism of the oscillations was investigated using a probe specially designed for simultaneous measurement of hemodynamics and intragastric pressure. A hemodynamics-measuring probe for either reflectance spectrophotometry or laser-Doppler flowmetry was tied to a pressure microtransducer, inserted through an incision in the forestomach, and brought into gentle contact with the corpus mucosa. Synchronous oscillatory changes (4-6 cycles/min) in hemodynamics and motility were observed in the resting state (mean blood pressure: 120 mmHg). During moderate hemorrhagic hypotension (mean: 81 mmHg), oscillations in the hemodynamics increased in both amplitude and frequency, while motility remained constant. Oscillations in the hemodynamics were also affected by fluctuations in blood pressure and by topical application of norepinephrine to the corpus serosa. In water-immersion restraint rats, changes in the oscillations in the hemodynamics and motility were virtually synchronous; frequency decreased and amplitude increased. These findings suggest that oscillatory changes in gastric mucosal hemodynamics are regulated not only by gastric motility but also by arteriolar vasomotion of the gastric wall.     

胃溃疡大鼠胃粘膜血流量与泌酸变化的研究

用手术将十二指肠内容物持续胃内反流制成大鼠胃溃疡及经转流后的溃疡愈合模型进行研究。结果表明,溃疡组于胃窦小弯侧可见8.84±3.08(m~2)~(-3)的慢性溃疡形成,并显示胃粘膜血流量降低,G细胞密度、壁细胞数增加。溃疡愈合组经转流后大部分溃疡已愈合,G细胞密度、壁细胞数降低,粘膜血流量增加。本实验提示,泌酸细胞增多,泌酸量增加和胃粘膜缺血可能是溃疡形成的重要因素,增加胃粘膜的血液供应,降低胃酸分泌可促进溃疡愈合。     

Influence of Helicobacter pylori infection and cetraxate on gastric mucosal blood flow during healing of endoscopic mucosal resection-induced ulcers

BACKGROUND AND AIM: Helicobacter pylori (H. pylori) infection is known to affect the gastric microcirculation, and cetraxate is reported to accelerate gastric ulcer healing, possibly by augmenting gastric mucosal blood flow (MBF). The aim of this study is to clarify the effect of H. pylori infection and cetraxate on MBF during gastric ulcer healing. METHODS: Forty-two patients who had undergone endoscopic mucosal resection (EMR) were studied. Mucosal blood flow was measured by the use of a laser Doppler flowmeter in the surrounding mucosa and at the ulcer margin, before, 1 day, 1 week and 4 weeks after EMR. Helicobacter pylori infection was confirmed by the use of bacterial culture and histology. After EMR, patients were randomly assigned to receive 30 mg lansoprazole (u.i.d; L-regimen) or 30 mg lansoprazole (u.i.d.) with 200 mg cetraxate (q.i.d; LC-regimen) for 4 weeks. RESULTS: The MBF ratio (MBF at ulcer margin/MBF in surrounding mucosa) 1 week after EMR was significantly lower than that before or 4 weeks after EMR only in H. pylori-positive patients treated with the L-regimen. No such decrease in MBF was observed after 1 week in H. pylori-positive patients treated with the LC-regimen or in H. pylori-negative patients. CONCLUSION: A transient decrease in MBF was detected at the ulcer margin during healing of EMR-induced ulcers in H. pylori-infected patients. Cetraxate seemed to prevent this decrease in MBF.     

