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Gastric Mucosal Energy Metabolism and “Stress Ulceration,”
Abstract
Acute gastric erosions following hemorrhagic shock (stress ulceration) have been attributed to gastric hyperacidity, altered gastric secretion of mucus and an abnormal permeability of the gastric mucosa to H(+). This report aims at presenting evidence supporting an alternate hypothesis: the event linking shock-induced gastric mucosal ischemia to mucosal necrosis is a deficit in gastric mucosal energy metabolism. Our experimental procedure consisted of harvesting the stomachs of rats and rabbits by "stop-freeze" (liquid N(2)) at different intervals after the induction of hemorrhagic shock. Levels of adenosine-phosphates and of glycolytic intermediates in gastric mucosa were measured. We studied the changes in the levels of these substrates produced by shock as well as by factors capable, when combined with shock, of rendering the gastric mucosa more vulnerable to stress ulceration. The influence of shock and of these modifying factors were evaluated by comparison with data from appropriately designed control experiments. In parallel experiments we examined the frequency of stress ulceration (gross and microscopic) under these same standard conditions. There have emerged from these studies a number of observations all based upon data with the highest statistical significance. The data are consonant with the hypothesis stated above: an energy deficit severe enough to cause cellular necrosis is the event linking shock-induced gastric mucosal ischemia and stress ulceration.
... Several human and animal studies have demonstrated that bioenergetics of the gastric epithelium are affected by various diseases (e.g., ischemia) and toxins (e.g., acetylsalicylic acid and non-steroidal anti-inflammatory drugs) [8][9][10][11] . Similarly, gastric tissue deficient in superoxide dismutase (a parietal cell enzyme that prevents the accumulation of superoxides) has mitochondrial dysfunction and perturbed energy metabolism, which manifests via reduced ATP and increased apoptosis [9] . ...
... Bioenergetic studies on the gastric epithelium are relatively limited, especially with respect to investigating human stomach diseases and the use of compound biomarkers [8,10,11,[20][21][22][23][24][25][26][27][28][29][30] . The main purpose of this study was to examine the suitability of using biochemical parameters (cellular respiration, ATP, GSH, and caspase activity) as biomarkers for the gastric mucosa. ...
... Bioenergetics of the gastric epithelium was investigated in specimens collected from animal and human tissues [8,10,11,20] . In the bullfrog gastric mucosa, cellular mitochondrial O2 consumption was increased and cellular ATP was decreased in the presence of acetylsalicylic acid [8] . ...
To measure biochemical parameters in stomach biopsies and test their suitability as diagnostic biomarkers for gastritis and precancerous lesions.
Biopsies were obtained from the stomachs of two groups of patients (n = 40) undergoing fiber-optic endoscopy due to upper gastrointestinal symptoms. In the first group (n = 17), only the corpus region was examined. Biopsies were processed for microscopic examination and measurement of mitochondrial O2 consumption (cellular respiration), cellular adenosine triphosphate (ATP), glutathione (GSH), and caspase activity. In the second group of patients (n = 23), both corpus and antral regions were studied. Some biopsies were processed for microscopic examination, while the others were used for measurements of cellular respiration and GSH level.
Microscopic examinations of gastric corpus biopsies from 17 patients revealed normal mucosae in 8 patients, superficial gastritis in 7 patients, and chronic atrophic gastritis in 1 patient. In patients with normal histology, the rate (mean ± SD) of cellular respiration was 0.17 ± 0.02 μmol/L O2 min(-1) mg(-1), ATP content was 487 ± 493 pmol/mg, and GSH was 469 ± 98 pmol/mg. Caspase activity was detected in 3 out of 8 specimens. The values of ATP and caspase activity were highly variable. The presence of superficial gastritis had insignificant effects on the measured biomarkers. In the patient with atrophic gastritis, cellular respiration was high and ATP was relatively low, suggesting uncoupling oxidative phosphorylation. In the second cohort of patients, the examined biopsies showed either normal or superficial gastritis. The rate of cellular respiration (O2. μmol/L min(-1) mg(-1)) was slightly higher in the corpus than the antrum (0.18 ± 0.05 vs 0.15 ± 0.04, P = 0.019). The value of GSH was about the same in both tissues (310 ± 135 vs 322 ± 155, P = 0.692).
The corpus mucosa was metabolically more active than the antrum tissue. The data in this study will help in understanding the pathophysiology of gastric mucosa.
... 365,366 On the other hand, exposure to stress is known to induce gastric hemorrhagic erosions due to hyperacidity and deterioration of microcirculation. 367,368 It has been shown that mental disorders such as depression, circadian disturbance, and stress are accompanied by microbiome profile alterations. 369−372 Interestingly, a ruthenium-based CO donor, CORM-2, has also been shown to prevent stress-induced gastric lesions formation. ...
Nature is full of examples of symbiotic relationships. The critical symbiotic relation between host and mutualistic bacteria is attracting increasing attention to the degree that the gut microbiome is proposed by some as a new organ system. The microbiome exerts its systemic effect through a diverse range of metabolites, which include gaseous molecules such as H 2 , CO 2 , NH 3 , CH 4 , NO, H 2 S, and CO. In turn, the human host can influence the microbiome through these gaseous molecules as well in a reciprocal manner. Among these gaseous molecules, NO, H 2 S, and CO occupy a special place because of their widely known physiological functions in the host and their overlap and similarity in both targets and functions. The roles that NO and H 2 S play have been extensively examined by others. Herein, the roles of CO in host−gut microbiome communication are examined through a discussion of (1) host production and function of CO, (2) available CO donors as research tools, (3) CO production from diet and bacterial sources, (4) effect of CO on bacteria including CO sensing, and (5) gut microbiome production of CO. There is a large amount of literature suggesting the "messenger" role of CO in host−gut microbiome communication. However, much more work is needed to begin achieving a systematic understanding of this issue. CONTENTS
... 365,366 On the other hand, exposure to stress is known to induce gastric hemorrhagic erosions due to hyperacidity and deterioration of microcirculation. 367,368 It has been shown that mental disorders such as depression, circadian disturbance, and stress are accompanied by microbiome profile alterations. 369−372 Interestingly, a ruthenium-based CO donor, CORM-2, has also been shown to prevent stress-induced gastric lesions formation. ...
... Shock-induced acute gastric mucosal lesions (stress ulceration) are attributed to multiple factors including gastric hyperacidity, impaired gastric mucus secretion, and an abnormal gastric mucosal permeability to hydrogen ions, stresspromoted tumor necrosis factor (TNF)-a, interleukin (IL)-1b, cytokine-induced neutrophil chemoattractants, and other inflammatory substances. Moreover, it is a well-documented fact that the presence of bile salts in the stomach during shock renders the mucosa more vulnerable to stress-induced ulceration (Jia et al., 2007;Menguy & Masters, 1974). ...
The adaptogenic properties of alkylglycerols (AGs) after 1 month’s treatment were investigated in a rat model of acute immobilization stress (AIS). The animals receiving AGs 157 mg/kg showed a body weight (BW) decrease in addition to a more pronounced increase in the adrenal glands index under stress conditions. Also, AGs at this dose prevented AIS-induced catalase inhibition. In addition, antiulcerative AG effects were already detected at a dose of 15 mg/kg. The data indicate that AGs promote adrenal gland activation in AIS. At the same time, AGs neutralize some of negative effects of stressful conditions, which include restoration of the oxidation–reduction balance, reduction of gastric mucosal stress lesion formation.
Lay summary: The effect of alkylglycerols, ether lipids from marine organisms, was studied in stressed animals. AGs have antioxidant activity and can be useful in the complex therapy of stomach lesions.
