Gastric Erosion Formation Research Articles

Comparison of the Effect of Keeping Rats in the Mountains and on the Plain on the Development of Streptozotocin-Induced Diabetes and Gastric Ulceration

Hypoxia can correct the development of diabetes and its complications in animals and humans, and diabetes exacerbates the gastric ulceration. However, the effect of hypoxia on the gastric ulceration in diabetes remains unknown. The task of the work was to compare the effect of keeping rats in the mountains under moderate natural hypoxia and on the plains on the development of type 1 diabetes and the gastric ulceration. Two weeks after the rats acclimatized to hypoxia (Elbrus region, 2125 m above sea level), they were injected with streptozotocin (STR, 50 or 70 mg/kg) or its vehicle. Simultaneously, rats on the plains were injected with STR (or its vehicle) at the same doses. Indomethacin (IM, 35 mg/kg) was administered two weeks after STR or its vehicle injection in rats after 24 h of fasting, both in the mountains and on the plains, which led to the gastric erosion formation 4 h later. The injection of STR (50 and 70 mg/kg) caused a dose-dependent increase in blood glucose levels in rats both in the mountains and on the plains, which indicates the development of diabetes of varying severity. In rats on the plains the administration of STR (50 and 70 mg/kg) led to a dose-dependent increase in the area of erosions induced by IM compared with those in control animals (STR vehicle). In rats in the mountains, an aggravation of gastric mucosal injury caused by IM was observed, both in control rats (STR vehicle) and in animals with STR-induced diabetes, compared with the gastric injury in rats of the corresponding groups on the plains. The greatest increase in the proulcerogenic effect of STR in the mountains was observed when it was administered at a dose of 70 mg/kg. Thus, persistent moderate hypoxia may lead to an increase in IM-induced gastric ulceration in rats with type 1 diabetes, and, in addition, by itself exacerbate the ulcerogenic effect of IM.

Gastroprotective effect of electrical spinal cord stimulation may be mediated by glucocorticoids produced in response to this stimulation

We demonstrated previously that stress-induced glucocorticoids are gastroprotective hormones but not ulcerogenic ones (Filaretova et al., 2016). Recently electrical spinal cord stimulation began to be used for both experimental studies of motor functions regulation and rehabilitation of motor functions in patients with spinal cord injury (Gerasimenko et al., 2021; Moshonkina et al., 2016). The spinal cord stimulation directed to the activation of spinal locomotor related networks affected visceral systems as well. Recently in our teamwork we have shown that the electrical spinal cord stimulation can cause an increase in blood glucocorticoid level accompanied by a gastroprotective effect (Filaretova et al., 2022). The aim of the present work was to verify the hypothesis that the gastroprotective effect of the electrical spinal cord stimulation may be mediated by glucocorticoids produced in response to this stimulation. Gastric injury was induced in anesthetized rats by prolonged gastric ischemia/reperfusion (I/R, 30 min occlusion of celiac artery followed by 3 h of reperfusion) or indomethacin administration (IM, 35 mg/kg, sc). For spinal stimulation, stainless steel wire electrodes were fixed in fasciae between T11-12 and L1–L2 vertebrae of anesthetized animals. Motor evoked responses in hindlimbs muscles to spinal stimulation were recorded. Spinal stimulation at 30 Hz was carried out with a subthreshold current for inducing muscle contractions (80% of the threshold). Sham-stimulated (control) rats were subjected to the same manipulations except for the stimulation itself. To test the participation of glucocorticoids in the gastroprotective effect of the stimulation, two approaches were used: pretreatment by the inhibitor of glucocorticoid synthesis, metyrapone (30 mg/kg, i.p.) and the antagonist of glucocorticoid receptors RU-38486 (20 mg/kg, i.p.). The concentration of corticosterone in blood plasma was determined using commercial ELISA kits. In control rats the spinal cord stimulation resulted in an increase of blood corticosterone level 1 h later. The spinal stimulation, applied 1 h before the onset of ulcerogenic stimuli, also significantly attenuated gastric erosion formation induced by I/R and IM as well. Metyrapone injected shortly before the stimulation caused a fast inhibition of corticosterone response and reversed the gastroprotective effect stimulation. The gastroprotective effect of the stimulation was also prevented by the pretreatment rats with glucocorticoid receptor antagonist RU-38486. The obtained results indicate on contribution of glucocorticoids to gastroprotective effect of spinal cord stimulation. In conclusion, the findings support the hypothesis that the gastroprotective effect of the electrical spinal cord stimulation may be mediated by glucocorticoids produced in response to this stimulation. The study was supported by the Ministry of Education and Science of the Russian Federation (agreement No. 075-15-2020-921 for the creation and development of the world-class scientific center “Pavlov Center “Integrative Physiology - to medicine, high-tech healthcare and technologies of stress resistance”). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of Electrical Spinal Cord Stimulation on the Activity of the Hypothalamic‐Pituitary‐Adrenocortical System and the Sensitivity of the Gastric Mucosa to Ulcerogenic Stimuli

