Physiological and Pharmacological Effects of Glucocorticoids on the Gastrointestinal Tract.

The review considers the data on the physiological and pharmacological effects of glucocorticoids on the gastric mucosa and focuses on the gastroprotective role of stress-produced glucocorticoids as well as on the transformation of physiological gastroprotective effects of glucocorticoids to pathological proulcerogenic consequences. The results of experimental studies on the re-evaluation of the traditional notion that stress-produced glucocorticoids are ulcerogenic led us to the opposite conclusion suggested that these hormones play an important role in the maintenance of the gastric mucosal integrity. Exogenous glucocorticoids may exert both gastroprotective and proulcerogenic effects.

[TRANSFORMATION OF GASTROPRO- TECTIVE EFFECT OF STRESS IN PROULCEROGENIC CONSEGUENCE: DEVELOPMENT OF EXPERIMENTAL MODELS].

The present work was focused on the development of experimental models, in which we can observe the transformation of gastroprotective effect of stress into the proulcerogenic one. For this aim the effect chronic stress on the formation of indomethacin (35 mg/kg)-induced gastric erosion or cold restrain (10 or 6 °C)-induced gastric erosion was investigated in rats. For chronic stress rats were repeatedly restrained for 14 days daily (1 h or 4 h mild restrain or 1 h intensive restrain) and examined on day 14.

[GASTROPROTECTIVE EFFECT OF CORTICOTROPIN-RELEASING FACTOR IN STREPTOZOTOCIN-INDUCED DIABETIC RATS].

The results of our previous studies suggest that corticotropin-releasing factor (CRF) protects the gastric mucosa of rats against stress- and indomethacin-induced gastric injury. In the present study, we investigated whether CRF may protect gastric mucosa against indomethacin-induced gastric injury on diabetic rats. Diabetes was induced by streptozotocin (70 mg/kg) 14 days before indomethacin injection.

[The Influence of Glucocorticoids on the Healing Processes in the Gastric Mucosa].

In this review, we analyzed the data of literature about the glucocorticoid influences on the gastric erosion and ulcer healing. The data show that multiple injections of glucocorticoids at pharmacological doses delay gastric erosion and ulcer healing. However, according to experimental results endogenic glucocorticoids, on the contrary, play significant role in maintenance of gastric mucosal integrity.

[Dual effects of glucocorticoids on the gastric mucosa].

In this review we systematise and analyze data of literature about the effect of glucocorticoids on the gastric mucosa. There are convincing results that show the adaptive gastoprotective nature of endogenous glucocorticoids, which are produced during acute stress-induced activation of the HPA axis. The role glucocorticoid hormones play in the effect of chronic stress remains little-studied.

From gastroprotective to ulcerogenic effects of glucocorticoids: role of long-term glucocorticoid action.

Glucocorticoids may have dual action on the gastric mucosa: gastroprotective and ulcerogenic. In this article, we review the data which suggested that an initial action of endogenous glucocorticoids, including stress-produced ones as well as exogenous glucocorticoids is gastroprotective and consider possible mechanisms of the conversion of physiological gastroprotective action of glucocorticoid hormones to their pathological ulcerogenic effect.

[A comparative analysis of corticosterone, cortisol and dexametasone effects on gastric erosion in rats].

We previously demonstrated that manifestation of gastroprotective or proulcerogenic effects of single dexamethasone injection depends on duration of the hormonal action before ulcerogenic stimulus, but not on the hormonal dose. In the present study we investigated dose and time dependence of corticosterone and cortisol effects on the gastric erosion in rats in comparative aspect with dexamethasone effects. Gastric erosion was induced by indomethacin (35 mg/kg, sc) in preliminary fasted rats.

High sensitivity of gastric mucosa to ulcerogenic effect of indomethacin in rats with diabetes.

One week after injection of streptozotocin (60 mg/kg intravenously), rats developed diabetes associated with a significant increase of gastric mucosa sensitivity to the ulcerogenic effect of indomethacin (35 mg/kg subcutaneously). Since potentiation of the ulcerogenic effect of indomethacin was observed only in rats subjected to fasting before drug injection, we hypothesize that this effect was caused by a drop of high glucose level in the blood after fasting.

[Gastric mucosal susceptibility for ulcerogenic effect of indometacin at different time points of streptozotocin-induced diabetes development].

In the study, we examined the gastric mucosal susceptibility for ulcerogenic effect of indometacin at different time points of streptozotocin-induced diabetes development. Indometacin was injected at ulcerogenic dose (35 mg/kg, s. c.

[Transformation of physiological gastroprotective effects of glucocorticoids into pathological ulcerogenic consequences].

