Formation Of Gastric Erosions Research Articles

Stress Preconditioning Effects on Heart Rate and Blood Pressure under Circumstances of Gastric and Small Intestine Injury Induced by Indomethacin in Conscious Rats

Nonsteroidal anti‐inflammatory drugs (NSAIDs) are commonly used medications. However NSAIDs exert side effects not only in the stomach and the small intestine but also in cardiovascular system. A disorder of the circadian heart rate (HR) under circumstances of indomethacin (IM)‐induced gastric and small intestinal injury is potentially lethal factor and our previous experimental findings confirmed this fact. Preconditioning is one of perspective approaches to protect the heart and other organs against adverse influences. We demonstrated previously that glucocorticoids released during mild stress contribute to protection of the gastric mucosa against severe stress through maintaining various links of the general body homeostasis, including blood pressure (BP). Here we studied the effects of stress preconditioning on HR and BP under circumstances of gastric and small intestine injury induced by IM in conscious rats. Preliminary fasting (24 h) rats were subjected IM (35 mg/kg, sc) administration with preconditioning stress (cold‐restraint, 10 °C, 30 min and keeping at room temperature 1 h before IM administration) or without it. HR and BP were measured by non‐invasive tail cuff method before IM injection and 4, 24 and 48 h after IM administration in stressed and non‐stressed animals. The gastric and the small intestinal mucosa were examined for injury 4 h (formation of the gastric erosions) and 24 and 48 h (formation of the small intestinal injury) after IM administration. Plasma corticosterone levels were also measured. IM administration induced formation of gastric erosions (4 h after its injection) and their healing for 48 h was followed by a development of the small intestinal injury. Formation of gastric erosions caused an elevation of corticosterone levels 4 h after IM; their following healing resulted in a decrease of IM‐induced corticosterone levels 24 and 48 h after IM injection till baseline level. IM‐induced gastrointestinal injury was accompanied by a gradual decrease of systolic BP and increase of the HR for 48 h after IM. Preconditioning stress reduced IM‐induced gastric erosions as well as small intestinal injury 4 and 24 h after its injection, respectively, and recovered HR and systolic BP 48 h after IM. Thus, the data suggest that preconditioning stress may reduce the vulnerability of the gastric and the small intestinal mucosa to ulcerogenic action of IM and stabilizes the hemodynamic parameters.Support or Funding InformationThe study was supported by grant of Russian Science Foundation (RSF) N 19‐15‐00430.

Effects of stress preconditioning on vulnerability of gastric and small intestinal mucosa to ulcerogenic action of indomethacin in rats.

The preconditioning effect of a mild stressor can reduce the ulcerogenic effect of a severe stressor on the gastric mucosa. The aim of the study was to investigate the effect of preconditioning stress on the gastric and the small intestinal injury caused by a single injection of indomethacin (IM) in conscious rats. Preliminary fasting (24 hours) rats were subjected IM administration (35 mg/kg, subcutaneously) with preconditioning stress (30 min cold-restraint at 10°C and further 1 hour keeping in cages at room temperature) or without stress. Plasma corticosterone level, heart rate (HR), blood pressure (BP) and somatic pain sensitivity (tail flick latency) were measured under circumstances of the gastrointestinal IM-induced injury in preliminary stressed and non-stressed rats. IM administration induced formation of gastric erosions well visible 4 hours after its injection. The healing of gastric erosions for 48 hours was accompanied by the development of a small intestinal injury. Corticosterone levels were elevated under formation of gastric erosions (4 hours after IM injection) but decreased following their healing (24 and 48 hours IM injection). Cold-restraint stress caused corticosterone rise 30 min after its onset. IM-induced gastrointestinal injury resulted in an increase of tail flick latencies (somatic hypoalgesia) and gradual decrease of systolic BP and increase of the HR. Stress preconditioning attenuated IM-induced gastric erosions as well as small intestinal injury 4 and 24 hours after its injection, respectively. The preconditioning also resulted in elimination of somatic hypoalgesia 4 hours after IM, but didn't influence an appearance of somatic hypoalgesia 24 and 48 hours after IM. Preconditioning stress recovered the HR and systolic BP (48 hours after IM). Elevated corticosterone level could be observed only in the 4th hour, but not in the 24th and 48th hours after IM administration. Thus, the data suggest that preconditioning stress reduces the vulnerability of the gastric and the small intestinal mucosa to ulcerogenic action of IM, stabilizes the hemodynamic parameters and normalizes somatic pain sensitivity.

