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.
Nonsteroidal anti‐inflammatory drugs (NSAIDs) such as indomethacin (IM) are commonly used; however their use is complicated by the side effects on the gastrointestinal tract. Gastrointestinal injury triggers the changes in visceral as well as somatic pain sensitivity in rats. Here we studied the effect of acute and chronic stress on somatic pain sensitivity under circumstances of IM‐induced gastric injury in conscious rats. Gastric erosion was caused by a single IM injection (35 mg/kg, sc) in preliminary (24 h) fasted rats. Somatic pain sensitivity was assessed by tail flick test. The animals were habituated for tail flick test for 7 days and examined for baseline tail flick latency on day 8. Then, animals were exposed to IM administration with acute or chronic stress or without stress. Cold‐restraint stress at 10 °C for 30 min and keeping at room temperature 1h before IM was used as acute stress. For chronic stress the rats were subjected to unpredictable stress of various modalities for 14 days daily and injected by IM on day 15. Tail flick latencies were measured after stress (before IM) and 4 h after IM administration. Gastric mucosa injury, plasma corticosterone levels, blood pressure, heart rate, adrenal and thymus weight were also measured. IM caused gastric injury 4h after its administration. Acute or chronic stress by itself did not influence gastric mucosa, but its action manifested under circumstances of IM‐induced gastric injury. Acute stress attenuated the ulcerogenic effect of IM on gastric mucosa, but chronic stress potentiated it. The formation of gastric erosion was accompanied by an increase in tail flick latencies (somatic hypoalgesia). We did not observe any changes in tail flick latencies 1h after cold‐restaint stress. However, acute stress prevented somatic hypoalgesia induced by gastric injury. In contrast to acute stress, chronic stress attenuated tail flick latencies before IM administration, but did not affect somatic hypoalgesia. The data obtained suggests that chronic stress aggravates the ulcerogenic action of IM on gastric mucosa that is accompanied by an increase in somatic pain sensitivity, whereas acute stress plays the protective role in the maintenance of integrity of gastric mucosa and preventing of pain abnormalities induced by pathological process in stomach. Support or Funding Information The study was supported by grant of Russian Science Foundation (RSF) №14‐15‐00790.
The hypothalamic-pituitary-adrenocortical (HPA) system is a key hormonal branch of the brain-gut axis in stress and corticotropin-releasing hormone (CRH) is a principal stimulator of the HPA system. According to our finding activation of the HPA system has gastroprotective role in stress and CRH may protect the gastric mucosa against stress-induced injury through involvement of glucocorticoids. To extend this idea to indomethacin-induced gastric injury in the present work we studied whether CRH may protect the gastric mucosa against ulcerogenic action of indomethacin (IM) through involvement of glucocorticoids. CRH administration (1.25 μg/kg and 2.5 μg/kg, i.p.) markedly, dose-dependently, increased plasma corticosterone level and significantly, dose-dependently, suppressed the occurrence of gastric erosion induced by IM (35 mg/kg, s.c.) in conscious rats. To estimate the role of glucocorticoids in CRH-induced gastroprotection, the effect of CRH (1.25 μg/kg) on the IM-induced gastric erosion was studied after acute reduction of corticosterone release by metyrapone (30 mg/kg, i.p., 30 min before CRH administration) or by CRH receptor type 1 antagonist NBI 27914 (10 mg/kg, i.p., 15 min before CRH administration) and also after occupation of glucocorticoid receptors by their antagonist RU-38486 (20 mg/kg, i.p., 2 h before CRH administration). The effects were compared with those in control rats without acute reduction of corticosterone release or occupation of glucocorticoid receptors. Both metyrapone and NBI 27914 injected shortly before CRH administration caused an inhibition of CRH-induced corticosterone response and prevented protective effect of CRH on the gastric mucosa against the IM-induced erosion. The gastroprotective effect of CRH was also eliminated by the pretreatment with glucocorticoid receptor antagonist RU-38486. The results obtained suggest that exogenous CRH may protect the gastric mucosa against IM-induced gastric injury through involvement of glucocorticoids.
We investigated the mechanisms underlying the protective action of glucocorticoids against indomethacin-induced gastric lesions. One-week adrenalectomized rats with or without corticosterone replacement (4 mg/kg sc) were administered indomethacin (25 mg/kg sc), and gastric secretion (acid, pepsin, and mucus), motility, microvascular permeability, and blood glucose levels were examined. Indomethacin caused gastric lesions in sham-operated rats, with an increase in gastric motility and microvascular permeability as well as a decrease in mucus secretion. Adrenalectomy significantly worsened the lesions and potentiated these functional disorders. Glucose levels were lowered by indomethacin in sham-operated rats, and this response was enhanced by adrenalectomy. The changes observed in adrenalectomized rats were prevented by supplementations of corticosterone at a dose mimicking the indomethacin-induced rise in corticosterone, whereas the protective effect of corticosterone was attenuated by RU-38486, a glucocorticoid receptor antagonist. We conclude that the gastroprotective action of endogenous glucocorticoids may be provided by their support of glucose homeostasis and inhibitory effects on enhanced gastric motility and microvascular permeability as well as maintaining the production of mucus.
