11beta-Hydroxysteroid dehydrogenase 1 (11HSD1) regulates local glucocorticoid activity and plays an important role in various diseases. Here, we studied whether arthritis modulates 11HSD1, what is the role of pro-inflammatory cytokines in this process and whether altered local metabolism of glucocorticoids may contribute to the feedback regulation of inflammation. Adjuvant arthritis increased synovial 11HSD1 mRNA and 11-reductase activity but treatments with tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) antagonists etanercept and anakinra reduced 11HSD1 upregulation. Treatment with carbenoxolone, an 11HSD inhibitor, increased expression of TNF-alpha, cyclooxygenase 2, and osteopontin mRNA without any changes in the plasma levels of corticosterone. Similar changes were observed when arthritic rats were treated with RU486, an antagonist of GR. This study suggests that arthritis upregulates synovial 11HSD1, this upregulation is controlled by TNF-alpha and IL-1beta and that the increased supply of local corticosterone might contribute to feedback regulation of inflammation.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasy genetika   metabolismus   MeSH
• antagonisté hormonů farmakologie   MeSH
• artritida experimentální genetika   metabolismus   MeSH
• cytokiny metabolismus   MeSH
• glukokortikoidy metabolismus   MeSH
• izoenzymy genetika   metabolismus   MeSH
• karbenoxolon farmakologie   MeSH
• krysa rodu Rattus MeSH
• kultivované buňky MeSH
• lidé MeSH
• messenger RNA metabolismus   MeSH
• mifepriston farmakologie   MeSH
• potkani inbrední LEW MeSH
• protivředové látky farmakologie   MeSH
• synoviální membrána cytologie   účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• antagonisté hormonů MeSH
• cytokiny MeSH
• glukokortikoidy MeSH
• izoenzymy MeSH
• karbenoxolon MeSH
• messenger RNA MeSH
• mifepriston MeSH
• protivředové látky MeSH

AIMS: The purpose of this study was to demonstrate the accumulation and distribution of lipids in the liver of the adult Prague hereditary hypertriglyceridemic (HHTg) rats. They reveal an increased expression of 11beta-hydroxysteroid dehydrogenase 1 (11HSD1), which locally increases concentration of corticosterone in the liver. We studied the effect of the 11HSD1 inhibition on the lipid content. METHODS: Samples of liver of three groups of adult female rats--HHTg, HHTg treated for 14 days with 50 mg/kg/day carbenoxolone (HHTg+CBX) and control Wistar rats, were examined histochemically. Cryosections of the samples were stained with Oil red O or Sudan black B to demonstrate different kinds of lipids. Extent and intensity of staining was evaluated semiquantitatively. RESULTS: The orientational analysis showed a higher extent and intensity of the staining of the liver of HHTg and HHTg+CBX rats (equal in both hypertriglyceridemic groups) than that of the control Wistar rats. Oil red O stained unsaturated fatty acids and neutral fats, mainly triglycerides. The difference was on average 30 per cent. Staining of phospholipids with Sudan black B showed similarly the higher positivity in the hypertriglyceridemic groups than in controls. CONCLUSIONS: Staining for triglycerides and phospholipids demonstrated a higher amount of lipids in the liver of HHTg and HHTg+CBX female rats than in controls. The inhibition of 11HSD1 activity had no effect on the lipid content in the liver of the HHTg rats.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 antagonisté a inhibitory   metabolismus   MeSH
• histocytochemie MeSH
• hypertriglyceridemie genetika   metabolismus   MeSH
• játra metabolismus   MeSH
• karbenoxolon farmakologie   MeSH
• krysa rodu Rattus MeSH
• metabolismus lipidů * účinky léků   MeSH
• potkani Wistar MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• karbenoxolon MeSH