Risk Evaluation for the Formation of Gastroduodenal Erosion and Ulceration Induced by Meloxicam in Patients with Seropositive and Seronegative Rheumatoid Arthritis

Aim. In this paper, the authors set out toascertain the prognostic value of the rheumatoid factor for the formation of gastroduodenal erosions and ulcers in patients with rheumatoid arthritis taking non-steroidal anti-inflammatory drugs (meloxicam).Materials and methods. A prospective, randomized study of 138 patients with rheumatoid arthritis taking methotrexate (12.5 mg per week) and meloxicam — nonsteroidal anti-inflammatory drug — (15 mg per day) was conducted. The formation of gastroduodenal erosions and ulcers was recorded for 4–8 years during esophagogastroduo-denoscopy (at study entry, following three months, then once a year). The groups of seropositive and seronegative patients comprised 69 people each.Results. During the period of patient monitoring, significant differences were found (P < 0.01) in the frequency of the formation of gastric and duodenal erosions and ulcers in patients with seropositive (79.7 %; 95 % CI: 70.2–89.2 %) and seronegative (4.4 %; 95 % CI: 0.01–9.2 %) rheumatoid arthritis (τ = 0.763; P < 0.01), taking meloxicam. In the course of monitoring patients (for 4–8 years) with rheumatoid arthritis who took meloxicam, the authors established high rates of the prognostic (rheumatoid) factor for predicting the formation of gastric and duodenal erosions and ulcers: forecast sensitivity — 94.8 %, forecast specificity — 82.5 %, the proportion of correct forecasts — 87.7 %.Conclusions. The rheumatoid factor is found to be a significant (P < 0.01) risk factor for gastroduodenal erosions and ulcers in patients with rheumatoid arthritis, who take non-steroidal anti-inflammatory drugs (meloxicam).

Role of Glucocorticoids in Gastroprotection Induced by Capsaicin

The pivotal role of capsaicin‐sensitive peptidergic sensory fibers in maintaining of gastric mucosal integrity against injurious interventions has been well established in rats and then in human. Clinical finding suggests that capsaicin‐induced gastric mucosal protection against the injurious effects of ethanol or indomethacin is due to the acute stimulatory effect of the compound. It was concluded that patients taking non‐steroidal anti‐inflammatory drugs (NSAID) regularly can decrease the incidence and severity of gastric ulceration, if they have moderate spicy foods. Opposite effect has been observed in rats desensitized by capsaicin. Functional blockade of gastric sensory nerve endings elicited by systemic capsaicin application was resulted in impaired mucosal protection against various ulcerogenic agents. Our previous findings suggest a pivotal compensatory role of glucocorticoids in maintenance of gastric mucosal integrity in rats desensitized by capsaicin. In this study, we tested if glucocorticoids can participate in capsaicin‐caused gastroprotection during NSAID‐caused gastropathy accompanied by prostaglandin deficiency in rats. Gastric injury was induced by indomethacin (IM). A single IM administration (35 mg/kg, sc) into fasting (24 h) rats caused the formation of gastric erosions 4 h after injection. The effects of small doses (0.1, 0.5, 1.0, 2.0, 3.0, 5.0, 10.0 mg/kg, sc) of capsaicin on the blood corticosterone and glucose levels and IM‐induced gastric injury were tested. A single capsaicin administration was performed one hour before IM administration. To test the participation of corticosterone in the gastroprotective effect of capsaicin, the pretreatment by the inhibitor of glucocorticoid synthesis, metyrapone (30 mg/kg, i.p., 30 min before capsaicin) was used. We found that the pretreatment with capsaicin (0.5–10.0 mg/kg, sc) reduced dose dependently the area of IM‐induced erosions. This protection was accompanied by a gradual increase in blood corticosterone and glucose levels. Metyrapone injected shortly before capsaicin administration (1.0 mg/kg) caused a fast inhibition of capsaicin‐induced corticosterone response and reversed the protective effect of capsaicin on the gastric mucosa against the IM‐produced injury. The present study confirms evidence for the powerful gastroprotective potency of capsaicin during NSAID‐caused gastropathy. The findings obtained demonstrate that capsaicin administration resulted in an increase in plasma corticosterone levels which in turn plays a pivotal role in maintaining of gastric mucosal integrity against injurious intervention of IM.Support or Funding InformationThe study was supported by grants of RSF N 19‐15‐00430 (NSAID‐caused gastropathy with prostaglandin deficiency) and RFBR N 19‐015‐00514a (capsaicin‐induced gastroprotection)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vulnerability of gastric and small intestinal mucosa to ulcerogenic action of indomethacin in C57/BL6/J mice and transient receptor potential channel vanilloid type 1 knockout mice.