... On the other hand, exposure to acute stress is known to cause hemorrhagic gastric lesions in the stomach of rats and mimics the clinical appearance of stress ulcerogenesis observed in humans after life-threatening conditions (26,27). The pathomechanism of stress-induced gastric lesions involves generation of reactive oxygen species, hypoxia, hyperacidity, hypermotility and increased permeability of this gastric mucosa to H + ions; all these factors and mechanisms impairing the gastric microcirculation (13,28,29). Therefore, our present study was designed to compare systemic anti-inflammatory effect of classic naproxen and its H 2 Sreleasing derivative, ATB-346 in experimental model of acute microbleedings induced by WRS. ...
Clinical use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin or naproxen is limited due to the gastrotoxicity evoked by these compounds. Endogenous hydrogen sulfide (H2S) and delivered via an H2S donor have been shown to play important role in the maintenance of gastric mucosal integrity. This study aimed to compare the effects of naproxen and an H2S-releasing naproxen derivative (ATB-346) on gastric lesion induction by water immersion and restraint stress (WRS), the alterations in gastric blood flow (GBF) and the influence of these drugs on systemic inflammation. Wistar rats were pretreated i.g. with vehicle, naproxen (20 mg/kg) or ATB-346 (equimolar dose) or NaHS (5 mg/kg), the H2S donor, combined with naproxen and exposed to 3.5 hours of WRS. The gastric lesion number and GBF were assessed by planimetry and laser Doppler flowmetry, respectively. Plasma concentrations of interleukins: IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and GM-CSF were determined by Luminex system and gastric mucosal protein expression of cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), hypoxia inducible factor-1α (HIF-1α), heme oxygenase-1 (HO-1) and cyclooxygenase (COX-2) were analyzed by Western blot. Pretreatment with naproxen increased the number of WRS stress-induced gastric lesions and significantly decreased GBF as compared with vehicle (p < 0.05). In contrast, pretreatment with ATB-346 or naproxen combined with NaHS significantly reduced WRS-lesions number and elevated GBF as compared with naproxen (p < 0.05). Naproxen significantly increased gastric mucosal protein expression of CSE, Nrf-2 and HIF-1α as compared with vehicle (p < 0.05), but failed to affect CBS, 3-MST and HO-1. ATB-346 significantly increased Nrf-2 and HO-1 protein expression as compared with vehicle (P < 0.05) but did not affect the protein expression of CSE, CBS, 3-MST or HIF-1α. ATB-346 but not naproxen decreased COX-2 protein expression in gastric mucosa compromised by WRS (p < 0.05). Exposure to WRS increased plasma concentration of all investigated cytokines (p < 0.05). ATB-346 but not naproxen decreased plasma content of IL-1α, IL-4, IL-5, IL-6, IL-10, IL-12, TNF-α and IFN-γ in rats exposed to WRS (p < 0.05). We conclude that H2S through its vasoactive properties attenuates the gastrotoxic effects of naproxen, which increased stress-induced hypoxia in gastric mucosa. In contrast to naproxen, ATB-346 decreased stress-induced systemic inflammation and pro-inflammatory COX-2 expression in the gastric mucosa. The decreased gastrotoxicity of ATB-346 could be due to upregulation of Nrf-2/HO-1 pathway mediated by the release of H2S.
... Hyperacidity as a consequence of gastric acid secretion disturbance, hypermotility and elevated membrane permeability of gastric cells to H + ions following deterioration of the microcirculation are major factors responsible for gastric hemorrhagic erosions following stress [112][113][114]. Water immersion and restraint stress (WRS) is a widely accepted and clinically relevant experimental model for studying local gastric ulcerogenic response to stress [115,116]. ...
Heme oxygenase (HO) catalyzes the degradation of toxic free heme to the equimolar amounts of biliverdin, Fe2+ and concurrently releases of carbon monoxide (CO). CO is nowadays increasingly recognized as an important signaling molecule throughout the body that is involved in many physiological processes and shows multidirectional biological activity. Recent evidence indicates that CO exhibits the anti-inflammatory, anti-proliferative, anti-apoptotic, anti-aggregatory and vasodilatory properties. The cellular mechanisms underlying the activity of CO involve stimulation of cGMP-dependent signaling pathway and large conductance calcium activated K+ channels, the activation of mitogen-activated protein kinases and the nuclear factor k-light chain-enhancer of activated B cells transcription factor pathway. Stimulation of endogenous CO production by HO inducers or the inhalation of CO or the delivery of this gaseous molecule by novel pharmaceutical agents have been found in experimental animal models to be promising in the future therapy of various diseases. CO appears to act as a significant component of the complex mechanism of gastrointestinal (GI) mucosal defense. This gaseous molecule plays an important role in diabetic gastroparesis, prevention of the upper GI mucosal damage, post-operative ileus and the healing of ulcerative colitis. This review focuses on the better understanding mechanisms through which CO contributes to the mechanism of protection, resistance to injury and ulcer healing. It is becoming apparent that the pleiotropic effect of this molecule may increase clinical applicability of CO donors and their implementation in many pharmacological research areas, pharmaceutical industry and health-care system.
... Gastric hemorrhagic erosions following stress are sometimes called "stress ulcerations". They have been attributed to hyperacidity resulting from changes in gastric acid secretion, hypermotility and increased permeability of the gastric mucosa to H + ions involving deterioration of the microcirculation [39][40][41]. ...
Carbon monoxide (CO) produced by heme oxygenase (HO)-1 and HO-2 or released from the CO-donor, tricarbonyldichlororuthenium (II) dimer (CORM-2) causes vasodilation, with unknown efficacy against stress-induced gastric lesions. We studied whether pretreatment with CORM-2 (0.1-10 mg/kg oral gavage (i.g.)), RuCl₃ (1 mg/kg i.g.), zinc protoporphyrin IX (ZnPP) (10 mg/kg intraperitoneally (i.p.)), hemin (1-10 mg/kg i.g.) and CORM-2 (1 mg/kg i.g.) combined with N(G)-nitro-l-arginine (l-NNA, 20 mg/kg i.p.), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 mg/kg i.p.), indomethacin (5 mg/kg i.p.), SC-560 (5 mg/kg i.g.), and celecoxib (10 mg/kg i.g.) affects gastric lesions following 3.5 h of water immersion and restraint stress (WRS). Gastric blood flow (GBF), the number of gastric lesions and gastric CO and nitric oxide (NO) contents, blood carboxyhemoglobin (COHb) level and the gastric expression of HO-1, HO-2, hypoxia inducible factor 1α (HIF-1α), tumor necrosis factor α (TNF-α), cyclooxygenase (COX)-2 and inducible NO synthase (iNOS) were determined. CORM-2 (1 mg/kg i.g.) and hemin (10 mg/kg i.g.) significantly decreased WRS lesions while increasing GBF, however, RuCl₃ was ineffective. The impact of CORM-2 was reversed by ZnPP, ODQ, indomethacin, SC-560 and celecoxib, but not by l-NNA. CORM-2 decreased NO and increased HO-1 expression and CO and COHb content, downregulated HIF-1α, as well as WRS-elevated COX-2 and iNOS mRNAs. Gastroprotection by CORM-2 and HO depends upon CO's hyperemic and anti-inflammatory properties, but is independent of NO.
... Because the endogenous mechanisms involved in seizure control in substantia nigra have failed, the ensuing seizures rapidly evolve to bilaterally clonic and tonic-clonic and, eventually, to death (4). Finally, BPC 157 may also avoid the particular stomach vulnerability to hypoglycemic conditions that was long ago recognized (29). Thus, we could argue that BPC 157 as antiulcer peptide (also effective against stomach ulcer in alloxan-animals (21) shown to maintain ATP content in stomach mucosa (30) may accordingly counteract also impaired peripheral glucose control providing at least some metabolic control, i.e., glycogen still preserved in the liver, normal liver weight, less fatty liver, less calcium deposition and no seizures despite excessive insulin consumption. ...