The study was designed to investigate how physiological gastroprotective action of glucocorticoids could be transformed to pathological proulcerogenic effect. Time-dependent effects of single injection of dexamethasone on stress-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in fasted rats. Dexamethasone injected at the same dose attenuated or aggravated the stress-induced gastric erosions depending on the time of the injection.

From gastroprotective to proulcerogenic action of glucocorticoids on the gastric mucosa.

Glucocorticoids may have dual action on the gastric mucosa: physiological gastroprotective and pathological proulcerogenic one. In the present study we investigated how gastroprotective action of glucocorticoids can be transformed to proulcerogenic effect. Dose- and time-dependent effects of single injection of dexamethasone on cold-restraint-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in fasted rats.

[Effect of dexamethasone on indomethacin-induced gastric erosion formation upon duration of the hormonal action].

The aim of the study was to verify a dependence of dexamethasone effect on the gastric erosion formation upon duration of the hormonal action. Gastric erosions were induced by indometha cin (35 mg/kg, sc) in male rats after 24-hour fasting. The rats were given a single injection of dexamethasone at a dose of 1 mg/kg and they underwent the ulcerogenic stimulus (indomethacin) at va rious time points after the hormonal injection (1, 6, 12, 18, 24 hours as well as 3, 5, 7 days).

The effects of desensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach in rats depend on the blood glucocorticoid hormone level.

The effects of densensitization of capsaicin-sensitive afferent neurons on the microcirculation in the stomach were studied before and after administration of indomethacin at an ulcerogenic dose in adrenalectomized rats receiving and not receiving replacement therapy with corticosterone and in sham-operated animals. Measures of the microcirculation consisted of blood flow rates in microvessels in the submucous layer of the stomach and the diameter and permeability of microvessels in the mucosa. Desensitization of capsaicin-sensitive afferent neurons was performed by administration of capsaicin at a dose of 100 mg/kg for two weeks and adrenalectomy one week before the experiment.

Dual action of glucocorticoid hormones on the gastric mucosa: how the gastroprotective action can be transformed to the ulcerogenic one.

Glucocorticoid hormones have dual action on the stomach: gastroprotective and ulcerogenic one. The present study was designed to investigate how physiological gastroprotective action of glucocorticoids can be transformed to pathological ulcerogenic effect. Dose- and time-dependent effects of single injection of dexamethasone on indomethacin-induced gastric erosions, corticosterone and blood glucose levels, somatic parameters were investigated in rats.

[Effects of desensitization of capsaicin-sensitive afferent neurons on gastric microcirculation in rats depend on the blood glucocorticoid hormone level].

The effects of desensitization of capsaicin-sensitive afferent neurons on gastric microcirculation were investigated before and after administration of indomethacin at ulcerogenic dose in adrenalectomized rats with or without corticosterone replacement and in sham-operated animals. We estimated the blood flow velocity in submucosal microvessels; the diameters and permeability of mucosal venous microvessels as parameters of gastric microcirculation. Desensitization of capsaicin-sensitive neurons was performed with capsaicin at the dose 100 mg/kg two weeks before the experiment.

[Compensatory gastroprotective role of glucocorticoid hormones].

Prostaglandings (PGs), nitric oxide (NO) and capsaicin-sensitive afferent neurons play a pivotal role in the defensive mechanisms against gastric mucosal injury. Glucocorticoid hormones released in response to ulcerogenic stimuli are naturally occurring gastroprotective factors and exert many of the same actions in the stomach as PGs, NO and capsaicin-sensitive afferent neurons. The results reviewed suggest that glucocorticoids exert a pivotal compensatory role in the maintenance of gastric mucosal integrity in the case of impaired gastroprotective mechanisms provided by PGs, NO and capsaicin-sensitive afferent neurons.

Compensatory gastroprotective role of glucocorticoid hormones during inhibition of prostaglandin and nitric oxide production and desensitization of capsaicin-sensitive sensory neurons.

Glucocorticoid hormones produced in response to various ulcerogenic stimuli contribute to the maintenance of the gastric mucosal integrity. The role of glucocorticoids in gastroprotection becomes especially important where there is deficiency of prostaglandins (PGs) or nitric oxide (NO) or desensitization of capsaicin-sensitive sensory neurons (CSN). It has been found that neither inhibition of PG or NO production nor desensitization of CSN by itself provokes damage in the gastric mucosa of rats with normal corticosterone levels.

Gastroprotective role of glucocorticoid hormones.