Capsaicin-sensitive sensory nerves are densely distributed in the gastrointestinal system and involved in maintenance of gastrointestinal mucosal integrity. capsaicin selectively stimulates nociceptive neurons and its action is mediated through the transient receptor potential channel vanilloid type 1 (TRPV1) receptor. Activation TRPV1 receptors that play a fundamental role in pain signaling, may also exert protective effects against gastrointestinal injury. The present study was performed to investigate and compare the vulnerability of gastric as well as small intestinal mucosa to ulcerogenic action of indomethacin (IM) in mice with genetically deleted TRPV1 receptor (TRPV1 KO) and in C57/BL6/J mice. IM-induced injury was assessed macroscopically as well as histologically; the somatic pain sensitivity was estimated by tail flick latency (tail flick test); plasma corticosterone levels and body weight were also monitored. A single IM administration (35 mg/kg, subcutaneously) into pre-starving (24 h) mice caused the formation of gastric erosions 4 h later and, then, after refeeding, induced formation of the small intestinal injury which was visible 24, 48, 72 h after IM administration. Although IM-induced gastrointestinal injury was detectable in both C57/BL6/J and TRPV1 KO mice, area of gastric damage was greater in C57/BL6/J than in TRPV1 KO mice, whereas the small intestinal injury (48 and 72 h after IM injection), on the contrary, prevailed in TRPV1 KO mice compared to C57/BL6/J mice. In 24 h after IM injection, the total area of intestinal injury did not differ in C57BL6/J and TRPV1 KO mice, however histological score was higher in TRPV1 KO mice than C57BL6/J mice. TRPV1 KO mice showed the increased tail flick latencies and the lacking IM-induced corticosterone rise. The data suggest that in TRPV1 KO mice the gastric mucosa is less vulnerable to ulcerogenic action of IM compared to C57/BL6/J mice, however, their small intestinal mucosa, on the contrary, is more vulnerable to the ulcerogenic action than in C57/BL6/J mice.

Role of Vascular Mechanisms Involved in the Acute Gastric Mucosal Injury Induced by Droxicam and Piroxicam in Rats

We describe the formation of severe gastric erosions produced in fasted rats by intragastric administration of droxicam and its active species piroxicam, non-steroidal anti-inflammatory drugs of the oxicam group. The time course of gastric damage and the possible role of mucus secretion, changes of gastric vascular permeability, and neutrophil activation in the development of droxicam- and piroxicam-induced gastric lesions, were also investigated. Both drugs dose-dependently (1.25-20 mg kg−1) caused acute gastric haemorrhagic erosions in the rat. These lesions were significantly greater with piroxicam treatment 6 h after dosing. Only the lower doses of droxicam and piroxicam (1.25 mg kg−1) induced a significant increase of mucus gel production at different times (3 and 6 h). However, there was no increase in the concentration of its components. Oral pretreatment of the animals with either agent did not induce any changes on the values of mucosal vascular permeability. In contrast, myeloperoxidase activity as an index of neutrophil infiltration was significantly increased. A marked relationship was found between the lesion index and myeloperoxidase activity. These results suggest that neutrophil infiltration could play an important role in the pathogenesis of gastric mucosal injury induced by these oxicam agents.