We focused on over-dose insulin (250 IU/kg i.p.) induced gastric ulcers and then on other disturbances that were concomitantly induced in rats, seizures (eventually fatal), severely damaged neurons in cerebral cortex and hippocampus, hepatomegaly, fatty liver, increased AST, ALT and amylase serum values, breakdown of liver glycogen with profound hypoglycemia and calcification development. Calcium deposits were present in the blood vessel walls, hepatocytes surrounding blood vessels and sometimes even in parenchyma of the liver mainly as linear and only occasionally as granular accumulation. As an antidote after insulin, we applied the stable gastric pentadecapeptide BPC 157 (10 microg/kg) given (i) intraperitoneally or (ii) intragastrically immediately after insulin. Controls received simultaneously an equivolume of saline (5 ml/kg). Those rats that survived till the 180 minutes after over-dose application were further assessed. Interestingly, pentadecapeptide BPC 157, as an antiulcer peptide, may besides stomach ulcer consistently counteract all insulin disturbances and fatal outcome. BPC 157 rats showed no fatal outcome, they were mostly without hypoglycemic seizures with apparently higher blood glucose levels (glycogen was still present in hepatocytes), less liver pathology (i.e., normal liver weight, less fatty liver), decreased ALT, AST and amylase serum values, markedly less damaged neurons in brain and they only occasionally had small gastric lesions. BPC 157 rats exhibited mostly only dot-like calcium presentation. In conclusion, the success of BPC 157 therapy may indicate a likely role of BPC 157 in insulin controlling and BPC 157 may influence one or more causative process(es) after excessive insulin application.
In the planning of clinical investigations on ulcer etiology, it is important to determine to what extent peptic ulcer patients can contribute to every day emotional stress. In this report, as a model to establishing an emotional stress condition, we took attention to the emotional conflict of the patients just before surgery. Changes of plasma concentration of corticosteroids (11-OHCS) were measured in resting, emotional-stressed preoperative condition and after surgery. Therewithal, gastric secretion was measured. In resting condition, determination of plasma 11-OHCS levels in patients with peptic ulcer failed to detect differences from control subjects.
Slight increase in plasma 11-OHCS levels was observed both in the patients with or without peptic ulcers. During emotional stress condition, a significant increase in gastric acid and pepsin secretion was observed in duodenal and gastro-duodenal ulcer patients. Stress-induced gastric acid and pepsin secretion were reduced by atropin sulfate injection to 50% and 30%.
The inhibitory rate of gastric secretion by the drug was less striking as compared with those levels in non-stressed resting condition. Laparotomy (physical stress) enhanced the gastric pepsin release in spite of vagotomy.
The role of the emotions in altering gastric secretion was recognized in individuals with duodenal or gastro-duodenal ulcers.
Emotional stress may plays an important role in the ulcer etiology.
Although, the precise mechanism by which emotional stress affects the ulcerogenesis remains to be clarified, the role of extra-vagal humoral pathway (via the hypothalamo-pituitary-adrenal axis) is not a negligible matter.
Gastric and duodenal ulcer are both peptic ulcer diseases. The term peptic refers to the fact that acid and pepsin are necessary to produce the break in the mucosa which is called an ulcer. In humans the best evidence for this statement occurs at the opposite ends of the secretory range. Individuals whose parietal cells are continuously stimulated to secrete acid by gastrin, being released from a tumor (gastrinoma or Zollinger–Ellison syndrome), develop ulcers in all but 7% of the cases.(1) Those having the achlorhydria of pernicious anemia rarely develop ulcers.
The stomach has many physiological functions, such as acid and pepsin secretion, mucus production and motility, which are supposed to be regulated by gastric mucosal blood flow. Therefore, blood flow is an extremely important defensive factor for the gastric mucosa. The present study was designed to elucidate the role of mucosal blood flow in the development of acute gastric mucosal lesions (AGML) after burn stress. Gastric mucosal blood flow and microcirculatory disturbance were investigated. Also, we examined the influence of gastric mucosal blood flow on the alternation of acid and pepsin activity, energy metabolism and mucus production (Hexosamine content).
Gastric and duodenal ulcer are both peptic ulcer diseases. The term peptic refers to the fact that acid and pepsin are necessary to produce the break in the mucosa which is called an ulcer. In humans the best evidence for this statement occurs at the opposite ends of the secretory range. Individuals whose parietal cells are continuously stimulated to secrete acid by gastrin, being released from a tumor (gastrinoma or Zollinger-Ellison syndrome), develop ulcers in all but 7% of the cases.(1) Those having the achlorhydria of pernicious anemia rarely develop ulcers.
Oxidative stress is caused by an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates, which ultimately leads to oxidative deterioration of protein, lipid and DNA. In humans, oxidative stress is involved in pathology of many diseases, such as atherosclerosis, Parkinson’s disease, heart failure, myocardial infarction, and chronic fatigue syndrome. Reactive oxygen species (ROS) can be beneficial, as they are used by the immune system as a way to attack and kill pathogens. To counteract oxidative stress, the body produces an armory of antioxidants to defend itself. It's the job of antioxidants to neutralize free radicals that can harm the cells. Body's internal production of antioxidants is not enough to neutralize all the free radicals. It’s a well-known fact that ROS are involved in the aetio-pathogenesis of the inflammatory and ulcerative lesions of the gastrointestinal tract. The present review focuses on the studies where oxidative damage due to stress has been linked causally to loss of cell integrity mainly in peptic ulcer cured by natural antioxidants.
Digestion is a process which takes place in resting conditions. Exercise is characterised by a shift in blood flow away from the gastrointestinal (GI) tract towards the active muscle and the lungs. Changes in nervous activity, in circulating hormones, peptides and metabolic end products lead to changes in GI motility, blood flow, absorption and secretion.
In exhausting endurance events, 30 to 50% of participants may suffer from 1 or more GI symptoms, which have often been interpreted as being a result of maldigestion, malabsorption, changes in small intestinal transit, and improper food and fluid intake. Results of field and laboratory studies show that pre-exercise ingestion of foods rich in dietary fibre, fat and protein, as well as strongly hypertonic drinks, may cause upper GI symptoms such as stomach ache, vomiting and reflux or heartburn. There is no evidence that the ingestion of nonhypertonic drinks during exercise induces GI distress and diarrhoea. In contrast, dehydration because of insufficient fluid replacement has been shown to increase the frequency of GI symptoms. Lower GI symptoms, such as intestinal cramps, diarrhoea — sometimes bloody — and urge to defecate seem to be more related to changes in gut motility and tone, as well as a secretion. These symptoms are to a large extent induced by the degree of decrease in GI blood flow and the secretion of secretory substances such as vasoactive intestinal peptide, secretin and peptide-histidine-methionine. Intensive exercise causes considerable reflux, delays small intestinal transit, reduces absorption and tends to increase colonic transit. The latter may reduce whole gut transit time. The gut is not an athletic organ in the sense that it adapts to increased exercise-induced physiological stress. However, adequate training leads to a less dramatic decrease of GI blood flow at submaximal exercise intensities and is important in the prevention of GI symptoms.
Summary Determination of the regional gastric blood flow in pigs with tracer microspheres indicates maximum blood flow in the fundus mucosa, even after dissection of the left gastric vessels. Excessive aerobic metabolism in this region was proved by measuring the arteriovenous oxygen difference. Fundus oxygen consumption was significantly depressed by cimetidine; change of blood flow distribution, a disadvantage for the seromuscular fundus layer, was inhibited.
Recently completed studies suggest that patients with the adult respiratory distress syndrome (ARDS) manifest early evidence of multiple-site endothelial injury. Ex trapulmonary disease is usually the cause of death in these patients. Furthermore, prognosis in individual cases of ARDS is strongly influenced by specific organ failures (e.g., hepatic and renal failure). The mechanisms by which ARDS and extrapulmonary organ system fail ure interact, however, are poorly delineated. We ad dress three aspects of the multisystemic nature of ARDS. First, we analyze evidence that suggests ARDS is a mul tisystem disorder fron the outset, involving panendothe lial injury mediated by cellular interactions and humoral substances that act similarly at many vascular target sites. Second, we discuss the role of three extrapulmo nary organs in the modulation of ARDS: the liver, the gastrointestinal mucosa, and the kidneys. Third, we ad dress the unifying hypothesis that uncontrolled ongoing inflammation, which is often but not always caused by infection, is the essential link between ARDS and its progression to multiple system organ failure.
