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In the early phases of an acute catabolic state, different cascades in the inflammatory process are activated. Among the many important mediators involved in the acute catabolic state are the eicosanoids. These substances are generated from phospholipids in response to a great variety of stimuli. After the discovery of prostaglandin in the 1930s, later work with these substances has elucidated the knowledge of a great diversity of eicosanoids with different properties.

Sucralfate is one of the best-known drugs which is frequently used for the treatment of peptic ulcers. 1,2 The mechanisms of action of sucralfate have been described in the preceding chapters. In this chapter, a detailed account will be given of the results of experimental studies of sucralfate conducted to assess its effects in preventing and heal- ing a variety of experimental ulcers induced in animals, and also of their correlation with the results of clinical use of the drug in humans.

Nowhere else in the digestive system is the mucosa more endangered than in the gastroduodenal region, the threats being primarily of a chemical nature and of both endogenous and exogenous origin. Most tissues would rapidly disintegrate if exposed to the concentrations of hydrochloric acid that bathe but do not harm the gastric surface epithelium. This is because a multitude of mechanisms constituting the gastric mucosal barrier prevents hydrogen ions from entering the tissues at quantities that would produce cell injury1. Yet even a weakening of the barrier will usually not lead to any major lesion formation because protective mechanisms will become operational, limit the damage and promote repair of the injured tissue.

We measured regional gastric mucosal blood flow by laser Doppler flowmetry before and after control (n = 8) or cigarette smoking (n = 8) in healthy human beings. The control group showed no change in both antrum (from 1.15 +/- 0.32 to 1.20 +/- 0.39 V, NS) and corpus gastric mucosal blood flow (from 1.15 +/- 0.32 to 1.12 +/- 0.28 V, NS). In contrast, cigarette smoking caused a significant reduction in gastric mucosal blood flow in the antrum (from 1.08 +/- 0.31 to 0.71 +/- 0.22 V, p < 0.01) and in the corpus (from 0.99 +/- 0.26 to 0.66 +/- 0.24 V, p < 0.01). The magnitude of reduction in gastric mucosal blood flow was similar between the antrum and the corpus (-34% +/- 11% versus -33% +/- 15%, NS). We conclude that cigarette smoking induces a significant reduction in gastric mucosal blood flow and that no heterogeneous response occurs in regional gastric mucosa. In addition, the laser Doppler flowmeter appears to be a sensitive method to assess rapid change in gastric mucosal blood flow in human beings.

The effects of polyethylene glycol (PEG) on gastric function and on lesion formation, evoked by topical applications of absolute ethanol to an ex-vivo stomach chamber preparation have been examined. Parenteral injection (i.p. or s.c.) of PEG with different molecular weights (PEG 300, 400 or 4000), dose-dependently reduced the gastric mucosal blood flow and volume of gastric secretion; these effects were greater in rats given PEG by the i.p. route, which also lowered acid output. Topical application of 1·5 mL absolute ethanol produced severe gastric mucosal injury, which was exacerbated by PEG; this lesion-aggravating effect was higher in the i.p.-injected groups. These findings indicate that when PEG is given by injection, it can adversely affect gastric function and increase the damaging action of alcohol. It is suggested that the use of PEG as a vehicle for injection should be re-assessed.

To investigate the mechanisms underlying the reduction in gastric blood flow induced by a luminal water extract of Helicobacter pylori (HPE).The stomachs of isoflurane-anesthetized mice were exteriorized, and the mucosal surface exposed. Blood flow was measured with the laser-Doppler technique, and systemic arterial blood pressure monitored. C57BL/6 mice were exposed to water extract produced from H pylori strain 88-23. To investigate the role of a nerve- or iNOS-mediated pathway, we used intraluminal lidocaine and iNOS-/- mice. Blood flow response to the endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) was also assessed.In wild-type mice, HPE decreased mucosal blood flow by approximately 30%. This reduction was abolished in iNOS-deficient mice, and by pre-treatment with lidocaine. Luminally applied ADMA resulted in reduction in blood flow similar to that observed in wild-type mice exposed to HPE.A H pylori water extract reduces gastric mucosal blood flow acutely through iNOS- and nerve-mediated pathways.