Suppression of Hypothalamo-Hypophyseal-Adrenocortical System Function as the Cause of Aggravation of the Ulcerogenic Action of Indomethacin on the Stomach after Administration of Pharmacological Doses of Hydrocortisone

We report testing of the suggestion that aggravation of the actions of glucocorticoid treatment on the formation of indomethacin-induced erosions may be mediated by inadequate production of glucocorticoid hormones resulting from the suppression of the hypothalamo-hypophyseal-adrenocortical system (HHACS) in these conditions. Administration of indomethacin (25 mg/kg, s.c.) to rats after 24 h of starvation was used to induce gastric erosions. The effects of hydrocortisone given at pharmacological doses on the indomethacin-induced formation of gastric erosions and plasma corticosterone levels were studied one and four weeks after hormone administration. Indomethacin induced increases in plasma corticosterone levels, which were almost completely prevented one week after hydrocortisone administration. The formation of indomethacin-induced erosions was aggravated one week after administration of hydrocortisone, though replacement therapy with corticosterone, which imitates the normal increase in corticosterone, prevented this aggravation. Return of both the increased corticosterone level and the normal sensitivity of the gastric mucosa to the ulcerogenic action of indomethacin occurred four weeks after hydrocortisone administration. These results provide evidence that suppression of HHACS function may be responsible for the aggravation of the action of glucocorticoid treatment on the formation of erosions after administration of indomethacin.

Role of endogenous glucocorticoids in the healing of gastric erosions and chronic gastric ulcers in rats

To investigate the role of endogenous glucocorticoids in the healing of gastric lesions, we compared the healing of indomethacin- or cold-restraint-induced gastric erosions as well as aceticacid-induced ulcers in sham-operated rats, adrenalectomized rats and adrenalectomized rats with corticosterone replacement. Adrenalectomy was performed immediately after the formation of gastric erosions (4 h after indomethacin administration or 6 h after the onset of cold-restraint stress) or chronic ulcers (in 3 days after ingestion of acetic acid into the luminal side of the stomach). All ulcerogenic stimuli caused an increase in corticosterone production. Adrenalectomy created corticosterone deficiency and delayed the healing of gastric erosions and chronic ulcers. Replacing corticosterone reversed the deleterious effect of adrenalectomy on healing of gastric damage in adrenalectomized rats. These results suggest that glucocorticoids participate in natural healing processes of injured gastric mucosa. The data obtained also indicate that participation of glucocorticoid in the healing of gastric lesions is more evident under prostaglandin deficient conditions.

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.

Gastroprotective action of glucocorticoids during the formation and the healing of indomethacin-induced gastric erosions in rats

The aim of the present study consisted of the investigation of glucocorticoid role in the formation and the healing of indomethacin-induced (25 mg/kg, sc) gastric erosions in rats. The effect of deficiency of glucocorticoid production followed by corticosterone replacement on the formation and the healing of the gastric erosions was evaluated. Glucocorticoid production was decreased by adrenalectomy or by delayed inhibitory action after a single pharmacological dose of cortisol (300 mg/kg ip) injected 1 week before the onset of ulcerogenic stimulus. Indomethacin induced corticosterone rise and caused gastric erosions. The loss of indomethacin-induced plasma corticosterone rise potentiated the formation of indomethacin-induced erosions in both models. The area of gastric erosions in rats with glucocorticoid deficiency was considerably larger than that in control animals 4 h after indomethacin administration as well as during 48 h after the drug administration (period of erosion healing). Injecting corticosterone in rats with glucocorticoid deficiency significantly decreased the formation of indomethacin-induced gastric erosions and promoted their healing. Thus, the present data support the gastroprotective action of glucocorticoids in the formation and in the healing of indomethacin-induced mucosal injury.

Pharmacokinetics of lansoprazole in adolescent patients with gastroesophageal reflux disease (GERD)

' =p <0.05 PGEz and TxB2 in the pouch exudate and in the stomach of the animals was measured by ELISA. Indomethacin dose-dependentl y caused a significant inhibition of synthesis of PGEz and TxB zboth at the inflammatory site and in the stomach and induced formation of gastric erosions. On the contrary , celocoxib or darbufel one treated animals did not develop any gastric damage and inhibition of PGEz and TxBz synthesis was observed mainly in the pouch exudate. The degree of inhibition of PGEz and TxBz synthesis observed at a dose of 10 mg/kg for the three drugs tested is reported in the table below (Average :!: St. Err.)(n). In conclusion, our data suggest s that darbufelone has a celocox ib-like profile and the preferent ial inhibition of synthesis of arachidonic acid metabolites at the inflammatory site but not in the stomach, could explain the low risk of developing gastrointestinal damage.

Involvement of reactive oxygen species and nitric oxide in gastric ischemia-reperfusion injury in rats: protective effect of tetrahydrobiopterin.

