Gastroprotective role of glucocorticoids during NSAID-induced gastropathy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) make significant contributions to gastric ulcer disease which remains widespread. Although several factors have been postulated as pathogenic elements of the gastric injury induced by NSAIDs, it is, however believed that prostaglandin deficiency plays a critical role in the pathogenesis of this injury. During prostaglandin deficiency, other defensive mechanisms might operate to attenuate NSAID-induced gastropathy. According to our results, NSAIDs, similar to stress, induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist the harmful actions of these drugs. In this article, we review our experimental data suggesting that glucocorticoids may play a role as natural defensive factors in maintaining the integrity of the gastric mucosa during NSAID therapy and might operate to attenuate NSAID-induced gastropathy.

[Contribution of glucocorticoid hormones to gastroprotective effect of ischemic preconditioning in rats with normal and deficient prostaglandin production].

The study was designed to investigate whether glucocorticoid hormones participate in gastroprotective effects of ischemic preconditioning in rats with normal and deficient prostaglandin production. To estimate the role of glucocorticoids adrenalectomy followed by appropriate corticosterone replacement and inhibition of corticosterone synthesis by metyrapone were used. Prostaglandin synthesis was inhibited by indomethacin. In control rats gastric ischemic preconditioning (a 0.5 h ischemia-reperfusion) induced plasma corticosterone rise and attenuated gastric injury caused by 3.5 h ischemia-reperfusion. The gastroprotective effect of ischemic preconditioning was prevented by adrenalectomy as well as metyrapone pretreatment in both groups, in the rats with normal and deficient prostaglandin production. Acute corticosterone replacement to adrenalectomized rats during ischemic preconditioning restored the protective effect of ischemic preconditioning on the gastric mucosa even in the rats with inhibited prostaglandin synthesis. Thus, the glucocorticoid hormones were shown to contribute to gastroprotective effect of ischemic preconditioning in the rats with normal and deficient prostaglandin production.

Hormonal influences of early postnatal indomethacin and ibuprofen in neonatal rats.

OBJECTIVE: Indomethacin and ibuprofen are administered to preterm neonates for symptomatic patent ductus arteriosus. The drugs suppress prostaglandins (PGs) which modulate growth and secretion of various hormones. We examined the hypothesis that early postnatal indomethacin and ibuprofen influence growth and GH-IGF-I-insulin and HPA axes in neonatal rats. DESIGN: Rat pups received IP injections of saline (Sal) on P1, P2, and P3; 10mg/kg ibuprofen on P1 followed by 5mg/kg on P2 and P3; or 0.2mg/kg indomethacin on P1 followed by 0.1mg/kg on P2 and P3. Serum and hepatic GH, GHBP and IGF-I; and serum corticosterone and insulin levels were determined. RESULTS: Ibuprofen suppressed somatic growth in the sucking rats, but the effect was transient, resolving by P14. Indomethacin had an opposite, latent effect on body weight and liver to body weight ratios in weanling rats. Both indomethacin and ibuprofen had profound hormonal effects that differed in magnitude and timing. Indomethacin resulted in a sustained elevation in corticosterone levels at P21, while ibuprofen increased serum and hepatic GH levels. Both drugs suppressed GHBP in serum at P7 and P14; and liver at P4 and P7, but a rebound increase in serum GHBP was noted at P21 with Ibuprofen only. Both drugs increased serum IGF-I at P7. The effect remained sustained with indomethacin. CONCLUSIONS: These results provide evidence for an involvement of PGs in the regulation of growth as well as the GH-IGF and HPA axes. Therefore, early postnatal exposure to PG inhibitors may further exacerbate postnatal growth restriction and ability to cope with stress.

[Gastroprotective role of glucocorticoid hormones during action of nonsteroidal anti-inflammatory drugs].