Diabetes mellitus (DM), as chronic stress activates the hypothalamo-pituitary-adrenocortical axis. We examined whether arginine vasopressin (AVP) and the hypothalamic paraventricular nucleus (PVN) participate in DM-induced chronic stress symptoms. AVP-deficient Brattleboro or PVN-lesioned Wistar rats were used with heterozygous or sham-operated controls. The rats were studied 2 wk after a single injection of streptozotocin. The appearance of DM (enhanced water consumption and blood glucose elevation) and the chronic stress-like somatic changes (body weight decrease, thymus involution, adrenal gland hypertrophy) were not influenced by the lack of AVP. By contrast, PVN lesion significantly attenuated DM-induced thymus involution and adrenal gland hypertrophy as well as the increase in water consumption. The corticotropin-releasing hormone mRNA in PVN was diminished by DM and elevated by the lack of AVP without interaction. DM elevated the proopiomelanocortin (POMC) mRNA in the anterior lobe of the pituitary. The lack of AVP had no effect, whereas lesioning the PVN significantly diminished the elevation. The elevated basal corticosterone plasma levels detectable in DM were influenced neither by the lack of AVP nor by lesioning the PVN. Thus the lack of AVP had no influence on DM-induced chronic stress symptoms, but lesioning the PVN attenuated part of them. However, the lack of elevation in POMC mRNA after PVN lesion, together with the maintained corticosterone elevation, suggests that direct adrenal gland activation occurs in untreated DM.
Diabetes is one of the major health issues globally. Diabetic gastropathy is a well-documented phenomenon. Current treatments for diabetes and its complications have proven to be unsatisfactory. Currently, standard insulin therapy alone is still not the best treatment for type 1 diabetes (T1D). Metformin, besides use in type 2 diabetes (T2D), might be considered for a treatment of T1D. This study analyzed the effects of insulin and metformin on the gastric injury caused by indomethacin in the streptozotocin (STZ)-induced diabetic (T1D) and control non-diabetic rats. STZ (60 mg/kg, i.p.) was administered once 2 weeks before indomethacin (IM, 35 mg/kg, s.c.) in rats. Control non-diabetic rats were injected with STZ vehicle. The development of diabetes was assessed by blood glucose levels, changes in the rats' body weight, and water consumption. Insulin (2 IU/kg, i.p.) and metformin (100 mg/kg, orally) were administered daily, separately to different groups of rats, starting from the 8th day after the administration of STZ, for 7 days. After the last administration of the drugs, the rats were fasted for 22 hours before IM administration. Four hours after IM administration, the rats were decapitated, the stomachs were removed to estimate the erosion area; the adrenal glands and thymus were removed to estimate their weight, and trunk blood was collected to test the corticosterone and glucose levels. During the first week after STZ administration characteristic signs of diabetes developed: increased blood glucose, increased water consumption, and slower body weight gain. A week after daily insulin administration (on the 14th day), the glucose level in diabetic rats was lower compared to the corresponding level on the 7th day (before insulin administration). At the same time, the glucose levels before (day 7) and after administration (day 14) of metformin did not differ significantly. The development of STZ-induced diabetes led to a pronounced worsening of the ulcerogenic effect of IM: the average area of erosions caused by IM was increased significantly compared to that in control non-diabetic rats. Administration of both insulin and metformin for 7 days prevented the ulcer-promoting effect of STZ. In addition, insulin, but not metformin, also had a gastroprotective effect in non-diabetic rats: it reduced the average area of IM-induced erosions. The development of STZ-induced diabetes was accompanied by the manifestation of signs of chronic stress: an increase in plasma corticosterone level, an increase in the relative weight of the adrenal glands, and a decrease in the relative weight of the thymus. Daily administration of insulin for 7 days, but not metformin, resulted in a decrease in corticosterone levels on day 14 in diabetic rats. In conclusion, both insulin and metformin effectively prevented the pronounced ulcer-promoting effect of STZ-induced diabetes on the gastric injury caused by indomethacin in rats. However, only insulin, but not metformin, also exerted gastroprotective effect against IM-induced injury in non-diabetic rats under our experimental conditions. Grant 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” and with financial support from the Ministry of Education and Science of the Russian Federation (No 075-15-2022-303 от 21.04.2022.). This is the full abstract presented at the American Physiology Summit 2024 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.
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