Brain ischemia and gastric mucosal damage in spontaneously hypertensive rats

Brain ischemia is often accompanied by acute gastric lesions. To clarify the underlying mechanism, the influence of acute ischemic insult to the brain on gastric hemodynamics and mucosal integrity was examined in spontaneously hypertensive rats. One hour after brain ischemia, gastric mucosal blood flow decreased to 71% of the preischemic levels in the control rats but was preserved significantly better, at 94 and 108%, in the prazosin-treated and guanethidine-treated rats, respectively. Vagotomy almost abolished the decrease in gastric mucosal blood flow during cerebral ischemia. Intragastric 0.6 N hydrochloric acid administered just after reperfusion induced more severe hemorrhagic ulcers in the control than in the prazosin-treated and vagotomized groups. These results suggest that noradrenergic neurons acting through ₁-adrenoceptors contributes to the decrease in gastric mucosal blood flow, and the subsequent disturbed integrity of the gastric mucosa, through the vagal adrenergic pathway during brain ischemia in spontaneously hypertensive rats.     

Gastric mucosal injury and associated changes in mucosal blood flow and gastric fluid secretion caused by dimethyl sulfoxide (DMSO) in rats

Dimethyl sulfoxide applied intragastrically for 10 min in rats caused extensive mucosal damage. In concentrations of 5%, 10%, or 100%, dimethyl sulfoxide caused superficial damage to 33%, 36%, and 97%, respectively, of the corpus mucosa, and 28%, 44%, and 96%, respectively, of the antral mucosa. Concentrated dimethyl sulfoxide also caused damage to the pits and glands in some areas of the mucosa. The amount of fluid in the stomach increased by 0.24 ml, 0.48 ml, and 2.07 ml during application of 5%, 10%, and 100% dimethyl sulfoxide. The 10% dimethyl sulfoxide increased mucosal blood flow by 0.57 ml/min/g in the antrum, and 100% dimethyl sulfoxide increased mucosal blood flow by 2.21 ml/min/g in the antrum and by 1.17 ml/min/g in the corpus. We conclude that dimethyl sulfoxide is a gastric irritant, which should be considered when it is used as an oxygen radical scavenger, as a drug or carcinogen vehicle, or as oral medication in patients. The protective effect of intragastric dimethyl sulfoxide against stress and various drug-induced gastric injury may be due to adaptive cytoprotection rather than an oxyradical scavenger effect.This work was supported by grants from the Norwegian Cancer Society. Dr. Sørbye is a Research Fellow of the Norwegian Cancer Society.     

Effects of a gastric mucosal protecting agent in rats with liver cirrhosis

Male Sprague-Dawley rats were fed a 0.1% ethionine-added choline-deficient diet for 8 weeks to induce liver cirrhosis. At the same time 100 mg/kg/day teprenone was administered orally in order to evaluate its effects on the liver and gastric mucosal blood flow. Blood flow increased not only in gastric mucosa but also in liver tissues in the teprenone group. Serum transaminase levels and histopathologic findings of the liver also improved. These findings suggest that teprenone alleviates hepatocellular injuries. This effect may be partly attributable to cytoprotective effects of the catenoid isoprenoid moiety of teprenone on liver cells.     

Monoamine oxidase B inhibition reduces gastric mucosal blood flow,basal acid secretion,and cold water restraint-induced gastric mucosal injury in rats

Inhibition of monoamine oxidase B (MAO B) by selective inhibitors pargyline and l-deprenyl increases dopamine (DA) and norepinephrine (NE) concentrations in nucleus accumbens (NACB) and is associated with reduction in cold water restraint-induced gastric mucosal injury, inhibition of basal gastric acid output, and regional gastric mucosal blood flow. Similar effects were not observed with administration of MAO A inhibitors. These observations suggest that activation of central dopamine and norepinephrine receptors, particularly in NACB, are involved in the control of gastric mucosal function.Supported by PHS grant DK 38198 (G.K.).     