The sections in this article are:
Of 285 dogs with gastric volvulus treated surgically, 30 (10.5%) required partial gastrectomy because of necrosis along the greater curvature of the body or fundic region of the stomach. Initially, the 30 dogs were treated with intravenous administration of lactated Ringer's solution, antibiotics, and corticosteroids. The stomach was decompressed with an oral gastric tube or by percutaneous gastrocentesis. Diagnosis of gastric volvulus was made by abdominal radiography and confirmed at surgery. At surgery, the stomach was decompressed and repositioned. Gastric viability was determined by evaluation of serosal color and perfusion, vascular patency, the degree of active bleeding from the incised gastric wall, and by palpation of the gastric wall; intravenous fluorescein dye evaluation was performed in some dogs. Twenty-seven dogs developed postoperative complications, 19 (63%) of which died. Eleven dogs recovered.
The sections in this article are:
Vergleichend-anatomische Daten zeigen, da Suresekretion und intragastrale Druckerhhungen typischerweise in rumlich getrennten Organen stattfinden. Im einhhligen Magen des Menschen laufen diese Vorgnge zeitlich getrennt ab. Finden beide Prozesse zur gleichen Zeit in einem Hohlorgan statt, kann es zu diskreten Durchblutungsstrungen kommen. Experimentell wurde das zugrundeliegende submucse Steal-Phnomen am Hund mit Hilfe der Mikrosphrenmethode nachgewiesen. Eine Analyse der Magenstrombahn des Menschen zeigt, da dieses Grenzlinienphnomen zu diskreten Kreislaufstrungen an den Prdilektionsorten des Magengeschwrs fhrt.Comparative vertebrate anatomy shows that acid secretion and wall stress processes typically occur in different compartments. In the human single-chamber stomach both processes are physiologically separated in time. If both processes take place in one hollow organ at the same time, focal ischemia will occur. Using the microsphere technique a submucous stealphenomenon, which the effect is due to, has been reproduced experimentally. A network model of the human gastric vascular bed produces borderline infarcts at the preferred sites of human gastric ulcer.
Ein cellularer Automat, der eine vereinfachte Abschtzung von Verteilungsmustern der Magendurchblutung erlaubt, wird beschrieben. Die auf der Basis des Energiebedarfs der Suresekretion und der Morphologie der Magenstrombahn simulierbaren Umverteilungsphnomene stimmen in Form und Lage mit dem menschlichen Magengeschwr berein. Sonderflle der peptischen' Lsion, wie das lineare Geschwr oder die peptische' Stenose der Speiserhre, sind mit der Theorie des submucsen Steal-Phnomens zu vereinbaren.A cellular automaton is described, which allows a simple simulation of patterns of gastric blood flow distribution. Effects of redistribution, which can be simulated on the basis of the energy requirements of acid secretion and the morphology of the gastric vascular bed, are isomorph to form and site of gastric ulcer in man. Special forms of the peptic lesion as linear ulcers or peptic stenoses of the oesophagus are consistent with the theory of a submucous steal-phenomenon.
Das Stressulcus ist die akute Schleimhautläsion des oberen Intestinaltraktes, die im Rahmen einer Erkrankung oder deren Behandlung innerhalb von wenigen Tagen bei vorher magengesunden Patienten auftreten kann. Gefährdet sind Patienten mit großen Operationen, Verbrennungen und verschiedenen Formen des Schocks. Begünstigend wirken Komplikationen, wie respiratorische Insuffizienz, paralytischer Ileus und Infektionen. Das Durchschnittsalter beträgt 53 Jahre, Männer sind häufiger betroffen. Häufigster Manifestationsort ist der proximale Magen; seltener sind Duodenum und terminaler Oesophagus beteiligt. Makroskopisch finden sich meist multiple Erosionen und flächenhafte Ulcerationen, im Duodenum überwiegen die solitären Ulcera. Pathogenetisch sind im wesentlichen drei Faktoren beteiligt, die Salzsäure, eine schockbedingte Störung der Schleimhautmikrozirkulation und ein duodeno-gastraler Reflux von Gallensäuren und Lysolecithin. Häufigstes Symptom ist die Blutung, doch über 50% der Stressulcera verlaufen inapparent. 60–70% der Stressulcera kommen unter konservativen Maßnahmen zur Ausheilung. Unter den operativen Verfahren dominiert die Vagotomie in Kombination mit Umstechung oder Resektion. Zur Prophylaxe dienen eine Vermeidung von Schockzuständen und respiratorischer Insuffizienz, Magensaftdauerableitung, frühe orale Ernährung und intragastrale Applikation von Antacida und Cholestyramin.
Total and regional gastric blood flow were measured in 15 dogs under control conditions (mean AOBP 100 mm Hg) using microspheres labelled with different isotopes (125J,141Ce,85Str,46Sc) of 8 µ size.
The mucosa in fundus and corpus showed significantly higher blood flow compared to the antrum. There was no difference in the muscular layer for either part of the stomach. It is concluded from these data that differences in regional blood flow in the unstimulated stomach of the dog are related to different energy-demands within the stomach.
The aim of these studies was to evaluate the light and electron microscopic changes of the gastric mucosa of restrained rats, and to determine if there were correlations between structural changes, histidine decarboxylase activity, histamine content, and gastric secretion.
In areas with high-grade mucosal lesions, signs of functional hyperactivity of the oxyntic and chief cells and cytoplasmic degranulation of the enterochromaffin-like cells were observed. These changes were not influenced by vagotomy. The hyperactivity of the chief cells was related to a higher proteolytic activity of the gastric juice and to an increased excretion of uropepsinogen (p<0.01). The hyperactivity of the oxyntic cells was not accompanied by an increase in total acidity, which could be explained by hydrogen ion back-diffusion through a damaged gastric mucosal barrier. The increase in histidine decarboxylase activity (p<0.01) and the decrease of histamine content (p<0.01) in the glandular mucosa of restrained rats, together with the microscopic and ultrastructural observations, suggest that the early microcirculatory changes are due to local alterations in the metabolism of vasoactive amines.
The role of a defined formula diet, Vivonex HN, in the prevention of gastric mucosal injury was evaluated in the cold, restrained rat model. The mean grade of gastric bleeding and mean number of gastric lesions were 3.95 and 7.35±1.02, respectively, in the stressed, unprotected control group. In four random groups of rats given Vivonex HN, Maalox, Cimetidine (20 mg/kg) and Cimetidine (60 mg/kg) prior to stress, the mean grade of gastric bleeding was 0; 1.55; 2.33; 1.75; and the mean number of gastric lesions was 0; 1.2±0.31; 2.83±0.82; 2.2±0.65, respectively. The differences were statistically significant. Our experiments show that Vivonex HN was more effective than Maalox or Cimetidine in high dose in peventing gastric bleeding and gastric mucosal lesions in the cold, restrained rat. Cimetidine in a standard dose was the least protectivo. Clinical trials are needed to establish the role of Vivonex HN in the prevention of stress ulcers in patients at risk.
A simple and safe method of medical treatment for control of massive acute gastric mucosal hemorrhage is described. The procedure was developed from the observation that gastric HCl played a central role in peretuating the syndrome. The treatment consists in neutralization of the gastric acid with antacid to pH of 7.0. In preliminary observations of consecutive admissions, 19 of 20 (95 per cent) patients treated with this techinique stopped bleeding. The one remaining patient required surgery. There were no deaths. In contrast, 10 of 15 (66 per cent) patients stopped bleeding with conventional medical therapy. Four of the remaining patients required surgery to control the bleeding. One patient did not stop on medical management. All five (33 per cent) patients died.