Our previous results of two areas of unrelated researches are the basis of the present study. We demonstrated previously that the hypothalamic‐pituitary‐adrenocortical (HPA) axis is gastroprotective component of the brain‐gut axis and stress‐induced glucocorticoids are gastroprotective hormones but not ulcerogenic ones (Filaretova et al., 2016). At the same time recently electrical spinal cord stimulation began to be used for both experimental studies of motor functions regulation and rehabilitation of motor functions in patients with spinal cord injury (Gerasimenko et al., 2021; Moshonkina et al., 2016). The spinal cord stimulation directed to the activation of spinal locomotor related networks affected visceral systems as well. The aim of the present experimental work was to verify whether electrical spinal cord stimulation may activate the HPA axis and affect a sensitivity of the gastric mucosa to ulcerogenic stimuli in rats. Two ulcerogenic stimuli were used in anesthetized rats: 1) prolonged gastric ischemia/reperfusion (I/R, 30 min occlusion of celiac artery followed by 3 h of reperfusion); 2) indomethacin administration (IM, 35 mg/kg, sc). For spinal stimulation, stainless steel wire electrodes (AS632; Cooner Wire, California, USA) were fixed in fasciae between T11‐12 and L1–L2 vertebrae of anesthetized animals. Electrodes for recording motor responses to stimulation placed to the muscles of the hind limbs. A‐M System, Model 2100 stimulator was used for spinal cord stimulation. At the beginning motor thresholds determined by stimulation with monopolar rectangular pulses (1 ms). Then the spinal cord was stimulated with a frequency 30 Hz and a subthreshold current (350–700 μA) in order to exclude the influence of movements for 20 min. Sham‐stimulated (control) rats were subjected to the same manipulations except for the stimulation itself. The concentration of corticosterone in blood plasma was determined using commercial ELISA kits. The spinal cord stimulation resulted in an increase of blood glucocorticoid level 1 h later suggesting an activation of the HPA axis. The spinal stimulation, applied 1 h before the onset of ulcerogenic stimuli, also significantly attenuated gastric erosion formation induced by I/R and IM as well. The data suggest that the electrical spinal cord stimulation may activate the HPA axis and affect a sensitivity of the gastric mucosa to ulcerogenic stimuli in rats producing gastroprotective effect. We consider the results as a basis for further research to verify a possibility of an involvement of glucocorticoids in the mechanisms that may provide the beneficial effects of spinal neuromodulation.

Non-Invasive Remote Ischemic Preconditioning May Protect the Gastric Mucosa Against Ischemia-Reperfusion-Induced Injury Through Involvement of Glucocorticoids.