The ulcerogenic gastrointestinal side-effects of nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the more serious complications in patients taking these drugs. It is known that prostaglandin (PG) deficiency plays a critical role in the pathogenesis of NSAID-induced gastric injury. The results presented in the article suggest that NSAIDs at ulcerogenic doses induce an increase in glucocorticoid production, which in turn helps the gastric mucosa to resist the harmful action of NSAID treatment. The gastroprotective action of glucocorticoids during NSAID treatment may be provided by their maintenance of glucose homeostasis, gastric blood flow and mucus secretion and their attenuation of enhanced gastric motility and microvascular permeability. We conclude that glucocorticoids produced in response to NSAIDs are natural defensive factors in maintaining the gastric mucosa integrity during PG deficiency caused by NSAIDs.

[Non-steroidal anti-inflammatory drugs and intestinal side effects]. / Niesteroidowe leki przeciwzapalne a powiklania jelitowe.

Non-steroidal anti-inflammatory drugs (NSAID), including acetylsalicylic acid, are the most commonly applied in the world, however at the same time they constitute a risk factor for gastrointestinal complications. The main mechanism of action of NSAID is based on reducing the synthesis of prostaglandins by means of inhibiting the activity of cyclooxygenase (COX), namely, of COX-1, which generates gut protective prostaglandins, and COX-2, induced at the sites of inflammation, tissue lesions and certain neoplasm. Complications caused by NSAID within the upper gut are subject to numerous studies; however those affecting the intestines are considerably less known. The complications accompanying the use of NSAID may include intestinal strictures, enteropathy with anemia and the loss of protein, macroscopically inflammatory changes as erosions and ulceration, aggravated diverticulosis, and recurrences of ulcerative colitis. During treatment with NSAID the incidence of changes within the intestine is comparable to that within the upper gut. The incidence and character of complications concerning the small and large intestines are still under investigation. Frequently, post-NSAID intestinal changes may not present any clinical signs; it is only a serious complication (haemorrhage, perforation) that becomes the first symptom. Introducing selective COX-2 inhibitors into the treatment has significantly reduced the complications within both upper and lower digestive tract; however, the knowledge of the security profile for these preparations is not yet complete.

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. However, each of these treatments results in mucosal damage in adrenalectomized rats; this effect being prevented by corticosterone replacement. Indomethacin-induced gastric erosions are potentiated to similar degrees by adrenalectomy, inhibition of NO production or desensitization of CSN. The potentiation caused by inhibition of NO production or CSN desensitization is further enhanced by concomitant glucocorticoid deficiency. These results suggest a pivotal compensatory role of glucocorticoids in the maintenance of the gastric mucosal integrity under the adverse conditions where the gastroprotective mechanisms provided by PGs, NO and capsaicin-sensitive sensory neurons are impaired.

Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.

BACKGROUND: Most epidemiological studies evaluating the association between nonsteroidal anti-inflammatory drugs (NSAIDs) and acute renal failure (ARF) found an increased risk for developing ARF while taking NSAIDs. Despite these studies, little is known about the effect of dose and duration of therapy, risk of individual NSAIDs, comorbidity, or concomitant use of other nephrotoxic drugs. METHODS: This is a nested case-control study using the General Practice Research Database from the United Kingdom. Participants were 386,916 patients aged 50 to 84 years on January 1, 1997, and free of known cancer, renal disorder, cirrhosis, or systemic connective tissue disease. After validation of cases identified from this cohort, 103 patients were confirmed as idiopathic cases of ARF and compared with 5,000 controls frequency matched by age and sex. RESULTS: Current users of NSAIDs had a relative risk (RR) for ARF of 3.2 (95% confidence interval [CI], 1.8 to 5.8), and the risk declined after treatment was discontinued. Increased risk was present with both short- and long-term therapy and was slightly greater among users of high doses. History of heart failure (HF), hypertension, diabetes, and hospitalizations and consultant visits in the previous year were all associated with a greater risk for ARF. There was a suggestion of a modification of the effect of NSAIDs in patients with hypertension and those with HF. Use of selected cardiovascular drugs was associated with a 5-fold increase in risk for ARF. Diuretics presented the greatest risk. Risk increased with concomitant use of NSAIDs and diuretics (RR, 11.6; 95% CI, 4.2 to 32.2) and NSAIDs and calcium channel blockers (RR, 7.8; 95% CI, 3.0 to 20.5). CONCLUSION: NSAID users had a 3-fold greater risk for developing a first-ever diagnosis of clinical ARF compared with non-NSAID users in the general population. NSAIDs should be used with special caution in patients with hypertension and/or HF.

Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2-derived prostaglandins.

There is concern that cyclooxygenase (COX)-2 inhibitors may promote atherothrombosis by inhibiting vascular formation of prostacyclin (PGI2) and an increased thrombotic risk of COX-2 inhibitors has been reported. It is widely accepted that the prothrombotic effects of COX-2 inhibitors can be explained by the removal of platelet-inhibitory PGI2. Using microarray chip technology, we have previously demonstrated that thrombomodulin (TM) mRNA is upregulated in cultured human coronary artery smooth muscle cells by the stable prostacyclin mimetic iloprost. This study is the first to demonstrate a stimulation of the expression of functionally active thrombomodulin in human smooth muscle cells by prostaglandins, endogenously formed via the COX-2 pathway. Because TM is an important inhibitor of blood coagulation, these findings provide a novel platelet-independent mechanism to explain the prothrombotic effects of COX-2 inhibitors. The full text of this article is available online at http://circres.ahajournals.org.

Immature rats show ovulatory defects similar to those in adult rats lacking prostaglandin and progesterone actions.

Gonadotropin-primed immature rats (GPIR) constitute a widely used model for the study of ovulation. Although the equivalence between the ovulatory process in immature and adult rats is generally assumed, the morphological and functional characteristics of ovulation in immature rats have been scarcely considered. We describe herein the morphological aspects of the ovulatory process in GPIR and their response to classical ovulation inhibitors, such as the inhibitor of prostaglandin (PG) synthesis indomethacin (INDO) and a progesterone (P) receptor (PR) antagonist (RU486). Immature Wistar rats were primed with equine chorionic gonadotropin (eCG) at 21, 23 or 25 days of age, injected with human chorionic gonadotropin (hCG) 48 h later, and sacrificed 16 h after hCG treatment, to assess follicle rupture and ovulation. Surprisingly, GPIR showed age-related ovulatory defects close similar to those in adult rats lacking P and PG actions. Rats primed with eCG at 21 or 23 days of age showed abnormally ruptured corpora lutea in which the cumulus-oocyte complex (COC) was trapped or had been released to the ovarian interstitum, invading the ovarian stroma and blood and lymphatic vessels. Supplementation of immature rats with exogenous P and/or PG of the E series did not significantly inhibit abnormal follicle rupture. Otherwise, ovulatory defects were practically absent in rats primed with eCG at 25 days of age. GPIR treated with INDO showed the same ovulatory alterations than vehicle-treated ones, although affecting to a higher proportion of follicles. Blocking P actions with RU486 increased the number of COC trapped inside corpora lutea and decreased ovulation. The presence of ovulatory defects in GPIR, suggests that the capacity of the immature ovary to undergo the coordinate changes leading to effective ovulation is not fully established in Wistar rats primed with eCG before 25 days of age.

Mechanisms involved in the attenuation of intestinal toxicity induced by (S)-(+)-ketoprofen in re-fed rats.