Due to poor results with conventional operative therapy for diffuse hemorrhagic gastritis (DHG), a prospective evaluation of gastric devascularization was performed on 21 patients. Sepsis, alcoholism, and steroid abuse were the common etiologic factors. In spite of the fact that these were all critically ill patients, all stopped bleeding with this operation and only two rebled (9%). The average operating time was 84 minutes. There were two operative complications and gastric necrosis did not occur. The mortality was high (38%) due to the primary disease. Gastric devascularization is a useful salvage procedure for the patient with DHG because it can be accomplished rapidly, with few complications, has a low rebleed rate, and causes no permanent sequelae. Since this procedure causes severe gastric mucosal ischemia, it casts doubt only on the importance of this mechanism alone as the cause of "stress ulceration."
In 55 rats the role of pancreatic juice for the development of stress ulcers was stuided. After ligation of the common bile duct the stress ulcer incidence was significantly decreased. An additional pancreaticogastrostomy was followed by an even lower ulcer frequency. After pancreaticojejunostomy a higher ulcer incidence was found as after bile duct ligation alone. The role of a duodenogastric reflux for development of stress ulcers is discussed. The ulcerogenic property of bile acids and of the combination of bile and pancreatic juice, caused by lysolecithin, is demonstrated. Pancreatic juice doesn't work as an ulcerogenic substance, but possibly has a protective function by uffering the hydrochloric acid.
1. The syndrome of reflux gastritis is produced by the actions of bile and upper intestinal and pancreatic secretions alone or in combination on an altered gastric mucosa. 2. The triad of epigastric pain unrelieved by antacids, bilious vomiting, and weight loss, particularly after a gastric operation should make one suspect this syndrome. Anemia due to loss of blood and dysphagia occur less frequently. 3. The definitive diagnosis is made by endoscopy. Barium studies are of less value. Acid secretory studies are not diagnostic and are of academic interest. 4. Medical treatment utilizes antacids and cholestyramine alone or together. Good, long-lasting results with these are infrequent. Despite these results, medical treatment should be tried first. 5. Surgical treatment consists of diversion of the biliary and upper intestinal secretions from the stomach and doing a vagotomy with or without a distal gastric resection to prevent a marginal ulcer from developing. 6. The two most popular operations are a Roux-en-Y diversion or interposed peristaltic jejunal limb. The simplicity of the former has made this more popular with most American surgeons. 7. The results of surgery are good to excellent in 75 to 95 per cent of cases. Relief of symptoms, improvement in histologic and secretory studies, and weight gain should be anticipated. 8. Less than optimal results are reported when the surgical diversion has not been total, gastric stasis persists, or other postgastrectomy sequelae accompany reflux gastritis.
Extrahepatic portal hypertension was induced in rats by portal venous constriction. Portal pressures on the fourth postconstriction day were significantly elevated in PVC rats when compared to control rats. Splenoportograms showed decreased hepatic flow and venous collaterals. Histologic sections showed gastric mucosal congestion in PVC rats. Gastric acid production and H+ ion equilibration were similar in PVC and control rats. Rats with portal hypertension had a significant increase (p less than 0.001) in mucosal erosions when subjected to a 7-hr restraint stress. Erosion formation was significantly augmented by aspirin administration. Although the exact relationship between the stress of a respiratory infection and variceal bleeding is unknown, these data demonstrate an increased susceptibility of PVC rats to nonhemorrhagic stress. This response is clearly augmented by aspirin treatment. Gastric congestion and the known effect of aspirin on gastric mucosal permeability and the gastric mucosal barrier are implicated in these observations. These findings correlated with clinical observations and strongly suggest avoidance of aspirin therapy in children with extrahepatic portal hypertension.
Intravital fluorescence microscopy and morphometry were used to study the microcirculation in the rat gastric mucosa during and after hemorrhagic shock. Under control conditions the circulation appeared homogeneous and unaffected by superfusion with 0.1 N HCl. During hemorrhagic shock, scattered areas of the mucosa lost circulation. Morphometry showed that the number of perfused mucosal vessels decreased significantly in the abluminal part of the mucosa both in perfused and ischemic areas, the reduction being most pronounced in the ischemic areas, where the number of perfused luminal vessels also decreased significantly. During reperfusion, bleedings occurred from the mucosa. A key finding was that the bleedings always had their origin at the border zone between ischemic and perfused areas. After hemorrhagic shock adenosine triphosphate and energy charge levels dropped significantly in both perfused and ischemic areas but with significantly lower levels in the ischemic areas. The hypoxanthine levels increased in both perfused and ischemic areas. The experiments show that local mucosal ischemia and accelerated nucleotide degradation are of pathogenetic importance in the development of stress ulcers after hemorrhagic shock. The border zone between circulated and ischemic areas seems to be an area of special interest.
The role of vasopressin in the development of gastric hemorrhagic erosions induced by the oral administration of 1 mL of 75% ethanol in rats was studied. The area of the lesions in homozygous Brattleboro rats, having a defective vasopressin synthesis, was only 20% of that found in Wistar and heterozygous Brattleboro rats, which have normal vasopressin production. It is well known that vasopressin acts via the V1 (pressor) and V2 (antidiuretic) receptors. Administration of V1 and V2 vasopressin-receptor agonists and antagonists in this model showed that pressor-receptor activity is needed for the generation of all lesions in Wistar and heterozygous Brattleboro rats. Ethanol damage to the gastric mucosa was diminished by the V1 antagonist with similar efficacy as in the case of a vasopressin deficiency. Administration of the V1 antagonist and the absence of endogenous vasopressin were shown to protect the deeper layer of the gastric mucosa (assessed by histology) and to reduce significantly the ethanol-induced vascular injury and increase in vascular permeability (assessed by the monastral blue technique). Thus, endogenous vasopressin is clearly of great importance in the pathogenesis of gastric hemorrhagic lesions induced by ethanol. These results strongly suggest that vasopressin is an endogenous aggressor toward the gastric mucosa.
Despite blockade and neutralization of gastric acid, acute gastric lesions cause substantial morbidity and mortality in critically ill patients. Pepsinogen release in response to noxious stimuli such as hypoxia and endotoxin might contribute to mucosal damage. Guinea pig fundic mucosa was mounted in Ussing chambers. Acid secretion, pepsinogen release, potential difference (PD), and resistance were monitored. Gassing with room air or nitrogen diminished acid secretion and PD but increased pepsinogen release 9.7- and 15.5-fold, respectively (both p less than 0.001). Similarly, endotoxin (0.01 and 0.1 units/ml) dose-dependently inhibited acid secretion and PD but increased pepsinogen release 3.3- and 6.1-fold (both p less than 0.05). Endotoxic and air-gassed tissues were edematous with scattered cellular damage by light and transmission electron microscopy; nitrogen-exposed membranes appeared necrotic. Pepsin release may therefore have resulted from cell damage rather than exocytosis. Intragastric peptic activity in critically ill H2-receptor-blocked patients (n = 20) was 5490 +/- 1701 U/ml. The gastric juice of H2-blocked convalescing surgical patients (n = 20) contained 315 +/- 101 U/ml (p less than 0.0001). Occult blood correlated with intragastric peptic activity (r = 0.59, p less than 0.0001) but not with gastric pH (r = 0.04, p = 0.6). These data suggest that the complex of pathophysiologic abnormalities common in critical illness causes substantial pepsin release. Efflux of this potent mucolytic barrier breaker may damage gastric mucosa in severely stressed patients.