Recent in vitro studies have shown the involvement of pro-inflammatory cytokines in the regulation of the local metabolism of glucocorticoids via 11beta-hydroxysteroid dehydrogenase type 1 and type 2 (11HSD1 and 11HSD2). However, direct in vivo evidence for a relationship among the local metabolism of glucocorticoids, inflammation and steroid enzymes is still lacking. We have therefore examined the changes in the local metabolism of glucocorticoids during colonic inflammation induced by TNBS and the consequences of corticosterone metabolism inhibition by carbenoxolone on 11HSD1, 11HSD2, cyclooxygenase 2 (COX-2), mucin 2 (MUC-2), tumor necrosis factor alpha (TNF-alpha), and interleukin 1beta (IL-1beta). The metabolism of glucocorticoids was measured in tissue slices in vitro and their 11HSD1, 11HSD2, COX-2, MUC-2, TNF-alpha, and IL-1beta mRNA abundances by quantitative reverse transcription-polymerase chain reaction. Colitis produced an up-regulation of colonic 11HSD1 and down-regulation of 11HSD2 in a dose-dependent manner, and these changes resulted in a decreased capacity of the inflamed tissue to inactivate tissue corticosterone. Similarly, 11HSD1 transcript was increased in colonic intraepithelial lymphocytes of TNBS-treated rats. Topical intracolonic application of carbenoxolone stimulated 11HSD1 mRNA and partially inhibited 11HSD2 mRNA and tissue corticosterone inactivation and these changes were blocked by RU-486. The administration of budesonide mimicked the effect of carbenoxolone. In contrast to the local metabolism of glucocorticoids, carbenoxolone neither potentiates nor diminishes gene expression for COX-2, TNF-alpha, and IL-1beta, despite the fact that budesonide down-regulated all of them. These data indicate that inflammation is associated with the down-regulation of tissue glucocorticoid catabolism. However, these changes in the local metabolism of glucocorticoids do not modulate the expression of COX-2, TNF-alpha, and IL-1beta in inflamed tissue.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 1 genetika   metabolismus   MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 genetika   metabolismus   MeSH
• antagonisté hormonů farmakologie   MeSH
• budesonid farmakologie   MeSH
• cyklooxygenasa 2 genetika   metabolismus   MeSH
• glukokortikoidy antagonisté a inhibitory   metabolismus   farmakologie   MeSH
• interleukin-1beta genetika   metabolismus   MeSH
• karbenoxolon farmakologie   MeSH
• kolitida chemicky indukované   metabolismus   MeSH
• kolon účinky léků   enzymologie   metabolismus   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA metabolismus   MeSH
• mifepriston farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• mucin 2 MeSH
• muciny genetika   metabolismus   MeSH
• peroxidasa metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• potkani Wistar MeSH
• TNF-alfa genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 1 MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• antagonisté hormonů MeSH
• budesonid MeSH
• cyklooxygenasa 2 MeSH
• glukokortikoidy MeSH
• interleukin-1beta MeSH
• karbenoxolon MeSH
• kortikosteron MeSH
• kyselina trinitrobenzensulfonová MeSH
• messenger RNA MeSH
• mifepriston MeSH
• Muc2 protein, rat MeSH Prohlížeč
• mucin 2 MeSH
• muciny MeSH
• peroxidasa MeSH
• Ptgs2 protein, rat MeSH Prohlížeč
• TNF-alfa MeSH

Although rat is the most widely used model of glucocorticoid programming of the fetus, the role of rat placental 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) in the transplacental pharmacokinetics of the naturally occurring glucocorticoid, corticosterone, has not yet been fully elucidated. In this study, expression of 11beta-HSD2 in the rat placenta on two different gestation days (16 and 22) was examined using quantitative RT-PCR and Western blotting, and dually perfused rat term placenta was employed to evaluate its functional capacity to transfer and metabolize corticosterone. Marked decrease in placental expression of 11beta-HSD2 toward term was observed on both mRNA and protein levels. In perfusion studies, increasing maternal corticosterone concentration from 3 to 200 nM resulted in the fall of 11beta-HSD2 conversion capacity from 64.3 to 16.3%, respectively. Enzyme saturation occurred at about 50 nM substrate concentration. When delivering corticosterone (3 or 100 nM) from the fetal side, a similar decline of 11beta-HSD2 conversion capacity was observed (66.5% and 48.5%, respectively). Addition of carbenoxolone (10 or 100 microM), a non-specific 11beta-HSD inhibitor, to maternal perfusate decreased conversion capacity from 66.7 to 12.6 or 8.1%, respectively. Similarly potent inhibitory effect was observed in feto-maternal studies. Neither saturation nor inhibition of 11beta-HSD2 was associated with transformation of corticosterone in metabolites other than 11-dehydrocorticosterone. These data suggest that 11beta-HSD2 is the principal enzyme controlling transplacental passage of corticosterone in rats and is able to eliminate corticosterone in both maternal and fetal circulations.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasa typ 2 antagonisté a inhibitory   genetika   metabolismus   MeSH
• biologický transport MeSH
• karbenoxolon farmakologie   MeSH
• kortikosteron metabolismus   MeSH
• krysa rodu Rattus MeSH
• perfuze MeSH
• placenta enzymologie   metabolismus   fyziologie   MeSH
• techniky in vitro MeSH
• těhotenství metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství metabolismus   MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasa typ 2 MeSH
• karbenoxolon MeSH
• kortikosteron MeSH