Circadian rhythms are present in several gastric functions including acid secretion and emptying rates. We hypothesize that aggressive and defensive factors in the gastric mucosa follow similar circadian rhythms. The purpose of this study was to determine if gastric mucosal blood flow, a known defensive factor, manifests a circadian rhythm in fasting rats. Ninety-six male Sprague-Dawley rats were light-adapted in isolation chambers for 3 weeks prior to the study. Half the rats experienced light from 6:00 AM to 6:00 PM, the other half from 6:00 PM to 6:00 AM. After an 18-hr fast, 12 rats were studied at each of eight sampling times: 0100, 0400, 0700, 1000, 1300, 1600, 1900, and 2200 hr after lights on (HALO). After anesthesia and laparotomy, the stomachs were opened along the anterior surface, gently stretched with mucosal surface upmost, and trapped between two lucite rings, with blood supply intact. Mucosal blood flow (ml/min/100 g) was measured in the forestomach, corpus, and antrum with a laser Doppler flowmeter (TSI Laserflo BPM 403). Cosinor analysis showed a significant (P less than 0.01) circadian rhythm in gastric mucosal blood flow within the corpus and antrum, but not in the forestomach. Peak time for corpus blood flow was 21:45 +/- 0:56 HALO (3:45 AM). In the antrum it was 0:51 +/- 1:08 HALO (6:51 AM). These results support the hypothesis that circadian rhythms in mucosal defensive functions are an integral part of normal gastric physiology.

This study investigated the increase in gastric acid secretion induced by intravenous administration of 2-deoxy-D-glucose (2-DG; 60 mg kg’1), insulin (5 U kg-1) or by electrical stimulation of the vagus nerve (1 mA, 1 ms, 3 Hz) in urethane-anesthe-tized rats pretreated when newborn with either capsaicin or the vehicle.

Ever since he had the extraordinary opportunity to view — through a trauma-induced gastrocutaneous fistula — the gastric lining of his patient Alexis St. Martin, Dr. William Beaumont has been admired by all who seek better ways to view the interior of the gastrointestinal tract. It was not until 1958 that the modern age of gastrointestinal endoscopy began with the introduction by Hirschowitz (Hirschowitz et al. 1958) of a prototype fiberoptic gastroscope. Previously, Schindler had developed first the rigid, and then the semiflexible gastroscope, the latter using a series of lenses and prisms. With the development of coherent, insulated optical glass fibers, however, the path was cleared for construction of a fully flexible endoscope.

Gastric mucosal blood flow and its regulating factors were studied in normal and stressed rats. In addition, vascular regulating factors and the role of CoQ10 anion radical and SOD (superoxide dismutase) level in gastric mucosa were also investigated as well as the influence of 5-HT (5-hydroxytryptamine) on gastric mucosal blood flow. Gastric mucosal blood flow was measured by the hydrogen gas clearance method. The vascular pattern of the stomach was investigated by the infusion method with two-colored silicon rubber. CoQ10 anion radical and SOD levels in gastric tissue were assayed by electron spin resonance (ESR) and radioimmunoassay. The gastric mucosal blood flow decreased significantly early after the induction of stress. Impairment of gastric mucosal blood flow was highly correlated with 5-HT and CoQ10 anion radical and SOD levels. Reduction in gastric mucosal blood flow was consequently due to opening of arteriovenular shunt and hyperpermeability of true capillaries influenced by 5-HT. These results demonstrate that ischemia and reperfusion after reduction of the gastric mucosal blood flow resulted in the sequence of events that led to formation of acute gastric mucosal lesions.

Gastric mucosal blood flow (GMBF) was measured by a laser doppler flow meter continually during and after transient forebrain ischemia in rats. The value of GMBF obtained after at 15 min of ischemia did not change significantly compared to that of the preischemic period. However, a 26% decrease of GMBF was detected after 30 min of ischemia. When circulation of the brain was restored, the GMBF increased slightly after 15 min. After 30, 45, and 60 min of restored cerebral circulation, the GMBF decreased significantly and the values were 63%, 58% and 51% of the control, respectively.