Nutritional support of critically ill patients in the intensive care unit is important, since adverse effects of malnutrition are multiple and common. Nutrition via the enteral or gastrointestinal tract is often preferred over central venous or total parenteral nutrition as the initial choice of nutritional therapy due to its relative ease of administration, lower cost and infrequent association with severe complications. Recent data suggest that nosocomial pneumonia, a severe and ominous complication of critical illness, is related to gastric colonization secondary to alkalinization of stomach contents by antacids and H2-antagonists. Nosocomial pneumonia may also be related to enteral nutrition. Gastric microbial growth increases after the onset of enteral nutrition. Gastric organisms can be transmitted to the trachea and result in tracheal colonization and nosocomial pneumonia. Gastric to tracheal transmission of organisms is probably related to pulmonary aspiration. Several factors are important in pulmonary aspiration, including nasogastric tube size, method of nutrient delivery, patient position, and gastric and intestinal motility. Enteral nutrition must be considered in both the evaluation of mechanisms of nosocomial pneumonia and the strategies of prophylaxis.
A brief description is made of agents that may damage the gastric and duodenal mucosa, and of the more important protective factors. The main protective mechanisms are the same in the two organs, but their relative contributions are different. Some bacteria are able to live on the gastric mucosa by utilizing mucosal defence mechanisms to protect themselves against acid and pepsin. Some drugs may damage the mucosa by interfering with the protective mechanisms. The non-steroidal anti-inflammatory drugs (NSAIDs) reduce the mucosal synthesis of prostaglandins, which are important protective factors.
The purpose of this study was to evaluate the early appearance and incidence of stress gastritis following severe head injury. We performed upper esophagogastroduodenoscopy in 44 patients within 24 hours of a head injury. All patients were comatose and required ventilatory support. Forty of the patients (91%) had gastritis at esophagogastroduodenoscopy. The lesions were distributed in the fundus and corpus of the stomach (77% of the patients), in the esophagus (30% of the patients), in the antrum (25% of the patients), and in the duodenum (7% of the patients). The grade of gastritis at esophagogastroduodenoscopy did not correlate with the severity of the head injury, the type of head injury sustained, the timing of esophagogastroduodenoscopy after head injury, or the presence of shock on admission. However, patients with grade III gastritis had a greater injury Severity Score than patients with grade 0 gastritis (normal mucosa). Gastroduodenal mucosal damage is common after severe head injury and occurs soon after the event.
This study was designed to determine whether oxygen-derived free radicals play a role in the pathogenesis of gastric lesions produced by hypotensive ischemia in the rat. To achieve this goal, allopurinol, an inhibitor of xanthine oxidase (the enzyme responsible for the formation of superoxide radicals); superoxide dismutase, a scavenger of superoxide radicals (O2-); and dimethyl sulfoxide, a scavenger of hydroxyl radicals (OH) were used. In the anesthetized rat, HCl (0.1 N) was instilled into the pylorus-ligated stomach, and the rat was bled to reduce the blood pressure to less than 30 mmHg. The blood pressure was maintained at less than 30 mmHg for 20 min and then the shed blood was retransfused. Twenty minutes after the retransfusion the rat was killed, the stomach was removed, and the area of gastric mucosal lesions was measured. Both allopurinol and superoxide dismutase, but not dimethyl sulfoxide, significantly protected against hemorrhagic shock-induced gastric lesions. These findings suggest that oxygen-derived free radicals, particularly O2-, play an important role in the formation of gastric lesions produced by ischemia plus HCl.
This study compares the prophylactic effects of two different diets and routes of feeding on restraint stress-induced gastric erosions in the rat. Thirty male Sprague-Dawley rats were food-deprived and immobilized for 24 hours using a steel wire mesh. A small silicone tube was placed into either the proximal jejunum or the stomach via a laparotomy. There were three groups of ten rats (five jejunum-fed, five stomach-fed), receiving infusions (50 ml/24 h) of: (A) normal saline; (B) free amino acids (Vivonex HN, Norwich Eaton Pharmaceuticals) (60 cal and 0.318 G nitrogen); or (C) a peptide diet, with the nitrogen source as lactalbumin hydrolysate, otherwise identical to B. Gastric acidity was measured every 4 hours. At 24 hours, blood was collected and serum gastrin levels determined. The animals were then sacrificed and the stomachs examined. The results were analyzed using one-way analysis of variance. Fewer gastric erosions and lower serum gastrin levels and gastric acidity were found in animals fed diets B and C, versus animals fed normal saline (p less than 0.05). There was no difference between groups B and C. Our results also show that enteral diets using the jejunal route are better than those using the gastric route in reducing the incidence of stress-induced gastric erosions in rats.
The ability of the gastric mucosa to resist autodigestion has been recognized for over 200 years. Since these early observations, several components of gastroduodenal defense against injury from damaging luminal contents have been identified. The first line of defense is the thick layer of mucus gel into which bicarbonate is secreted by the underlying epithelial cells. The "mucus-bicarbonate" barrier sustains a pH gradient between the lumen and cell surface such that epithelial cells are maintained at pH 7 to 8, despite the presence of intraluminal acid. The epithelial cells form a second line of defense; since the pH gradient may be overwhelmed by physiologic concentrations of intraluminal acid, this mechanism may be important in maintaining mucosal integrity. The physical properties of the apical cell membrane and intercellular junctions and the presence of surface-active phospholipids on the membrane may be responsible for preventing hydrogen ions (H+) from diffusing into the mucosa by providing a physical barrier to their movement. Furthermore, epithelial cells are capable of rapid turnover and migration and may breach a defect in the epithelium within hours. The aftermath of mucosal damage may generate a further defense mechanism: a thick layer of mucus containing sloughed epithelial cells together with passive movement of bicarbonate-rich fluid from the damaged mucosa. This may prevent exposure of undamaged cell nests to acid and thus aid re-epithelialization. Finally, mucosal blood flow plays a vital role in maintaining epithelial integrity. Studies have shown that increasing or decreasing mucosal blood flow will, respectively, reduce or enhance susceptibility to damage. Although the precise physiologic control mechanisms for mucosal protection have not been defined, there is evidence that local endogenous prostaglandin metabolism may play an important role [4]. The release of neurotransmitters and hormones may also contribute to or modulate the defense mechanisms.
The role of oxygen derived free radicals in gastric lesions induced by haemorrhagic shock and the protective effect of oxygen radical scavengers, allopurinol and ranitidine, were investigated. Forty five rabbits underwent haemorrhagic shock for 30 minutes and reinfusion of shed blood. They were killed 30 minutes later. The animals were divided in five groups: A (n = 10): Control, B (n = 10): intravenous ranitidine pretreatment, C (n = 10): oral allopurinol, 24 and 2 h before surgery; D (n = 10): intravenous pretreatment with superoxide Dismutase plus catalase, E (n = 5): 60 minute haemorrhagic shock without reinfusion and treatment. Erosions and/or petechiae in all animals in Group A were observed. Three animals in group B and C and 2 in group D (p less than 0.005, p less than 0.001) had gastric lesions. The lesions in the pretreatment groups were significantly smaller than in controls. Oxygen radicals plus HCl play an important role in shock induced gastric lesions. Oxygen radical antagonists show a significant protective role.
A cellular automaton is described, which allows a simple simulation of patterns of gastric blood flow distribution. Effects of redistribution, which can be simulated on the basis of the energy requirements of acid secretion and the morphology of the gastric vascular bed, are isomorph to form and site of gastric ulcer in man. Special forms of the 'peptic' lesion as linear ulcers or 'peptic' stenoses of the oesophagus are consistent with the theory of a submucous steal-phenomenon.