Gastric ulcer disease remains widespread; a stressful lifestyle and nonsteroidal antiinflammatory drugs (NSAIDs) make significant contributions to this pathological situation. The findings overviewed here support the idea that glucocorticoid hormones released in response to acute stress or NSAIDs act as gastroprotective substances and exert many of the same actions in the stomach as prostaglandins (PGs) and nitric oxide (NO) as well as capsaicin-sensitive afferent neurons. Glucocorticoids exert a gastroprotective effect by both maintaining local defensive factors (mucosal blood flow and mucus production) and inhibiting pathogenic elements (gastric motility and microvascular permeability).

[The effects of desensitization of capsaicin-sensitive neurons on the blood flow in microvessels of the rat gastric serous muscular membrane with normal and insufficient contents of glucocorticoids].

The effects of desensitization of capsaicin-sensitive neurons on the blood flow velocity in microvessels of the gastric muscular membrane were investigated before and after indomethacin (35 mg/kg) administration in adrenalectomized rats with or without corticosterone replacement (4 mg/kg sc) and in sham-operated animals. Desensitization of capsaicin-sensitive neurons was performed with neurotoxic dose of capsaicin (20 + 30 + 50 mg/kg sc) two weeks before the experiment. Adrenalectomy was created one week before the experiment.

[Compensatory gastroprotective action of glucocorticoid hormones in the rats with ablation of capsaicin-sensitive neurons].

We tested the hypothesis that contribution of glucocorticoids in gastroprotection become especially important during ablation of capsaicin-sensitive neurons. For this, the effect of desensitization of capsaicin-sensitive neurons on the gastric mucosa was compared in groups of rats with different glucocorticoid supply: sham-operated and adrenalectomized without and with corticosterone replacement (4 mg/kg sc). Functional ablation of capsaicin-sensitive neurons was performed with neurotoxic doses of capsaicin (20 + 30 + 50 mg/kg sc).

Gastric microcirculation as target of gastroprotective action of glucocorticoid hormones in rats with desensitization of capsaicin-sensitive sensory neurons.

The study was designed to investigate whether gastric microcirculation is involved in mechanisms of gastroprotective action of glucocorticoids during desensitization of capsaicin-sensitive sensory neurons (CSN). The effects of desensitization of CSN on gastric microcirculation and gastric erosions after indomethacin administration (35 mg/kg) were compared in sham-operated rats and adrenalectomized animals without and with corticosterone replacement (4 mg/ kg s.c.

Hypothalamic-pituitary-adrenocortical axis: the hidden gold in gastric mucosal homeostasis.

The results overviewed in the present article suggest that glucocorticoids released during acute activation of hypothalamic-pituitary-adrenocortical (HPA) axis are important gastroprotective factors, allowing us to re-evaluate the traditional point of view about their ulcerogenic role. It has been shown that various ulcerogenic stimuli induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist against a harmful action of ulcerogenic stimuli. Glucocorticoids released in response to mild stress contribute to adaptive gastric cytoprotection.

Gastroprotective action of glucocorticoid hormones during NSAID treatment.

In this article we present an overview of the results of our studies suggesting that endogenous glucocorticoid hormones play a role as natural defensive factors in maintaining the integrity of the gastric mucosa during treatment with non-steroidal anti-inflammatory drugs (NSAIDs). In-domethacin and aspirin at ulcerogenic doses induce a rise in corticosterone, which helps the gastric mucosa to resist the harmful actions of these ulcerogenic agents. The gastroprotective action of glucocorticoids during NSAID treatment may be mediated by multiple actions, including maintenance of glucose homeostasis, mucus production and attenuation of enhanced gastric motility and microvascular permeability.

Mechanisms underlying the gastroprotective action of glucocorticoids released in response to ulcerogenic stress factors.

Our previous results demonstrate the gastroprotective but not ulcerogenic action of glucocorticoids released in response to ulcerogenic stress factors. The present study was undertaken to investigate the possible mechanisms underlying the gastroprotective action of glucocorticoids in rat stomachs. The effects of deficiency of glucocorticoid production, with or without corticosterone supplementation, on blood flow velocity in gastric microvessels, microvascular permeability, mucus production, motility as well as gastric lesions were studied 3 to 4 h after the onset of ulcerogenic stimuli: water-restraint stress or indomethacin administration.

Effect of adrenalectomy on healing of indomethacin-induced gastric erosions in rats.

We studied the effects of adrenalectomy and replacement therapy on healing of gastric erosions in adult Sprague-Dawley rats developed 4 h after subcutaneous injection of indomethacin in a dose of 25 or 35 mg/kg. Adrenalectomy was performed 1 week before or 4 h after indomethacin administration. Healing was evaluated by changes in the area of erosions over 24 h after indomethacin administration at fixed time intervals.