The development of acute stress bleeding in intensive-care patients occurs on a multifactorial basis. The basic mechanism lies in the imbalance between aggressive and protective factors. Most intensive care patients show a reduced acid secretion, a reduction of the gastric mucosal blood flow, and a decreased mucus and bicarbonate secretion. Sucralfate enhances most of the defensive mechanisms. These actions are the pathophysiologic basis of the efficacy of sucralfate in the prevention of stress bleeding. Because sucralfate has only a minor influence on the gastric pH and at the same time has proven bactericidal effects, gastric and gut bacterial overgrowth is significantly reduced. These effects explain the observed differences in mortality between sucralfate and alkalinizing drugs like antacids or H2-antagonists. The indications and limits of sucralfate in stress bleeding prophylaxis are pointed out.

Despite the development of numerous methods for measuring gastrointestinal blood flow, important physiological questions remain unanswered regarding the gastrointestinal circulation, its regulation, and its relationship to gastrointestinal function. For example, investigators of the gastrointestinal circulation generally agree that alterations in blood flow participate in the etiology of a variety of gastrointestinal disorders ranging from gastric ulcers to necrotizing enterocolitis. However, the role of blood flow in maintaining mucosal integrity in the stomach and intestine is still poorly understood.

Since its incorporation in 1961, TSI’s primary business has been identifying requirements for the measurements of details of fluid flow, and then developing solutions to meet these needs. The company’s earliest products were a series of thermal anemometers used for measuring the flow of hot gases. This product line soon expanded into a broad line of hot wire and hot film probes and electronics for fluid flow measurement in research, medical, and industrial applications.

The use of recruitment manoeuvres (RM) has recently been introduced into clinical practice for treatment of atelectasis during mechanical ventilation. Transient high airway pressures, such as those employed in RM, may lead to adverse general or regional circulatory effects. The aim of this study was to evaluate effects of RM on gastric mucosal blood flow, systemic oxygenation and respiratory mechanics.

Factors controlling gastric mucosal blood flow are now better understood, and improved techniques have been established to study microcirculation in the gastrointestinal tract. In this paper, four areas are reviewed: gross and microscopic vessels that supply blood to the stomach; factors that control gastrointestinal blood flow; pathogenic role of disturbed mucosal blood flow circulation induced by stress; and findings in early vascular permeability and injury caused by cold restraint stress in the rat.

The aim of this study is to define the effect(s) of centrally administered neurotensin (NT) on gastric mucosal integrity, prostaglandin E2 (PGE2) generation, and blood flow during stress induced by cold-water restraint (CWR) in rats. Intracerebroventricular (icv) NT reduced macroscopic and microscopic damage. The former effect was dose dependent and was totally blocked by indomethacin pretreatment. Gastric mucosal PGE2 increased 27 and 30% at 30 and 60 min, respectively, in nonrestrained rats given icv NT. PGE2 generation was reduced in control rats during CWR but was maintained in CWR rats treated with icv NT. Gastric mucosal blood flow (GMBF) was significantly reduced in control rats during CWR. Mucosal blood flow was maintained at nonrestraint levels in the presence of icv NT during CWR; however, this effect was abolished by parenteral indomethacin pretreatment. Similarly, intravenous 16,16-dimethyl-PGE2 (200 micrograms.kg-1.h-1) maintained GMBF of non-CWR levels as well as preventing the macroscopic damage normally associated with CWR. These data suggest a protective role for central NT on the gastric mucosa, mediated, at least in part, by PGE2 generation and gastric mucosal blood flow.