In addition to suppression of prostaglandins synthesis a number of factors have been implicated in nonsteroidal antiinflammatory drugs (NSAIDs) enteropathy, including oxygen radical-dependent microvascular injuries, depletion of glutathione, and food. Inflammatory cytokines such as tumor necrosis factor-alpha regulate endothelial adhesion molecules expression and promote vascular neutrophil adherence. Racemic ketoprofen is a potent NSAID with a chiral structure existing in two enantiomeric forms. Its therapeutic effects reside almost exclusively in the (S)-(+) isomer nevertheless the potential contribution to side effects of the (R)-(-) isomer cannot be ignored. The aims of this study were to explore the role of prostaglandins depletion, tumor necrosis factor-alpha production, and glutathione homeostasis in the comparative pathogenesis of intestinal injury induced by racemic-ketoprofen and its enantiomers in re-fed rats. Racemic ketoprofen and (R)-(-)-ketoprofen dose-dependently caused similar and multiple lesions in the mid-jejunum significantly higher than those observed with (S)-(+)-ketoprofen. All the treatments significantly decreased prostaglandins content. A significant increase of tumor necrosis factor-alpha production and decreases in glutathione levels and glutathione reductase activity after treatment of the racemate and (R)-(-)-ketoprofen, were observed whereas the (S)-(+)-isomer did not change these parameters. In conclusion, (S)-(+)-ketoprofen possesses a better intestinal toxicity profile than the racemate and its (R)-(-)-isomer. Despite inhibiting cyclooxygenase activity, the attenuation of (S)-(+)-ketoprofen-induced intestinal toxicity could be correlated with a reduced oxidative damage characterized not only by a lack of changes in glutathione reductase activity and glutathione levels but also by an absence of up-regulation of tumor necrosis factor-alpha production in intestinal mucosa.

Gastroduodenal ulcers: causes, diagnosis, prevention and treatment.

During the past decade, new acid antisecretory drugs have been developed, and our understanding of the mechanisms of mucosal ulceration has been broadened. However, the major change has been an appreciation of the role of Helicobacter pylori in peptic ulcer disease.

Calcium-dependent low renin syndrome in a diabetic patient with prostaglandin deficiency.

Calcium and prostaglandin are supposed to play a critical role in the renin-angiotensin aldosterone system. Calcium has been described as an inhibitory second messenger for renin exocytosis whereas vasodilatory prostaglandins, such as PGE2, are known to stimulate the production of renin. These factors are probably interrelated since calcium also enhances urinary prostaglandin release. We report the case of a 52 year-old diabetic patient treated with insulin injections with intestinal malabsorption leading to chronic hyperkalemia and hypocalcemia in whom a low renin syndrome and low levels of urinary prostaglandins were observed. The correction of the hypocalcemia was able to improve plasma renin as well as urinary prostaglandin levels. This observation suggests a prominent role played by calcium on the in vivo regulation of renin and prostaglandin release. These results illustrate the closed loop between plasma calcium level, urinary prostaglandins production and renin release.

Analysis of pathogenic elements involved in gastric lesions induced by non-steroidal anti-inflammatory drugs in rats.

Pathogenesis of gastric damage induced by non-steroidal anti-inflammatory drugs (NSAID) involves multiple elements, such as deficiency of prostaglandins (PG), gastric hypermotility, neutrophil activation and luminal acid. The present study was performed to examine the effects of these elements, either alone or in combination, on the rat gastric mucosa and investigate which element is most closely associated with the gastric ulcerogenic response to NSAID. The following treatments were used to express various pathogenic elements: (i) a low dose of indomethacin (IM) to cause PG deficiency; (ii) 2-deoxy-D-glucose (2DG) to induce gastric hypermotility and acid secretion; (iii) histamine to induce acid hypersecretion; and (iv) n-formyl-Met-Leu-Phe (fMLP) to elicit neutrophil activation. When rats fasted for 18 h were subjected to each treatment alone, only 2DG caused slight macroscopic damage in the gastric mucosa within 4 h. Indomethacin showed over 90% inhibition of mucosal PG generation and fMLP increased myeloperoxidase activity four-fold greater than normal values, yet either of these treatments alone did not cause any damage in the stomach. However, the combination of IM with 2DG or His provoked severe lesions in the stomach or the duodenum, respectively, while fMLP did not modify or potentiate the mucosal ulcerogenic response to other treatments. We conclude that among various pathogenic elements only gastric hypermotility is sufficient, by itself, to induce mild damage in the mucosa, that PG deficiency may be critical in the increase of mucosal susceptibility to injury and that neutrophil activation alone is not ulcerogenic in the gastric mucosa nor does it potentiate the ulcerogenic effect of other elements. Luminal acid may be a prerequisite for later extension of damage to severe lesions.