Effects of gastric distension and prostaglandin on acid ethanol-induced mucosal lesions in the rat

The effects of gastric distension on the morphology of acidified ethanol (AE) -induced mucosal lesions and on the protective action of 16,16-dm PGE₂ were investigated in rats. AE (50% ethanol in 150 mM HCl) was given by gavage in the intact stomach or through a fistula prepared in the forestomach in the pylorus-ligated stomach. AE produced elongated bands of hemorrhagic necrosis within 1 hr in the former, while in the pylorus-ligated stomach the shape of lesions varied depending upon the volume of irritant. One milliliter produced bandlike lesions, whereas 2 ml or more induced widespread lesions; such volumes were observed to remove the mucosal folds. 16,16-dm PGE₂ (0.3–10 g/kg, subcutaneous) dose dependently reduced bandlike lesions in the intact stomach, but had no or little effect on non-band-like lesions in the pylorus-ligated stomach. This agent (10 g/kg) had a slight effect on the reduction of PD caused by 10-min exposure of the stomach to AE (2 ml) in the intact stomach, while such effects were not apparent in the pylorus-ligated stomach. Oral gentian violet (2 ml, 0.3% w/v) produced bandlike staining of the mucosa in intact rats, but the effect was blocked by pyloric ligation. 16,16-dm PGE₂ also significantly prevented the localized staining pattern seen in intact rats. These results suggest that (1) the bandlike pattern of AE-induced injury is dependent on the presence of mucosal folds (distending the stomach abolishes mucosal folds and widespread injury results); (2) 16,16-dm PGE₂ prevented the fold-related, bandlike lesions and bandlike staining of the mucosa, but failed to abolish the generalized lesions; and (3) PG cytoprotection appears associated with the formation of bandlike lesions which are dependent on the presence of mucosal folds.     

Antiulcer drugs and gastric mucosal integrity

Although prostaglandins (PGs) of the E series have gastric antisecretory and cytoprotective properties, many have different effects on the barrier integrity of the gastric mucosa. The direct effect of antiulcer drugs on gastric mucosal blood flow, mucosal barrier permeability, and metabolic rate have not been adequately studied. These factors are important in the defense of the gastric mucosa. Part of the difficulty relates to the possible influence of gastric mucosal blood flow on gastric acid secretion. To rule out this confounding factor, omeprazole can be used to reveal the true pharmacologic effects of these antiulcer drugs independent of the effect of gastric secretionper se. The study examined the effects of 16,16-dimethyl PGE₂ (dmPGE₂) misoprostol, and cimetidine on gastric mucosal blood flow, oxygen consumption, potential difference (PD), electrolytes, and fluid flux using theex vivo gastric chamber dog model. The PGs were administered intraluminally with an isotonic acid solution; cimetidine was administered by arterial infusion. None of the drug treatments had any significant effect on mean systemic arterial pressure, arterial blood gases, body temperature, or oxygen consumption. dmPGE₂ significantly (P<0.001) decreased PD and enhanced the electrolytes (Na⁺, K⁺) and fluid flux across the mucosa (P<0.05). Misoprostol significantly increased gastric mucosal blood flow (P<0.02) and fluid efflux but decreased PD values. Cimetidine did not have any significant effects on barrier or metabolic functions of the stomach. These results suggest that a considerable difference exists in the pharmacology of gastric antisecretory drugs in relation to their effect on several factors affecting gastric mucosal integrity.This study was supported by the National Institutes of Health grant GM23095 and by the University of Utah.     

Modulatory action of adenosine on gastric function and ethanol-induced mucosal damage in rats

This study examines the gastric effects of adenosine and its antagonist, theophylline, on secretory function, mucosal blood flow, and on ethanol-induced glandular mucosal damage in rats that were fasted for 24 hr before experimentation. The animals were anesthetized with sodium pentobarbitone (50 mg/kg intraperitoneal) and their tracheae cannulated. An ex vivo stomach chamber then was prepared. The luminal bathing solution was collected every 15 min and the concentrations of H⁺ and Na⁺ were determined by a pH autotitrator and an ionmeter, respectively. The glandular mucosal blood flow was measured by a laser Doppler flowmeter and the severity of lesions was determined by measuring the hemorrhagic areas. Adenosine administration (2.5 or 7.5 mg/kg, subcutaneous) markedly lowered the H⁺ and Na⁺ output but increased the secretory volume and mucosal blood flow in a dose-dependent manner. The same doses of the nucleoside also prevented ethanol-induced mucosal damage. These effects were prevented by pretreatment with theophylline (30 or 60 mg/kg, subcutaneous). Ethanol given alone significantly depressed the H⁺ and Na⁺ secretion. Both effects were not modified by adenosine treatment. However, the depressive action of ethanol on mucosal blood flow was prevented by adenosine. These findings indicate that adenosine modulates the physiological function of the stomach. It also directly activates the defensive mechanism of the stomach, which is partially mediated by the improvement of the gastric mucosal blood flow and an increase in the nonacid component of gastric secretion.     