Clearance of plasma aminopyrine (an index of mucosal blood flow, MBF) into acid (0.1 N HCl) instilled into Heidenhain pouches was about 200 ml per 30 min under basal conditions. Glucagon 50 μg/kg s.c. significantly decreased the MBF from 200 to 132 ml per 30 min at one hr; the decrease lasted about 60 min. Infusion of glucagon 50 μg/kg i.v. for 1 hr produced a delayed reduction of MBF lasting for more than 90 min. Under the same experimental conditions, atropine 50 μg/kg reduced MBF from 200 to 166 ml per 30 min upon subcutaneous administration and showed no significant effect by i.v. infusion. The increase in residual volume of the pouch caused by glucagon could not account for all the decrease in clearance of aminopyrine. We conclude that glucagon reduces gastric mucosal blood flow under basal conditions.

After various types of sympathectomy (surgical, chemical, isolated adrenod-emedullation; AMX, combined procedurs) in the rat, basal gastric secretion, gastric mucosal blood flow (MBF), associated gluc

The involvement of gastric mucosal metabolism of ethanol in ethanol-induced mucosal damage was studied in urethane anaesthetised rats. Pyrazole, an inhibitor of alcohol dehydrogenase (ADH), slightly aggravated the mucosal lesions produced by intragastric instillation of 30% (v/v) ethanol, but had no effect on increased mucosal permeability to ions, pepsinogen and fluid output or on gastric mucosal blood flow associated with mucosal injury. Induction of ADH by ethanol pre-treatment had no effect on the above-mentioned parameters. Intragastric instillation of acetaldehyde, the product of ethanol oxidation, did not cause lesions in the gastric mucosa. The results suggest that the gastric mucosal toxicity of ethanol may not be related to its metabolism in the gastric mucosa.

Focal gastric mucosal blood flow as measured by the hydrogen gas clearance method was compared with total gastric blood flow as determined by venous outflow in an isolated segment of canine stomach before, during, and after exposure to aspirin. Despite an increase in total gastric blood flow from 10.8 +/- 1.6 ml/min per chamber to 17.4 +/- 1.9 ml/min per chamber and mucosal blood flow at nonulcerated sites from 29.5 +/- 4.3 ml/min per 100 g to 83 +/- 14.4 ml/min per 100 g, mucosal blood flow at the site of aspirin-induced ulceration was significantly reduced from 29.5 +/- 4.3 ml/min per 100 g to 12.5 +/- 2.5 ml/min per 100 g. After the removal of aspirin, mucosal blood flow returned to control levels. Such a redistribution of mucosal blood flow in response to aspirin is consistent with the localized nature of acute aspirin-induced injury. The findings also explain the inability of previous methods measuring blood flow of the entire stomach to demonstrate mucosal ischemia during such injury.

We compared focal gastric mucosal blood flow (GMBF) values simultaneously obtained by laser-Doppler flowmetry (LDF) and hydrogen gas clearance (HGC) from the same point in a chambered segment model of the gastric corpus in two sets of experiments (Experiments 1 and 2) involving nine anesthetized dogs (weighing 20-30 kg). We also investigated the feasibility of obtaining a conversion factor for LDF signal to absolute flow values. The GMBF values showed a highly significant linear correlation within individual experiments and for the combined data in experiments 1 (r = 0.7132, P less than 0.0001, n = 37) and 2 (r = 0.5660, P less than 0.0001, n = 61). The combined data did not corroborate a common regression line hypothesis in both experiments (Experiment 1: F = 6.59, P less than 0.0005; Experiment 2: F = 10.57, P less than 0.0005). There was a statistically significant difference between the slopes of the 5 and 4 linear regression lines obtained in Experiments 1 (F = 13.15, P less than 0.0005) and 2 (F = 21.14, P less than 0.0005), respectively. The LDF signal was stable and optical coupling is not a problem in this experimental model. HGC and GMBF values were reliable and highly reproducible within dog measurements. We conclude that LDF and HGC are comparable in the measurement of focal GMBF. Our data, however, did not suggest the existence of a conversion factor for LDF signal to absolute flow values from experiment to experiment. Conversion will have to be within individual experiments. Thus, LDF may only be useful in situations where qualitative changes in focal blood flow are investigated.