Remote ischemic preconditioning (RIPC) is one of the most effective approaches to attenuate tissue injury caused by severe ischemia-reperfusion (I/R). Experimental studies have demonstrated that RIPC is capable of producing a protective effect not only on heart, but also on brain, lungs, kidneys, liver, intestine, and stomach. We previously demonstrated that glucocorticoids participate in protective effect of local gastric ischemic preconditioning against I/R-induced gastric injury. In the present study we investigated whether RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids. Anesthetized fasted Sprague Dawley male rats were exposed to prolonged gastric I/R (30 min occlusion of celiac artery followed by 3 h of reperfusion) alone or with preliminary brief RIPC (10 min non-invasive occlusion of right hind limb blood flow followed by reperfusion for 30 min). First, we investigated the effect of RIPC on I/R-induced injury by itself. Then to study the role of glucocorticoids similar experiments were carried out: 1) in rats pretreated with the inhibitor of glucocorticoid synthesis, metyrapone (30 mg/kg, i.p), and in control animals; 2) in adrenalectomized rats without or with corticosterone replacement (4 mg/kg, s.c.) and in sham-operated animals; 3) in rats pretreated with glucocorticoid receptor antagonist RU-38486 (20 mg/kg, s.c.) and in control animals. I/R induced corticosterone rise and resulted in the gastric erosion formation. RIPC significantly reduced the erosion area in control animals. Metyrapone injected shortly before RIPC caused a decrease in plasma corticosterone levels and prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. Adrenalectomy performed 1 week before experiment created long-lasting corticosterone deficiency and had no effect on the gastroprotective effect of RIPC. Nevertheless, corticosterone replacement which mimics the corticosterone rise, similar to RIPS, significantly reduced erosion areas of gastric mucosa in adrenalectomized rats supporting the role of glucocorticoids in gastroprotection. RU-38486, which occupied glucocorticoid receptors, similar to metyrapone prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. The results of the present study demonstrate for the first time that RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids.

Corticosterone at physiological dose accelerates the healing of experimental gastric erosions in rats

The data of literature about the action of glucocorticoids on the gastric ulcer/erosion healing mainly concern the effects of lasting glucocorticoid therapy or single injection of glucocorticoids at pharmacological doses. These data clearly indicate that glucocorticoids delay the natural healing of experimental gastric injury. However, the role of endogenous glucocorticoids in the gastric mucosal healing processes remained unknown for a long time. In our previous studies we tested this question and the results obtained argue the contribution of endogenous glucocorticoids to the healing of injured gastric mucosa. In the present study we verified whether natural exogenous glucocorticoids (such as corticosterone in rodents) injected at physiological doses similar to endogenous ones may contribute to the healing of gastric erosions accelerating the healing process. For this, in experiments in male SD rats we studied the effects of corticosterone injected at physiological dose 4 mg/kg or dexamethasone injected at the dose 1 mg/kg on the healing of injured gastric mucosa. The glucocorticoid receptor antagonist RU‐38486 (20 mg/kg) was injected to one half of each group 2 h before the glucocorticoid administration. Glucocorticoid or RU‐38486 vehicle (propylene glycol) was injected as a control. Indomethacin (IM) at the dose 35 mg/kg and 3.5 h gastric ischemia‐reperfusion (IR, 30 min occlusion of celiac artery followed by 3 h of reperfusion) were used as ulcerogenic stimuli in preliminary fasted rats. To estimate IM‐ or IR‐induced gastric erosion formation (erosion area) two groups of rats were sacrificed in 4 h after IM injection or 3.5 h after IR. Corticosterone or dexamethasone as well as their vehicle were injected 4 h after IM administration or 3.5 h after IR (0 time point of healing) to other groups to estimate their effects on the healing of injured gastric mucosa in 6 h and 24 h after the hormonal or vehicle administration. IM‐ and IR‐induced erosions healed with time. In control (vehicle treated rats) an average area of erosions in 6 h time point did not differ from that in 0 time point. At the same time an average area of erosions in 24 h time point was significantly lower than that in 0 time point (healing). Corticosterone but not dexamethasone injection accelerated the healing: in corticosterone treated rats significant decrease in an average area of erosions was already observed in 6 h time point. The preliminary glucocorticoid receptor antagonist RU‐38486 injection prevented accelerating effect of corticosterone on the healing process. The findings suggest that natural glucocorticoid corticosterone injected at physiological dose may accelerate the healing of experimental gastric erosions in rats.Support or Funding InformationThe study was supported by grant of Russian Science Foundation (RSF) N 19‐15‐00430.