The rat undergoes profound maturational changes in the intestinal structure and function during the third week of its life. To investigate the role of peripheral glucocorticoid metabolism in this process, we studied the postnatal maturation of intestinal structure and function. The peripheral metabolism of glucocorticoids depends on enzyme 11beta-hydroxysteroid dehydrogenase (11betaHSD), which is responsible for the interconversion of corticosterone to 11-dehydrocorticosterone and thus for the modulation of glucocorticoid access to corticosteroid receptors. The pups were treated with carbenoxolone (CBX), an inhibitor of 11betaHSD, for 10 d during the suckling (days 8-18) or weaning period (days 14-24 or days 20-30), and we determined the parameters of intestinal growth and activities of sucrase, alkaline phosphatase, and Na,K-ATPase. The CBX treatment increased plasma concentrations of corticosterone as a result of a significant reduction of peripheral degradation of corticosterone catalyzed by 11betaHSD. This also stimulated intestinal growth without changing somatic growth. The mucosal cell mass was significantly higher in CBX-treated suckling rats, whereas the effect of this treatment was less obvious in weanling animals. CBX increased the crypt depth and villus height in 18- and 24-d-old pups but not in 30-d-old animals. The small intestinal activities of sucrase, alkaline phosphatase, and Na,K-ATPase were not influenced by CBX. In contrast, colonic Na,K-ATPase was stimulated by CBX. We conclude that the administration of CBX results in acceleration of intestinal growth and structural maturation without any influence on the developmental pattern of brush-border hydrolases. The results indicate an important role of peripheral glucocorticoid metabolism in the regulation of intestinal growth during early postnatal life.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasy antagonisté a inhibitory   MeSH
• inhibitory enzymů farmakologie   MeSH
• karbenoxolon farmakologie   MeSH
• kortikosteron krev   MeSH
• krysa rodu Rattus MeSH
• novorozená zvířata MeSH
• protivředové látky farmakologie   MeSH
• střeva účinky léků   enzymologie   růst a vývoj   MeSH
• střevní sliznice účinky léků   enzymologie   růst a vývoj   MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• inhibitory enzymů MeSH
• karbenoxolon MeSH
• kortikosteron MeSH
• protivředové látky MeSH

Glucocorticoids promote the development of many organs including intestine. At the cellular level, the activity of glucocorticoids is regulated by 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) which converts active glucocorticoids to inactive metabolites. As 11 beta HSD is also expressed in the intestine, this enzyme may be an important regulator of intestinal maturation. To investigate this, we have performed the systematic study of the development of intestinal 11 beta HSD activity and its cofactor preference as well as of the effect of 11 beta HSD inhibition by carbenoxolone on postnatal development of sucrase, alkaline phosphatase and Na,K-ATPase in the intestine. The activity of 11 beta HSD was low in ileum of suckling rats and significantly increased during the weaning period. In colon, the activity was already high in suckling rats and gradually rose during the postnatal development. 11 beta HSD activity was undetectable in jejunum both in young and adult rats. At 14.5 nM corticosterone, colonic 11 beta HSD utilized predominantly NAD as a cofactor, but displayed significant sensitivity also to NADP. Ileal 11 beta HSD had similar sensitivity to both cofactors. With NAD as a cofactor, ileal 11 beta HSD had a Km (59 +/- 10 nM) compatible with the colonic enzyme (81 +/- 14 nM). Carbenoxolone administration to suckling and weanling rats in vivo did not result in any changes of sucrase activity in jejunum and ileum, alkaline phosphatase activity in ileum and distal colon or Na,K-ATPase activity in ileum. However, carbenoxolone significantly increased Na,K-ATPase activity in distal colon. Our results indicate that the high-affinity type of 11 beta HSD is expressed not only in colon but also in ileum and that 11 beta HSD is an important factor in the regulation of tissue levels of active glucocorticoids in developing colon but not in the small intestine.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• alkalická fosfatasa metabolismus   MeSH
• hydroxysteroiddehydrogenasy antagonisté a inhibitory   fyziologie   MeSH
• inhibitory enzymů farmakologie   MeSH
• karbenoxolon farmakologie   MeSH
• krysa rodu Rattus MeSH
• odstavení MeSH
• potkani Wistar MeSH
• sacharasa metabolismus   MeSH
• sodíko-draslíková ATPasa metabolismus   MeSH
• střeva enzymologie   růst a vývoj   MeSH
• střevní sliznice enzymologie   růst a vývoj   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• alkalická fosfatasa MeSH
• hydroxysteroiddehydrogenasy MeSH
• inhibitory enzymů MeSH
• karbenoxolon MeSH
• sacharasa MeSH
• sodíko-draslíková ATPasa MeSH