The purpose of this study was to examine whether tetrahydrobiopterin (BH4), a cofactor of nitric oxide (NO) synthase, attenuates gastric ischemia-reperfusion injury induced by clamping of the celiac artery. Gastric injury was assessed by a formation of gastric mucosal erosions. The gastric injury was observed at 30 and 60 min after reperfusion following 30-min ischemia and was reduced by superoxide dismutase (SOD), catalase, or NO synthase inhibitors. Therefore, reactive oxygen species (ROS) and NO seem to be implicated in the ischemia-reperfusion injury. Treatment with BH4 reduced the ischemia-reperfusion injury. Pretreatment with sepiapterin, a precursor of BH4, also reduced the ischemia-reperfusion injury with an increase in BH4 content in serum and stomach. Both the increase in BH4 content and the protective effect of sepiapterin were prevented of pretreatment with N-acetylserotonin, an inhibitor of BH4 synthesis. These results suggest that the increase in BH4 content may protect against gastric ischemia-reperfusion injury via reduction of ROS and/or NO toxicity. BH4 might be useful as a therapeutic agent for gastric ischemia-reperfusion injury.

Corticosterone increase inhibits stress-induced gastric erosions in rats.

The role of glucocorticoids released in response to stress in the pathogenesis of stress-induced gastric erosions has been reevaluated. Gastric erosions elicited in male rats by 3-h cold-restraint or water-restraint stresses were studied after acute reduction of corticosterone release or occupation of glucocorticoid receptors by the antagonist RU-38486 during stress. Stress-induced corticosterone production was reduced by creating a lesion on the hypothalamic paraventricular nucleus (PVN) 4 days before stress as well as by pretreatment with a rabbit antiserum to adrenocorticotropin (ACTH) 30 min before stress. RU-38486 (10 mg/kg po) was administered 20 min before and 60 min after the onset of stress. Corticosterone for replacement was injected 15 min before the onset of stress to mimic stress-induced corticosterone response. Plasma corticosterone levels were measured by fluorometry or RIA. Gastric erosions were quantitated by measuring the area of damage. Four days after PVN lesion, stress-induced corticosterone release was decreased and gastric erosions were increased. Injecting corticosterone significantly attenuated the effect of PVN lesion on gastric erosions. The ACTH antiserum inhibited corticosteroid secretion in response to stress and markedly increased gastric erosions. The administration of the glucocorticoid/progesterone antagonist RU-38486 significantly potentiated the formation of stress-induced gastric erosions. These observations support the suggestion that glucocorticoids released during stress have a gastroprotective action rather than an ulcerogenic effect as was generally accepted.

A protease inhibitor attenuates gastric erosions and microcirculatory disturbance in the early period after thermal injury in rats.

The effects of camostat mesilate, a synthetic serine protease inhibitor on gastric microcirculation and active oxygen species generated by leucocytes from the gastric and jugular veins in the early period after thermal injury were assessed. Male Wistar rats were anaesthetized and a 30% full skin-thickness dorsal burn was inflicted. Camostat mesilate (100 mg/kg) was dissolved in distilled water and administered orally to rats 40 min before thermal injury (the camostat group). The control animals (the vehicle group) were administered distilled water orally. Rolling leucocytes as well as Monastral blue B deposits in venules were observed using in vivo microscopy. Active oxygen species were measured by chemiluminescence. Camostat mesilate decreased the total length of gastric erosion, venular deposits of Monastral blue B, and rolling of leucocytes in venules, and relatively increased luminol-dependent chemiluminescence activity generated by zymosan-stimulated leucocytes 15 min after thermal injury. These results suggest that serine proteases are involved in the formation of gastric erosions and gastric microcirculatory disturbance in the early period after thermal injury.