Regulation of Somatic Pain Sensitivity under the Circumstances of Indometacin‐InducedGastric Injury: Participation of Cortricotropin‐Releasing Factor

In the present study we investigated the somatic pain sensitivity under the circumstances of indometacin (IM)‐induced gastric ulceration and effect of cortricotropin‐releasing factor (CRF) on the somatic pain sensitivity under the circumstances in conscious rats. IM (35 mg/kg) was administered subcutaneously to preliminary (24h) fasted as well as fed rats. CRF was injected 30 min before IM administration. The somatic pain sensitivity was estimated by tail flick latencies. A single IM administration caused the gastric erosion formation 4 h after the injection only in fasted but not fed rats. IM‐induced gastric injury was accompanied by an increase in tail flick latency in fasted rats. Pretreatment with CRF prevented this increase. CRF by itself did not influence the somatic pain sensitivity. Since we did not observe any changes in tail flick latency in fed IM‐treated rats without gastric mucosal lesions, it was reasonable to assume that an increase in tail flick latency in preliminary fasted IM‐treated rats was associated with the pathological changes in the gastric mucosa, but not with IM‐caused analgesic action by itself. Thus, IM‐induced gastric injury resulted in the suppression of the somatic pain sensitivity and CRF might be involved in regulation of the somatic pain sensitivity under the circumstances in conscious rats. Supported by the Russian Scientific Foundation (grant N 14‐15‐00790).

A wider view on gastric erosion: detailed evaluation of complex somatic and behavioral changes in rats treated with indomethacin at gastric ulcerogenic dose.

Gastric erosion is widespread side effect of nonsteroidal anti-inflammatory drugs. To examine the complexity of the brain-gut axis regulation, indomethacin-induced gastric erosion formation was studied in connection with somatic and behavioral changes. During a constant telemetric recording of heart rate, body temperature, and locomotion of male rats we examined the effects of 24 h fasting, indomethacin (35 mg/kg s.c.) injection, and refeeding at 4 h. Behavior was analyzed on elevated plus maze (EPM) at 24 h and somatic changes at 72 h. Gastric erosion developed 4 h after indomethacin injection, healed 72 h later contrasted by large injury in the small intestine. As classical signs of chronic stress, body and thymus weight were reduced while adrenal weight was enhanced 72 h after indomethacin injection. Fasting by itself changed all telemetrically recorded parameters with most prominent decrease in heart rate. Indomethacin induced similar diminishing effects with earliest and strongest temperature decrease. As a sign of more anxious phenotype locomotion reducing effect of indomethacin injection was detected on EPM. The EPM-induced temperature elevation was missing in indomethacin-treated animals. Fasting by itself induce somatic changes, which can make the animals more vulnerable to ulcerogenic stimuli. Development of indomethacin-induced gastrointestinal lesions happened in parallel with disturbances of heart rate, core body temperature, and chronic stress-like somatic changes as well as anxiety-like behavior. We have to be more aware of the existence of the brain-gut axis and should study changes in the whole body rather than focusing on a specific organ. elevated plus maze.

Aggravation of nonsteroidal antiinflammatory drug gastropathy by glucocorticoid deficiency or blockade of glucocorticoid receptors in rats

Our previous investigations suggest that the reduction of stress-induced corticosterone release, or inhibition of corticosterone actions, promotes stress-induced gastric erosions in rats. In this study the effect of glucocorticoid deficiency on susceptibility to gastric mucosal injury by nonsteroidal antiinflammatory drugs (NSAIDs) was evaluated in rats. Gastric erosions induced in male rats by indomethacin (25 mg/kg sc) or acidified aspirin (40 mM po) were studied one week after adrenalectomy with or without corticosterone replacement or after occupation of glucocorticoid receptors by the antagonist RU-38486 during the period of erosion formation. Corticosterone for replacement (4 mg/kg sc) was injected 15 min before the administration of indomethacin or acidified aspirin to adrenalectomized rats. The antagonist RU-38486 (10 mg/kg po) was administered twice, 20 min before and 60 min after NSAID administration. Plasma corticosterone levels were measured by fluorometry. Gastric erosions were quantitated by measuring the area of damage. Indomethacin or acidified aspirin induced both plasma corticosterone rise and gastric erosions. Adrenalectomy decreased both basal and NSAID-induced corticosterone levels and markedly promoted gastric erosion formation caused by the NSAID. An acute corticosterone replacement mimicking indomethacin-and aspirin-induced corticosterone rise prevented the effect of adrenalectomy on the gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of gastric erosions induced by indomethacin as well as aspirin. These observations suggest a gastroprotective action of glucocorticoids released in response to NSAID treatment against NSAID-induced injury.