Aldosterone selectivity of mineralocorticoid target tissues has been suggested to be due to the inactivation of glucocorticoids in the target tissue by 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD). The distribution of 11 beta-OHSD was studied in the intestine which is composed of aldosterone-sensitive and insensitive segments. The activity of the enzyme was high in distal colon and medium in ileum, cecum, and proximal colon. Zero activity was found in duodenum and jejunum. Carbenoxolone completely blocked the enzyme. Low-salt diet increased the activity in proximal colon and decreased in ileum. Adrenalectomy decreased the activity in ileum and proximal colon. The existence of segmental differences in the distribution of 11 beta-OHSD and the hormonal effect on the activity of the enzyme suggest a physiological role of 11 beta-OHSD in the intestine.

• MeSH
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• adrenalektomie MeSH
• aldosteron metabolismus   MeSH
• cékum enzymologie   MeSH
• duodenum enzymologie   MeSH
• hydroxysteroiddehydrogenasy analýza   antagonisté a inhibitory   metabolismus   MeSH
• jejunum enzymologie   MeSH
• karbenoxolon farmakologie   MeSH
• kolon enzymologie   MeSH
• kortikosteron analogy a deriváty   biosyntéza   metabolismus   MeSH
• krysa rodu Rattus MeSH
• potkani Wistar MeSH
• receptory mineralokortikoidů analýza   metabolismus   MeSH
• sodík metabolismus   MeSH
• střeva enzymologie   MeSH
• střevní sliznice enzymologie   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 11-beta-hydroxysteroiddehydrogenasy MeSH
• 11-dehydrocorticosterone MeSH Prohlížeč
• aldosteron MeSH
• hydroxysteroiddehydrogenasy MeSH
• karbenoxolon MeSH
• kortikosteron MeSH
• receptory mineralokortikoidů MeSH
• sodík MeSH

The potential involvement of increased mucus secretion in the antiulcer activity of a cytoprotective agent, pentacaine, and of the H2-antagonist ranitidine was studied in stressed rats. Cold-restraint stress decreased the gastric mucus content and induced haemorrhagic erosions in the stomach. Pretreatment with pentacaine and ranitidine dose-dependently diminished the extent of stress-induced gastric damage. Pentacaine prevented the depletion of mucus after stress, while ranitidine failed to affect it. In non-stressed rats only pentacaine was able to enhance mucus secretion. The stimulating effect of pentacaine on gastric mucus secretion may account for some of its antiulcer properties.

• MeSH
• fyzické omezení MeSH
• fyziologický stres etiologie   patologie   MeSH
• inbrední kmeny potkanů MeSH
• karbamáty farmakologie   terapeutické užití   MeSH
• karbenoxolon farmakologie   MeSH
• krysa rodu Rattus MeSH
• nízká teplota MeSH
• ranitidin farmakologie   terapeutické užití   MeSH
• žaludeční sliznice účinky léků   metabolismus   patologie   MeSH
• žaludeční vředy etiologie   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• karbamáty MeSH
• karbenoxolon MeSH
• pentacaine MeSH Prohlížeč
• ranitidin MeSH

Histological and histochemical patterns of the gastric and duodenal mucosa was investigated in nine subjects with duodenal ulcer or ulcerlike syndrome after 4 to 5 weeks treatment with cimetidine or carbenoxolone. No spectacular changes were found after carbenoxolone except for a slight increase in goblet cells in the duodenal bulb. In the patients treated with cimetidine, findings suggesting an influence of this drug on the biochemical cytology of parietal cells and some interference in the differentiation of enterocytes were established.

• MeSH
• cimetidin terapeutické užití   MeSH
• dospělí MeSH
• duodenum metabolismus   MeSH
• dvanáctníkové vředy farmakoterapie   MeSH
• karbenoxolon terapeutické užití   MeSH
• kyselina glycyrhetinová analogy a deriváty   MeSH
• lidé MeSH
• střevní sliznice metabolismus   MeSH
• žaludeční sliznice metabolismus   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cimetidin MeSH
• karbenoxolon MeSH
• kyselina glycyrhetinová MeSH

• MeSH
• benzodiazepinony terapeutické užití   MeSH
• cimetidin terapeutické užití   MeSH
• dospělí MeSH
• karbenoxolon terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptický vřed farmakoterapie   MeSH
• pirenzepin MeSH
• protivředové látky terapeutické užití   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• benzodiazepinony MeSH
• cimetidin MeSH
• karbenoxolon MeSH
• pirenzepin MeSH
• protivředové látky MeSH