New method of evaluating gastric mucosal blood flow by ultrasound

Objective. Evaluation of gastrointestinal blood flow is important. However, a non-invasive measurement method has not yet been established. The aim of this study was to compare measurement of normal gastric mucosal blood flow by advanced dynamic flow (ADF) flash echo imaging (FEI) with intravenous Levovist with measurement by laser Doppler flowmetry (LDF) to clarify the usefulness of ADF-FEI and thereby consider its feasibility as a non-invasive gastric mucosal blood flow measurement method. Material and methods. Measurements were obtained in 25 beagle dogs (8-month-old males, body-weight, 10.6±1.3 kg, mean±SD). After insertion of a gastrointestinal endoscope, gastric mucosal blood flow at the greater curvature of the corpus was measured by LDF, and images of gastric mucosal blood flow were obtained by ADF-FEI (frequency; 4.7 MHz) with intravenous injection of Levovist (30 mg/kg). ADF-FEI images were transferred to a personal computer. A region of interest was set on the mucosa of the greater curvature of the corpus, and a time intensity curve (TIC) was plotted from the measured echo intensities. The area under the curve (AUC) calculated from the TIC and the median flow determined by LDF were analyzed and compared. Results. Evaluation of normal gastric mucosal blood flow by ADF-FEI was possible in all animals. There was a strong, significant correlation between gastric mucosal blood flow measured by LDF and the AUC obtained by ADF-FEI (r=0.869, p<0.0001). Conclusions. Gastric mucosal blood flow can be accurately measured by ADF-FEI with intravenous Levovist injection.     

Effects of electroacupuncture on gastric mucosal blood flow and transmucosal potential difference in stress rats

ＥｆｅｃｔｓｏｆｅｌｅｃｔｒｏａｃｕｐｕｎｃｔｕｒｅｏｎｇａｓｔｒｉｃｍｕｃｏｓａｌｂｌｏｏｄｆｌｏｗａｎｄｔｒａｎｓｍｕｃｏｓａｌｐｏｔｅｎｔｉａｌｄｉｆｅｒｅｎｃｅｉｎｓｔｒｅｓｓｒａｔｓＸＵＧｕａｎＳｕｎ１，ＳＵＮＹｏｎｇ１，ＷＡＮＧＺｈｅ...     

Effect of hepatic collateral hemodynamics on gastric mucosal blood flow in patients with liver cirrhosis

The dependence of the gastric mucosal change in liver cirrhosis on the extrahepatic collaterals is still unknown. Therefore we studied the influence of these collateral hemodynamics on gastric mucosal blood flow and gastric mucosal lesions. The subjects were 23 cirrhotic patients and were divided into two groups by the findings of percutaneous transhepatic portography. The first group consisted of 14 cases whose extrahepatic collaterals were via esophageal varices (group I). The second group included 9 cases having collaterals other than esophageal varices (group II). Multiple red spots were observed in 13 of 14 cases in group I, and two of nine cases in group II. Gastric mucosal blood flow was 2.0±0.9 volts (mean±sd) in group I, 4.0±1.2 in group II. A statistically significant difference was observed between groups I and II. Gastric mucosal blood flow was not significantly correlated with portal venous pressure in group I. It is concluded that, in liver cirrhosis, gastric mucosal blood flow is changeable according to the types of the extrahepatic collaterals.