Infusion of neurotoxic doses of N-methyl-D-aspartate into the lateral hypothalamus in rats produces stomach erosions, hyperthermia, and a disruption in eating behavior.

The present study examined whether damage to intrinsic lateral hypothalamic (LH) neurons induced by microinfusions of N-methyl-D-aspartate (NMDA) would produce effects similar to those seen after electrolytic LH lesions. In Experiment 1, rats receiving electrolytic (1.2 mA anodal current, 10 s) LH lesions displayed motor impairments, whereas those receiving NMDA (20 microg/microl) infusions did not. Both electrolytic lesions and NMDA infusions were associated with eating deficits, hyperthermia, and gastric erosion formation 24 hr after surgery. In Experiment 2, either 20 microg/microl or 10 microg/microl NMDA destroyed LH cells and produced dose-dependent gastric mucosal erosions as well as similar increases in body temperature. These results indicate that an alteration in the acute activity of intrinsic LH neurons plays a role in the production of gastric mucosal injury and hyperthermia and lend support to other studies implicating a role of LH neurons in eating behavior.

Infusion of neurotoxic doses of N-methyl-D-aspartate into the lateral hypothalamus in rats produces stomach erosions, hyperthermia, and a disruption in eating behavior.

The present study examined whether damage to intrinsic lateral hypothalamic (LH) neurons induced by microinfusions of N-methyl-D-aspartate (NMDA) would produce effects similar to those seen after electrolytic LH lesions. In Experiment 1, rats receiving electrolytic (1.2 mA anodal current, 10 s) LH lesions displayed motor impairments, whereas those receiving NMDA (20 microg/microl) infusions did not. Both electrolytic lesions and NMDA infusions were associated with eating deficits, hyperthermia, and gastric erosion formation 24 hr after surgery. In Experiment 2, either 20 microg/microl or 10 microg/microl NMDA destroyed LH cells and produced dose-dependent gastric mucosal erosions as well as similar increases in body temperature. These results indicate that an alteration in the acute activity of intrinsic LH neurons plays a role in the production of gastric mucosal injury and hyperthermia and lend support to other studies implicating a role of LH neurons in eating behavior.

Body Temperature and Wheel Running Predict Survival Times in Rats Exposed to Activity-Stress

The relationship between restricted feeding, core body temperature ( T b), wheel running, survival, and gastric erosion formation was examined in female rats exposed to activity-stress. Core body temperature and gross motor activity were telemetrically monitored in four groups of rats that had free access to running wheels and in one group that was not allowed to run on the wheels. Twenty-four hours prior to the onset of hypothermia and predicted mortality, different groups were left undisturbed, warmed with a heat lamp, denied access to running wheels, or euthanized. Length of survival in wheel-running rats varied from 2 to 12 days. During the first day of food deprivation, premorbid changes in the variability of T b during the diurnal period and the mean number of wheel revolutions during the nocturnal period were strongly predictive of length of survival. Warming rats with a heat lamp or preventing rats from ever running on the wheel increased the length of survival and attenuated gastric erosion formation. Only rats that were warmed had a greater likelihood of survival. Gastric pathology was also reduced in rats that were euthanized prior to becoming moribund. Rats that were left undisturbed or locked from the running wheel over the last 24 h of testing became moribund and had extensive gastric mucosal damage. These results indicate that thermoregulatory disturbances induced by restricted feeding and not wheel running alone are critical in determining survival and the degree of gastric mucosal injury in rats exposed to activity-stress. Results further suggest that predisposing factors may put some rats at risk for the development of activity-stress-induced mortality.