Hipertensión arterial y prostaglandinas / High blood pressure and prostaglandins

Grandes esfuerzos investigativos se realizan en el mundo tratando de encontrar la verdadera patogenia de la hipertensión arterial. Entre las más recientes hipótesis figuran las acciones vasodilatadoras de productos humorales como los del sistema Kallcrein-quinina y las prostaglandinas. En el presente trabajo se revisan algunos de los efectos de estas sustancias, las realaciones entre ellas y la importancia que puede tener en el tratamiento de la hipertensión arterial la aplicación de drogas capaces de estimular dichos productos, entre los que se hallan los inhibidores de la enzima convertidora de la angiotensina, el ácido linoléico y el cicletanín, los cuales, al parecer, tienen un efecto estimulador terapeútico sobre prostaciclina y bradiquina, aunque se necesitamayor experencia todavía para aseverar los mecanismos de acción de estosproductos como hipotensores

Hipertensión arterial y prostaglandinas / High blood pressure and prostaglandins

Grandes esfuerzos investigativos se realizan en el mundo tratando de encontrar la verdadera patogenia de la hipertensión arterial. Entre las más recientes hipótesis figuran las acciones vasodilatadoras de productos humorales como los del sistema Kallcrein-quinina y las prostaglandinas. En el presente trabajo se revisan algunos de los efectos de estas sustancias, las realaciones entre ellas y la importancia que puede tener en el tratamiento de la hipertensión arterial la aplicación de drogas capaces de estimular dichos productos, entre los que se hallan los inhibidores de la enzima convertidora de la angiotensina, el ácido linoléico y el cicletanín, los cuales, al parecer, tienen un efecto estimulador terapeútico sobre prostaciclina y bradiquina, aunque se necesitamayor experencia todavía para aseverar los mecanismos de acción de estosproductos como hipotensores (AU)

Importance of gastric acid in gastric ulcer formation in rabbits with antibody-induced prostaglandin deficiency.

The role of gastric acid in the development of gastroduodenal ulcers in prostaglandin-deficient conditions is unclear. In the current study, the effect of the proton pump inhibitor omeprazole on the formation of gastric ulcers was examined in a previously validated rabbit model of antibody-induced prostaglandin deficiency. Intragastric administration of 20 mg/kg omeprazole every 12 hours caused a profound suppression of gastric acidity (i.e., pH above 5 continuously). This same dose of omeprazole significantly reduced gastric ulcer formation induced by passive immunization with 6-keto-prostaglandin F1 alpha antibodies. It is concluded from these observations that gastric acid plays a critical role in the formation of gastric ulcers in rabbits with antibody-induced prostaglandin deficiency.

The syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate: is there a deficiency in vasodilator prostaglandins?

1. In Gordon's syndrome (GS; a syndrome of hypertension and hyperkalaemia with normal glomerular filtration rate), excessive proximal sodium reabsorption leads to suppression of renin and aldosterone, hyperkalaemia and hyperchloraemic acidosis. 2. Low urinary levels of vasodilator prostaglandins (PG) have been reported in GS, suggesting renal hypoprostaglandinism as a pathophysiological mechanism. 3. In four cases of GS, levels of vasodilator prostaglandins PGE2 and 6-keto-PGF1 alpha were low. 4. In one case of GS, low PGE2 levels were normalized by dietary salt restriction or diuretic therapy.

Prostaglandin deficiency.

Healthy cells from virtually all tissues synthesize a variety of prostaglandins, autacoids which can significantly alter cellular functions. An absolute or relative deficiency of prostaglandins has now been demonstrated in many diseases or clinical conditions. These include 'natural' disorders such as peptic ulcer disease and diabetes mellitus. These also include 'acquired' or iatrogenic conditions such as cyclosporine nephrotoxicity and the gastropathy induced by nonsteroidal anti-inflammatory drugs. We believe that the diversity of the disorders associated with prostaglandin deficiency may be wider and of greater pathogenetic importance than is currently recognized. We propose: 1) that prostaglandin deficiency will be demonstrated in many abnormalities which are now described as of uncertain etiology; and 2) that adverse effects from many commonly prescribed drugs may also be related to an unrecognized and unfavorable alteration in prostaglandin synthesis, disposal, or activity.