A crossed thermocouple method in combination with endoscopy was applied to determine the blood flow rate of the human gastric mucosa. Determination was carried out with 11 healthy control subjects at 8 sites of the stomach. The blood flow rates at all sites in the corpus were found to be higher than those at the antrum. In subjects less than 50 years old the blood flow rate in the corpus was higher than in older subjects. These results were in agreed well with those obtained by the hydrogen gas clearance method, which is widely adopted clinically. The crossed thermocouple method is easily applicable to all sites in the gastric mucosa and the time required for the assay is very short. This method dose not require the inhalation of hydrogen gas which is necessary for the hydrogen gas clearance method and which is possibly harmful to humans. Although the values obtained by the crossed thermocouple method are relative to the value at a certain fixed site, this method will holds great potential for the determination of gastric mucosal blood flow rate.

Article, 信州医学雑誌 36(1): 73-82(1988)

"Ice-cold" gastric lavage is an important part of the treatment of bleeding from stress ulceration. The purpose of this study was to find out if cooling modifies ischemic injury of the gastric mucosa. Four series of experiments were performed in rabbits. In the first, we studied the influence of cooling on the rate of breakdown of gastric mucosal high energy phosphates during complete, ex vivo ischemia achieved by rapid excision of the stomach. We then studied the influence of cold versus warm gastric lavage on the severity of gastric mucosal injury and on the rate of breakdown of gastric mucosal adenosine phosphates during hemorrhagic shock. In a fourth series of experiments, we examined the influence of cold versus warm gastric lavage on gastric mucosal blood flow measured by injection of radioactive microspheres. Although the rate of breakdown of mucosal high energy phosphates was less rapid during a short period of complete, ex vivo ischemia when the stomach was cooled, this rate was more rapid during hemorrhagic shock under in vivo conditions when the stomach was lavaged with cold solution. The latter also increased the severity of shock-induced gastric mucosal injury. Cold gastric lavage reduced gastric mucosal blood flow before, during and after hemorrhagic shock.

To elucidate the anti-ulcer mechanism of mezolidon (KM-1146, 2-(3,4-dimethoxyphenyl)-5-methylthiazolidine-4-one), we investigated gastric mucosal blood flow (laser-Doppler method), transmucosal potential difference, gastroduodenal mucosal surface pH and blood viscosity in rats under a water-immersion stress condition. In the control group, gastric mucosal ulcers occurred three hours after the onset of water-immersion. At that time, gastric mucosal blood flow decreased to 40% and the potential difference decreased to 48%. In the mezolidon-pretreated group, gastric mucosal ulcers were significantly reduced, and the potential difference was significantly higher than in the control group. Gastric mucosal blood flow increased significantly to 120% twenty minutes after the onset of water-immersion and then decreased, but was significantly higher than in the control group. Gastroduodenal mucosal surface pH was not affected by the pretreatment with mezolidon under this condition. Pretreatment with mezolidon did not affect blood viscosity. In conclusion, the anti-ulcer effect of mezolidon may involve the increase and/or maintenance of gastric mucosal blood flow, but more investigations are necessary to understand the mechanism involved.

The effects of U-46619, a stable analogue of the prostaglandin endoperoxide PGH2, were studied on canine gastric acid secretion, gastric mucosal blood flow, and secretion of mucus into gastric juice and compared to those of PGE2. U-46619 was approximately four and three times as potent as PGE2 in inhibiting acid secretion and stimulating mucus secretion, respectively. When infused at a low dose, U-46619 inhibited acid secretion directly without causing a decrease in the ratio of mucosal blood flow to volume rate of secretion (R), this effect being similar to that observed for PGE2. However, unlike PGE2, U-46619 when administered in a higher dose caused a decline in R while decreasing acid secretion and mucosal blood flow, suggesting a primary restriction of blood flow. The antisecretory effects of arachidonic acid may be due in part to the endogenous formation of prostaglandin endoperoxides as opposed solely to prostaglandin formation. Considering the antisecretory and mucogenic actions of U-46619, nontoxic analogues of prostaglandin endoperoxides may be of value as antiulcer agents.