Gastric ECL-cell hyperplasia produces enhanced basal and stimulated gastric acid output but not gastric erosion formation in the rat

1. 1. The purpose of this study was to examine the change in gastric acid output and gastric erosion formation produced by inducing gastric enterochromaffinlike (ECL) cell hyperplasia in female rats. 2. 2. Rats were treated with vehicle or ranitidine (1,200 μmol/kg/day×4 wks) administered via SC Alzet minipumps. Experiments were performed 24 hours after removing the minipump, when the inhibitory effect of ranitidine on gastric acid secretion had been lost. 3. 3. Basal gastric acid secretion was 7-fold higher in chronic ranitidine animals than in sham control. 4. 4. Both total and net gastric acid secretions stimulated by carbachol/pentagastrin infusion or histamine injection were significantly higher in chronic ranitidine animals than in controls. 5. 5. By contrast, intracisternal injection of the chemical vagal stimulant RX77368 (100 ng) resulted in no net increase in acid output of the recovered ranitidine-pretreated group. 6. 6. No significant changes in gastric erosions produced experimentally by cold exposure plus restraint or indomethacin pretreatment were noted in recovered chronic ranitidine animals compared to sham controls. 7. 7. These findings suggest that achlorhydria-induced ECL cell hyperplasia augments both basal and stimulated gastric acid secretory function. The histamine results implicate an enhanced parietal cell mass, upregulation of H 2 receptors, and/or second-messenger events at the parietal cell as the mechanism for the enhanced gastric secretory response.

Neutropenia does not prevent etodolac- or indomethacin-induced gastrointestinal damage in the rat.

Neutrophils have been implicated in the acute formation of gastric mucosal erosions induced by nonsteroidal antiinflammatory drugs. The aims of the present study were to determine, in rats, the role of neutrophils in the pathogenesis of etodolac- and indomethacin-induced gastrointestinal ulceration and blood loss. Both drugs caused gastrointestinal ulceration, which was associated with increased blood loss, a rise in plasma haptoglobin concentration, and a rise in the number of circulating neutrophils. A marked infiltration of neutrophils occurred only in ileal tissue. Pretreatment with a selective antineutrophil serum induced a significant neutropenia, which failed to inhibit either etodolac- or indomethacin-induced gastrointestinal ulceration and blood loss. A further study demonstrated that the antineutrophil serum did not prevent gastric erosions induced by indomethacin, but it inhibited carrageenan paw edema, which is dependent, in part, on neutrophil infiltration and activation. It is concluded that neutrophils do not contribute to gastrointestinal ulceration and blood loss induced by nonsteroidal antiinflammatory drugs. Furthermore, in contrast with previous studies, our results provide no evidence that neutrophils contribute to indomethacin-induced acute gastric erosion formation.

Caudal raphe-dorsal vagal complex peptidergic projections: Role in gastric vagal control

Subpopulations of raphe pallidus (Rpa) and raphe obscurus (Rob) neurons containing TRH, serotonin (5-HT), and substance P contribute projections to the dorsal vagal complex (DVC). Activation of Rpa and Rob neurons induces a vagal cholinergic-dependent stimulation of gastric secretory and motor function and modulates resistance of the gastric mucosa to gastric injury in rats and cats. The caudal raphe nuclei-DVC pathways containing TRH/5-HT are involved in mediating cold-induced vagal stimulation of gastric function and erosion formation. These results suggest that Rpa/Rob-DVC projections containing TRH/5-HT may be an important pathways in the medullary regulation of vagal activity to the viscera.