The studies reviewed suggest that the presence of luminal acid is essential for acute gastric stress ulceration to occur and that acid promotes ulceration by diffusing into the mucosa in an ulcerogenic situation. Disruption of the mucosal barrier by the presence of e.g. intragastric bile salts, aspirin, or ethanol increases the hydrogen ion back diffusion, thereby increasing the susceptibility of the mucosa to ulceration. Such a disruption is presumably needed for development of ulcerations in species with a "tight" gastric mucosa, such as the dog, the pig and man, whereas in species with a "leaky" mucosa, such as the rabbit or rat, ulceration occurs even without these agents. However, the response of the mucosa to hydrogen ions is not uniform. Luminal acidities and rates of hydrogen ion back diffusion that are normally harmless may in certain situations cause severe damage to the mucosa. Thus, the ability of the mucosa to withstand the influxing hydrogen ions is as important as the absolute amount of hydrogen ions diffusing into the mucosa. If the rate of hydrogen ion back diffusion exceeds the ability of the mucosa to dispose of hydrogen ions, acidification of the mucosa occurs, with resultant breakdown of the tissue. The main factors modulating the response of the mucosa to hydrogen ions are availability of bicarbonate in the mucosa and the mucosal blood flow. Bicarbonate contributes to mucosal protection through secretion by the epithelium to form an "alkaline" buffer layer at the epithelial surface, which seems to act as a "firstline" defence mechanism against the influxing hydrogen ions.(ABSTRACT TRUNCATED AT 250 WORDS)
The efficacy of prophylactic therapy with cimetidine or antacids combined with early enteral feeding to prevent gastrointestinal bleeding in patients with severe burns was evaluated. Fifty patients with burns exceeding 30 per cent of the total body surface area (TBSA) were divided into two groups, each of them treated by one of these agents in combination with early feeding. Bleeding was not encountered in either group. It is assumed that the combination of either agent with enteral feeding early in the post-burn course equally protected against gastrointestinal bleeding. Because of the ease and lack of side-effects of cimetidine in this series, its use was preferable.
The purpose of this study was to compare the gross and histologic changes in the corpus and antrum in the rat hemorrhagic shock plus acid model of gastric injury, and to determine the effect of transfusion of shed blood or albumin on gastric lesion formation. The data indicate that (a) despite the gross appearance of more severe damage in the corpus, histologic damage was more severe in the antrum; (b) covering mucus and cell debris partly explain the difficulty in recognizing antral lesions grossly; (c) the severity of histologic injury was similar in transfused and nontransfused rats; and (d) transfusion of shed blood rendered corpus lesions more recognizable grossly but did not affect the severity of histologic injury. The latter findings raise questions about the pathogenetic importance of reperfusion in gastric ischemic injury and the validity of using gross lesions as an index of gastric injury.
The hemorrhagic hypotension model in anesthetized rats was used to study the relationship between gastric and duodenal mucosal blood flow and susceptibility to acid-induced injury. Mucosal blood flows measured by the hydrogen gas clearance technique in the corpus, antrum, and duodenum all showed a significant linear correlation with mean blood pressure, decreasing progressively as blood pressure fell. Significant gastric mucosal lesions occurred only after mean blood pressure and hence, mucosal blood flow was reduced to below 40% of baseline values. In contrast, duodenal mucosal lesion formation was related in a linear manner to decrease in mean blood pressure or blood flow. We conclude that mild reductions in blood flow are more important in the duodenum than in the stomach in increasing susceptibility of the mucosa to acid-induced injury.
Since many of the proposed etiologic factors leading to gastric stress ulceration involve stimulation of calcium influx, the effect of verapamil, a potent calcium channel blocker, on the gastric mucosa in cold-restrained inbred rats was assessed. Twenty-nine rats received intraperitoneal normal saline (2 ml) while the experimental group (N = 29) received 1 mg/kg verapamil in an equal volume of normal saline intraperitoneally. All animals were then stressed at 4 degrees C for 4 hr and sacrificed. Gastrin and fatty acid levels were measured and blinded ulcer scoring of the gastric mucosa was carried out. Verapamil-treated animals had decreased frequency and severity of gastric stress ulceration as assessed by ulcer index, ulcer grade, and number of ulcers/animal. In addition, the plasma gastrin levels tended to be lower in the verapamil group. Fatty acid levels were similarly depressed following cold restraint in both groups. Pretreatment with verapamil significantly decreased gastric ulcerative response to cold-restraint stress in the rat. This effect of verapamil pretreatment may be secondary to cytoprotection of the gastric mucosa, preservation of gastric mucosal blood flow, or blockade of calcium-mediated ulcerogenic stimuli.
Although cimetidine is more effective than a placebo for the prophylaxis of stress-induced ulcers, it has no advantage over titrated antacid dosing. Several comparative studies even suggest that combining cimetidine with antacid is no more effective than use of full-dose antacid. Therefore, we recommend prophylactic use of cimetidine only when very large dosages of antacid are required, in order to minimize acid-base disturbances.
Publisher Summary The ATPase activity which requires Na + , K + , and Mg ++ together and is inhibited by cardiac glycosides is a part of the enzyme system for the stoichiometric transport of Na + outward and K + inward across cell membranes. It is widely distributed in animal tissues and species. Organs, which transport Na+ and K+ to energize electrical activity or secretion, show much activity. The chapter examines the preparation, purification, and properties of sodium and potassium-stimulated ATPase. From the rate of release of inorganic phosphate from ATP in the presence of Na + , K ++ , and Mg ++ is subtracted the rate of release in the presence of Mg ++ and a cardiac glycoside inhibitor, such as ouabain. Released inorganic phosphate may be measured simply by adding 2.5 ml of 0.48 M HC104, mixing, filtering, and taking a 2.0-ml aliquot for assay. The method is described that separates phosphomolybdate from ATP by extraction into butyl acetate. The general principle of purification procedure described in the chapter is to obtain a microsomal fraction by differential centrifugation of a sucrose homogenate and to form dispersed and activated particles with a detergent, urea, or a concentrated iodide solution. Aging, freezing and thawing, and mild detergents may improve the activity or sensitivity of fresh homogenates or microsomal fractions. The K m for ATP is about 0.3 mM with Mg ++ in slight excess. As the amount of Mg ++ is reduced with maximal ATP, the activity decreases but the sensitivity increases. The Km for Na + is about 1.5 mM and for K + about 0.4 mM. The apparent affinity of the Na + -site for K + is about 7-fold less than for Na + whereas the apparent affinity of the K + -site for Na + is about 160-fold less than for K + .
This chapter discusses the mitochondrial respiratory control and the polarographic measurement of ADP : O ratios. The polarographic oxygen electrode technique is used for measuring rapid changes in the rate of oxygen utilization by cellular and subcellular systems. Although the polarographic method measures changes in oxygen concentration of photosynthetic systems, yeast cells, and nerve, but the oxygen electrode technique is applied to a study the mitochondrial respiration and oxidative phosphorytation. The principle of the oxygen electrode has been summarized, and the design of the vibrating oxygen electrode for use with speetrophotometric studies is illustrated. The oxygen electrode apparatus can be calibrated in a number of ways. A more accurate calibration of oxygen content can be obtained by gas equilibration with various nitrogen-oxygen mixtures. When tightly coupled mitochondria are suspended in an isotonic buffer, a slow rate of oxygen uptake is measured in the presence of substrate and absence of ADP. Addition of ADP causes an immediate increase in the rate of oxygen utilization. The concentration of oxygen utilized is proportional to the amount of ADP phosphorylated to ATP. The type of oxygen electrode tracings is presented from which an ADP : O ratio (equivalent to a P : O ratio) can be directly calculated.
The rate of secretion and the biochemical composition of mucus secreted by the gastric antrum of dogs were studied before and during administration of ACTH. ACTH caused a decrease in the rate of secretion of the mucus and an alteration in its biochemical composition, characterized by a decrease in the carbohydrate:protein ratio. The data suggest that ulceration during ACTH administration and during stress may be due to impaired mucosal defense mechanisms. © 1967 Hoeber Medical Division • Harper & Row, Publishers, Incorporated.