Alendronate induces gastric injury and delays ulcer healing in rodents

Gastric ulceration associated with the use of NSAIDs is most frequently observed in elderly women, the same sector of society most likely to be receiving therapy for osteoporosis. As some anti-osteoporosis medications have been suggested to irritate the upper gastrointestinal mucosa, we evaluated the ability of one such drug, alendronate, to damage the gastric mucosa and to influence the severity and healing of gastric ulcers in rodents. The effects of alendronate on indomethacin-induced antral ulceration was evaluated in the rabbit, while effects on ulcer healing and on the formation of gastric erosions was evaluated in the rat. Effects of alendronate on gastric acid secretion, blood flow and prostaglandin synthesis were also evaluated. Alendronate caused erosions in the rabbit stomach, but not antral ulceration. However, at the highest doses tested (80 mg) alendronate increased the incidence and size of indomethacin-induced antral ulcers. Alendronate also enhanced indomethacin-induced gastric damage in the rat, and delayed gastric ulcer healing. These effects of alendronate were not attributable to changes in gastric acid secretion, blood flow, prostaglandin synthesis or the pharmacokinetics of indomethacin. The damaging effects of alendronate on the stomach were due to topical irritant effects and could be observed at concentrations as low as 4 mg/ml within 30 min of oral administration or topical superfusion. These results support preliminary clinical evidence that alendronate can damage the gastric mucosa. While gastric injury may be a rare occurrence in patients taking this drug, concomitant use of alendronate and NSAIDs may increase the incidence or severity of ulceration.

Role of endogenous sulphydryls and neutrophil infiltration in the pathogenesis of gastric mucosal injury induced by piroxicam in rats.

In the present report we studied the formation of severe gastric erosions produced in fasted rats by intragastric administration of piroxicam (PRX), an enolic acid-derived NSAID. The time course of gastric damage and the possible role of mucus secretion, endogenous sulphydryl compounds, changes of gastric vascular permeability and neutrophil infiltration in the development of PRX-induced gastric lesions were also investigated. PRX dose-dependently (1.25-20 mg/kg) caused acute gastric haemorrhagic erosion in the rat. The lesions increased with time until 9 hr after dosing. Mucus secretion did not change significantly with respect to the control group with 5, 10 and 20 mg/kg of PRX at different times (3 and 6 hours) of treatment. There was also no increase in the concentration of its components. In addition, oral pretreatment of the animals with PRX did not significantly change the amount of dye trapped in the stomach. In contrast, non-protein SH fraction was decreased after administration of PRX and MPO activity as an index of neutrophil infiltration was significantly increased. These results suggest that independently of the PRX dose, depletion of endogenous non-protein SH and neutrophil infiltration could play an important part in the pathogenesis of gastric mucosal injury induced by PRX.

Use of animal models in peptic ulcer disease.

Considerable progress has been made in the understanding of the formation of gastric erosions by the use of animals. The role of gastric acid secretion in their pathogenesis has been clarified. Gastric erosions are associated with the presence of acid in the stomach and slow gastric contractions. With several different experimental procedures, the animal's body temperature falls; preventing the fall averts erosions. A fall in body temperature or exposure to cold are associated with the secretion of thyrotropin-releasing hormone (TRH), and both increased and decreased concentration of corticotropin-releasing factor (CRH) in discrete regions of rat brains. Thyrotropin-releasing hormone when injected into specific sites in the brain produces gastric erosions and increases acid secretion and slow contractions, whereas CRH has the opposite effects. One of the major sites of interaction of the two peptides is in the dorsal motor complex of the vagus nerve. Thyrotropin-releasing hormone increases serotonin (5-HT) secretion into the stomach. Serotonin counter-regulates acid secretion and slow contractions. Many other peptides injected into discrete brain sites stimulate or inhibit gastric acid secretion.

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.

Suppression of Ischemia-Reperfusion Injury in Murine Models by Neopterins

We investigated the effects of D-neopterin (NP) and its reduced form, 5,6,7,8-tetrahydro-D-neopterin (NPH4), in two models of ischemia-reperfusion injury, i.e., ischemic paw edema in mice and gastric ischemia in rats. In ischemic paw edema, iv administration of either NP or NPH4 more potently inhibited the increase of paw thickness after release from ischemia than did administration of superoxide dismutase plus catalase or allopurinol. In gastric ischemia, NP and NPH4 also significantly suppressed the formation of gastric mucosal erosions. Lipid peroxidation in the stomach was increased by ischemia-reperfusion treatment, and the increase was inhibited by the administration of NP or NPH4. The minimum dose of NPH4 required to suppress the gastric ischemic injury in this experiment was 0.3 mg/kg of body weight. These results suggest that neopterin may be effective as a protective agent against ischemia-reperfusion injury, in which active oxygen species are believed to play a major role.

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.