Modulation by drugs acting on the autonomic nervous system of platelet-activating factor in the stomach of rats

Platelet-activating factor (PAF), an ether linked choline glycerophospholipid, is a potent initiator of diverse physiological and pathological processes. We have reported that gastric endogenous PAF levels were reduced and the contents of each of its molecular species changed during waterimmersion stress in rats (Sugatani J et al., FASEB J 3: 65–70, 1989 and Sugatani J et al., Lipids 26: 1347–1353, 1991). In this study, we determined the effects of autonomie drugs on the level of gastric PAF, its molecular heterogeneity and formation of gastric erosions in unstressed rats and those subjected to water-immersion stress. Atropine, an anticholinergic drug, suppressed both the stress-induced changes and development of gastric lesions. 6-Hydroxydopamine-induced sympathectomy induced a small decrease in the gastric PAF levels and the addition of stress further decreased the PAF levels and development of gastric lesions. Carbamylcholine induced a transient decrease in the gastric PAF level of normal rats, which was not associated with gastric erosion formation. In contrast, the endogenous gastroprotective factor dopamine evoked transient dose- and time-dependent increases in the gastric PAF levels. These observations indicate that cholinergic muscarinic-receptor activation in rats led to decreases in gastric PAF levels and a prolonged and marked decrease in its level was associated with the development of gastric lesions, and that dopamine increases gastric PAF levels. Gastric endogenous PAF levels are closely associated with the autonomie nervous system and should be considered further in investigations of gastric function.

Effects of amygdaloid lesions on gastric erosion formation during exposure to activity-stress

To examine the role of the amygdala in the production of gastric ulcers induced by activity-stress, electrolytic lesions were placed in the centromedial (CENT) and medial (MED) amygdaloid nuclei, as well as in the intra-amygdaloid division of the bed nucleus of the stria terminalis (BNST). As compared to sham-operated controls (CONT), gastric ulceration was attenuated in rats with CENT lesions and exacerbated in rats with lesions located in the BNST or MED. Wheel running did not differ significantly between control animals and lesioned rats, but did differ within lesioned groups. Rats with MED lesions ran more than rats with CENT or BNST lesions. Results support the view that the integrity of the centromedial amygdala is critical for the maintenance of the viscera and demonstrate that neurogenic factors contribute to the development of gastric erosions during exposure to activity-stress.

Gastric mucosal erosions induced by lateral hypothalamic damage: neuronal and dopaminergic mechanisms

Electrolytic lateral hypothalamic (LH) lesions produce numerous disorders including aphagia, gastric mucosal erosions and autonomic and sensorimotor dysfunctions. This series of experiments examined whether damage to LH neurons or dopaminergic fibers of passage produce similar forms and severity of gastric erosions, as well as other disorders. In Experiment 1, LH neurons were destroyed by the excitatory neurotoxin, kainic acid, that presumably leaves axonal fibers of passage intact. Relatively selective damage to LH neurons with kainic acid produced glandular gastric erosions, as well as sensorimotor and autonomic dysfunctions similar to those seen following electrolytic LH lesions. This suggests that direct damage to LH cell bodies may be a primary cause of many of the disorders observed following LH lesions. In Experiments 2 and 3, electrolytic lesions were used to destroy cell bodies in the substantia nigra and their dopaminergic fibers (some of which pass through the LH area). This resulted in the production of gastric erosions in the absence of significant autonomic dysfunctions. Furthermore, atropine methylnitrate prevented the occurence of gastric erosions following substantia nigra lesions, suggesting that the erosion formation is mediated via parasympathetic-vagal activity. In contrast, destruction of the ventral tegmental area (and its associated dopaminergic fibers) had no significant effect on gastric erosion formation. Experiment 4 showed that apomorphine, a central and peripheral dopamine agonist, provided protection against LH lesion-induced gastric erosion formation, whereas domperidone, a peripheral dopamine antagonist, had no effect. Taken together, this study suggests that (a) both LH neurons and fibers of passage provide a potential anatomical basis for the development of gastric mucosal erosions, (b) that an alteration in dopamine levels, either centrally or peripherally, may represent an important neurochemical mechanism for the development of erosions, and (c) that the occurrence of gastric erosion can be dissociated from other symptoms of the LH syndrome.