The rate of exfoliation of canine gastric surface epithelial cells was estimated by measuring the concentration of deoxyribonucleic acid in Heidenhain pouch washings before, during, and after the administration of cortisone, adrenocorticotropic hormone (ACTH), aspirin, and phenylbutazone. Also, the mitotic frequency in gastric mucosal biopsies was determined before and during the administration of ACTH and aspirin. In addition, the influence of aspirin on the rate of uptake of thymidine-H³ by the gastric mucosa of rats was evaluated by radioautography. The rate of exfoliation of surface epithelial cells was reduced by ACTH and cortisone and was increased by aspirin and phenylbutazone. Whereas ACTH decreased the mitotic frequency in gastric mucosal biopsies, aspirin had no significant effect; moreover, aspirin did not affect the rate of uptake of thymidine-H³ by gastric mucosa of rats. The data suggest that one of the mechanisms of gastric mucosal injury by ACTH and cortisone may be a reduced rate of renewal of surface epithelial cells. Aspirin and phenylbutazone, on the other hand, appear to affect the gastric mucosa in such a way that shedding of surface cells increases without a concomitant increase in the rate of cell renewal.
The role of bile in the etiology of experimental stress ulceration was studied in 38 piglets. In six animals, neither anesthesia, gastrotomy, nor application of homogenous bile on antral mucosa caused gastric ulceration. Hemorrhagic shock of three hours duration induced ulceration of the gastric corpus in 13 surviving piglets within 72 hours. In six others, application of homogenous bile on antral mucosa prior to shock resulted in both antral and corpus gastritis and ulceration which occurred between 30 minutes and 24 hours after retransfusion. Ligation of the common bile duct prior to shock totally prevented gastric ulceration in six piglets, suggesting that bile reflux in association with shock is essential in the etiology of experimental swine stress ulcer.
Bleeding stress ulcers developed in seventy-four young men without previous ulcer disease and with major injuries received in the Vietnam war. Of four forms of management for this complication, the best results were obtained by nonoperative treatment. Surgery was used only in the event of rapid blood loss. Vagotomy and pyloroplasty with oversewing of ulcers and ligation of bleeding points appeared to be the most effective of the three types of surgical procedure used. The aspect of management having the greatest therapeutic potential for this complication is rapid aggressive treatment for the underlying illness; amelioration of the general condition leads to parallel healing of the ulcers.
A clinical syndrome of massive bleeding from acute multiple gastric ulcers associated with respiratory failure, hypotension, sepsis, and jaundice developed in eight of 150 consecutive patients admitted to the respiratory-surgical intensive care unit of the Beth Israel Hospital. These ulcers were almost exclusively located in the fundus of the stomach. Only one of these eight patients survived. Twenty-one gastric secretory studies performed in eighteen critically ill patients indicate that increased secretion of acid may be an important cause of this disease. One patient in whom acute gastric ulceration later developed had a maximally stimulated parietal cell mass in the basal state. Patients in whom this lethal complication develops and who do not respond to nonoperative therapy are probably best treated by gastric resection and vagotomy.
The ‘high-energy phosphate’ content of liver tissue declines during the course of hemorrhagic shock in the dog. The degree of decline does not correlate with the loss of responsiveness to transfusion therapy. Phosphate energy stores depleted during hemorrhagic shock are rapidly rebuilt following replacement transfusion. Prior treatment with aureomycin reduces the depletion of phosphate energy stores during hemorrhagic shock. Aureomycin given in the same manner has been found to preserve the dog's responsiveness to transfusion therapy. The protective action of aureomycin in hemorrhagic shock is not attributable to the preservation of phosphate energy stores, however, because the change in these stores does not correlate with responsiveness to blood replacement.
1.Six species of experimental animals were tested for the production of gastric ulcers by restraining the animals in wire screen for 24 hours. Mice, rats, guinea pigs, and hamsters had an incidence of gastric ulceration of 92, 86, 46, and 4 per cent, respectively. Gastric ulcers were not induced in rabbits or monkeys by the restraint technique.
2.As the time period of the restraint of the rat was increased from 6 to 24 hours, the incidence of gastric ulcer increased. Recovery of the stomach to normal after 24 hours of restraint required 72 hours.
3.The incidence of gastric ulcers in rats that were deprived of food was found to be higher than that of fed rats, when both groups were restrained for the same time period. Food deprivation also prolonged the time required for the gastric mucosa to return to normal.
4.Younger rats (50 to 185 gm.) had a higher incidence of gastric ulcers than older rats (over 250 gm.) when both groups were subjected to short periods of restraint. Weight did not seem to be an important variable when the rats were restrained for a period of 24 hours.
5.Repeated periods of restraint, 18 hours a day, increased the incidence and severity of gastric ulcers. Rumen ulcers were produced by this procedure.
6.In rats, 8 days after operation, hypophysectomy and bilateral subdiaphragmatic vagotomy did not reduce significantly the incidence of animals with ulcers. Bilateral adrenalectomy significantly increased the incidence and severity of the ulcers produced by restraint.
7.The restraint technique provides a simple, rapid, nonsurgical means of producing ulcers in the glandular portion of the stomach.
Intramuscular administration of cortisone to dogs prepared with denervated antral pouches caused a substantial decrease in the rate of mucus secretion by these pouches. Changes in the composition of mucus were also observed. We propose that this steroidinduced decrease in mucus production lowers the threshold of susceptibility to peptic ulceration by interfering with the rate of renewal of the mucous barrier, and is the basic cause of "steroid ulcer.".
Massive Upper Gastrointestinal Hemorrhage Following Surgical Operations An Experimental Model and Clinical Definition of Stress Ulceration Role of Intestinal Chyme in the Pathogenesis of Gastric Ulceration Following experimental Hemorrhagic Shock
- A A Goodman
- C F Frey
- A A Goodman
- M P Osborne
Goodman, A. A. and Frey, C. F.: Massive Upper Gastrointestinal Hemorrhage Following Surgical Operations. Ann. Surg., 167:180, 1968. 10. Goodman, A. A. and Osborne, M. P.: An Experimental Model and Clinical Definition of Stress Ulceration. Surg Gynecol. Obstet., 134:563, 1972. ID MASTERS Ann. Surg. * October 1974 11. Guilbert, J., Bounous, G. and Gurd, F. N.: Role of Intestinal Chyme in the Pathogenesis of Gastric Ulceration Following experimental Hemorrhagic Shock. J. Trauma, 9:723, 1968.
Sodium and Potassium-Stimu-lated ATPase Production by Restraint of Gastric Ulcers and of Hydrothorax in the Rat
- R L Post
- A K Sen
Post, R. L. and Sen, A. K.: Sodium and Potassium-Stimu-lated ATPase. In Methods in Enzymology, Vol. X. S. P. Colowick and N. 0. Kaplan, editors. 762-768, 1967. 24. Robert, A., Philips, J. P. and Nezamis, J. E.: Production by Restraint of Gastric Ulcers and of Hydrothorax in the Rat. Gastroenterology, 51:75, 1966.
The role of Vagotomy in Preventing Bile Salt-induced Stress Ulcers During Hemorrhagic Shock Respiratory Failure, Hypotension, Sepsis and Jaundice. A Clinical Syndrome Associated with Lethal Hemorrhage From Acute Stress Ulceration of the Stomach
- Safaie
- S Shirazi
- L Denbesten
- K N Hamza
Safaie-Shirazi, S., DenBesten, L. and Hamza, K. N.: The role of Vagotomy in Preventing Bile Salt-induced Stress Ulcers During Hemorrhagic Shock. J. Trauma, 12:678, 1972. 27. Skillman, J. J., Bushnell, L. S., Goldman, H. and Silen, W.: Respiratory Failure, Hypotension, Sepsis and Jaundice. A Clinical Syndrome Associated with Lethal Hemorrhage From Acute Stress Ulceration of the Stomach. Gastroenterology, 57:241, 1969.
The Prophylactic Use of an "Elemental
- C Bounous
- N G Sutherland
- A H Mcardle
- F N Curd
Bounous, C., Sutherland, N. G., McArdle, A. H. and Curd,
F. N.: The Prophylactic Use of an "Elemental" Diet in
Experimental Hemorrhagic Shock and Intestinal Ischemia.