抗炎症薬ｎａｂｕｍｅｔｏｎｅとｌｏｘｏｐｒｏｆｅｎ，ｎａｐｒｏｘｅｎの胃腸障害作用に関する比較検討

The effects of nabumetone, naproxen or loxoprofen were examined for anti-inflammatory activity and for effects on gastric mucosal integrity in a rat model of carrageenan-induced paw oedema. All three compounds produced effective anti-inflammatory activity which was associated with dose-related reductions in PGE2 concentration of the inflammatory exudate. However, naproxen and loxoprofen markedly inhibited gastric mucosal 6-keto-PGF1α, production which was accompanied by increases in gastric erosion formation. In contrast, nabumetone inhibited gastric mucosal 6-keto-PGF1α production by only 47% and did not induce gastric damage.In experiments designed to detect gastric and intestinal irritancy, nabumetone, naproxen or loxoprofen were administered orally in single high anti-inflammatory doses. At 6, 24 or 48 hr after dosing, none of the three drugs had caused gastric damage but loxoprofen induced significant ileal damage over the course of the experiment. Associated with loxoprofen-induced ileal damage was a significant increase in myeloperoxidase activity of the ileal tissue 6 hr after dosing, indicating that an inflammatory reaction either precedes or accompanies such damage. Gastrointestinal blood loss was unaltered by any of the drugs over a period of 48 hr. In a cold-restraint rat model of gastric damage where mucosal integrity is compromised, nabumetone failed to increase existing gastric damage whereas both naproxen and loxoprofen increased damage signifcantly. The present study shows that nabumetone, unlike naproxen or loxoprofen, does not cause gastrointestinal irritancy in this species when administered in a high anti-inflammatory dose.

Energy expenditure during stress ulcer formation in vulnerable rats.

Rat pups separated early from their mothers at day 15 become vulnerable to hypothermia and gastric erosion formation when food deprived and physically restrained on postnatal day 30 (S.H. Ackerman, M. A. Hofer, and H. Weiner, Science Wash. DC. 201: 373-376, 1978, and Gastroenterology 75: 649-654, 1978). We tested the hypothesis that this hypothermia is associated with a decrease in oxidative metabolism. We measured O2 consumption of 30-day-old rat pups that had been previously separated at either day 15 (15w) or day 21 (21w). When food was available, 15w rats used as much O2 as 21w rats. When rats were food deprived or food deprived and restrained, 15w rats used significantly less O2 than 21w rats, implying less heat production. We hypothesized that this decrease in heat production during food deprivation and/or restraint was due to impaired thermogenesis resulting from inadequate release of endogenous norepinephrine (NE), which is a stimulant of brown adipose tissue- (BAT) mediated thermogenesis. To test this hypothesis we administered exogenous NE to 15w to 21w rats. Exogenous NE failed to increase O2 consumption in 21w or 15w rats when injected during either food deprivation or restraint. We concluded that 30-day-old 15w rats have decreased oxidative metabolism during food deprivation and restraint and therefore become hypothermic. This decreased oxidative metabolism does not appear to be attributable to insufficient endogenous NE, since it is not reversed by the addition of exogenous NE. We suggest that a decrease in oxidative metabolism may explain susceptibility to stress ulcers in a number of previously reported experimental models.

The potentiation of taurocholate-induced rat gastric erosions following parenteral administration of cyclo-oxygenase inhibitors.

Subcutaneous administration of anti-inflammatory doses of aspirin, indomethacin, naproxen and flurbiprofen inhibited prostacyclin formation ex vivo in the luminally-perfused gastric mucosa of anaesthetized rats. These doses of anti-inflammatory compounds potentiated the formation of gastric mucosal erosions following 3 h luminal perfusion of the topical irritant, acidified sodium taurocholate (2 mM in 100 mM HCl). The increase in luminal acid-loss during gastric perfusion of acidified taurocholate was not significantly enhanced by these anti-inflammatory agents. A correlation was found between the increase in gastric erosion formation and the inhibition of mucosal prostacyclin formation ex vivo by intravenous injection of aspirin or ketoprofen during acid-taurocholate perfusion. BW755C, which failed to inhibit mucosal prostacyclin formation ex vivo, did not significantly augment acid-taurocholate induced gastric damage. The present findings support the potentiating interactions between topical irritation and inhibition of gastric cyclo-oxygenase in the genesis of the gastric lesions.