Endogenous Prostaglandin Synthesis Research Articles

Geranylgeranylacetone and cetraxate hydrochloride increase UDP-galactosyltransferase activity in rat gastric mucosa.

UDP-galactosyltransferase (UDP-Gal-T) is a key enzyme in the synthesis of mucus glycoprotein which plays an important role in gastric mucosal defensive mechanisms. Analysis of gastric UDP-Gal-T activity should clarify the mechanisms of the action of antiulcer drugs regarding gastric defensive factors. Here, we examined UDP-Gal-T activity in rat gastric mucosa treated with the antiulcer drugs geranylgeranylacetone (GGA) and cetraxate hydrochloride (CET). The effects of coadministration of indomethacin and exogenous administration of prostaglandins (PGs) were also studied. GGA and CET significantly increased UDP-Gal-T activity, and coadministration of indomethacin inhibited the increase of enzyme activity. UDP-Gal-T activity level with GGA was significantly higher than the control level, even in the presence of indomethacin. With CET, however, this was not the case. Among PGs, PGE1 significantly increased enzyme activity. Concomitant administration of PGE1 and GGA or CET increased UDP-Gal-T activity even with indomethacin to the levels achieved when these antiulcer drugs were administered without indomethacin. Our findings suggest that GGA and CET exert antiulcer effects by increasing mucus glycoprotein synthesis and that endogenous PG synthesis may be involved in this process. However, mechanisms not mediated by endogenous PGs may also exist in the stimulatory action of GGA on UDP-Gal-T activity.

Effect of 50% Small Bowel Resection on Gastric Prostaglandin E 2 Levels in Rats

The mechanism for the production of increased gastric secretion following massive intestinal resection is not clearly defined. The loss of an intestinal inhibitor has been most frequently suggested to explain this hypersecretion. The role of endogenous prostaglandins which can inhibit gastric secretion is not established. The present study was undertaken to determine the effect of 50% proximal small bowel resection on Prostaglandin E 2 (PGE 2) levels in rat gastric mucosa. This study was performed in 30 rats divided into three groups. The first group of rats served as unoperated controls, the second group was sham operated and the third group underwent 50% resection of proximal small intestine. The PGE 2 levels in rat gastric mucosa was decreased significantly (p < 0.001) in the resection group (422.85 ± 7.66 pg/gm) as compared with the sham group (478.77 ± 7.25 pg/gm) and the control group (493.38 ± 4.61 pg/gm). Total gastric acidity was increased significantly (p llt 0.001) in the resection group (63.05 ± 2.64 mEq/L) as compared with the sham group (15.21 ± 0.99 mEq/L) and the control group (17.19 ± 0.80 mEq/L). The PGE 2 levels and total gastric acidity were not significantly changed in either the control or sham operation groups (p > 0.05). The results suggest that endogenous prostaglandin synthesis has a regulatory role in gastric hyperacidity after 50% proximal small bowel resection in rats.

Absorption, Retention and Urinary Excretion of Chromium-51 in Rats Pretreated with Indomethacin and Dosed with Dimethylprostaglandin E2, Misoprostol or Prostacyclin

Drug-nutrient interactions affecting chromium were investigated in this study. Rats were injected with indomethacin to reduce endogenous prostaglandin synthesis and dosed with prostaglandin analogues or prostacyclin. Effects on absorption, tissue distribution and urinary excretion of 51Cr from 51CrCl3 were evaluated using a 2 x 4 factorial experimental design. Forty-eight adult male rats were food deprived for 12 h and then injected intraperitoneally with indomethacin (5 mg/kg body wt) or placebo. Thirty minutes later, rats were intubated and dosed with one of four treatments: a prostaglandin E1 analogue (misoprostol) at 50 microg/kg body wt; a prostaglandin E2 analogue (16,16-dimethylprostaglandin E2) at 7.5 microg/kg body wt; prostacyclin at 20 microg/kg body wt; or control (7.64 mmol/L Tween-80 suspended in 0.15 mol/L NaCl containing 0.48 mol/L ethanol). Immediately after intubation, rats were dosed with 3.7 mBq of 51CrCl3 by micropipette. Blood was collected from the tail at intervals after 51Cr dosing. Six hours after dosing, 51Cr rats were exsanguinated by cardiac puncture. Indomethacin, an inhibitor of prostaglandin synthesis, significantly increased (P < 0.05) 51Cr in blood at all time periods tested except at 15 min. In tissues, indomethacin significantly increased 51Cr retention. Urinary 51Cr excretion at 6 h was higher (P < 0.05) in indomethacin-pretreated rats than in control rats. Administration of indomethacin, which blocks prostaglandin synthesis, enhanced 51Cr absorption, whereas dosing with 16,16-dimethylprostaglandin E2 decreased 51Cr absorption.

Effects of altered body fluid balance and high blood pressure on the plasma brain natriuretic peptide in rats.

The present study was aimed to investigate the regulatory mechanisms of BNP release. Effects of acute and chronic perturbations in body fluid balance, changes in BP, and regulatory roles of NO and endothelin systems on BNP release were examined in rats. Although acute extracellular volume expansion did not have significant effects on plasma BNP, prolonged high-salt intake increased plasma BNP levels. Plasma BNP levels were also higher in 2K1C rats compared with the control. Although infusion of L-NAME increased the plasma BNP in control, it did not further affect the plasma BNP in rats with high-salt intake. Although L-arginine (20 mg.kg-1 per min) per se did not have significant effects on plasma BNP, it blocked the stimulatory effect of L-NAME (200 micrograms.kg-1 per min). Plasma BNP was severalfold increased following a single injection of endothelin (0.3 micrograms/kg) in normal and high-salt intake groups, the magnitude of which was not significantly affected by the high-salt intake. Although indomethacin did not have significant effects on plasma BNP in normal rats, it blocked the stimulatory effect of 2K1C hypertension. It is concluded that BNP is regulated by chronic changes in body fluid balance and blood pressure. It is also suggested that endothelin and NO systems may directly regulate the secretion of BNP in vivo. An endogenous prostaglandin synthesis may be involved in the stimulated release of BNP in hypertension.

Prostaglandin regulation of gene expression and growth in normal and malignant tissues.

Prostaglandins bind with cell surface receptors and cause an activation of adenylate cyclase and generation of adenosine 3′5′ cyclic monophosphate (cAMP) (1,2). C-AMP is thought to play a central role in the regulation of cell growth since the growth of many types of cultured cells is arrested by adding exogenous dibutyryl adenosine 3′5′ cyclic monophosphate (dbcAMP) (3,4). In 1971, a report by Pastan and Johnson demonstrated that growth of L-929 cells was inhibited by prostaglandin E1 (PGE1). Like epinephrine and glucagon, many prostaglandins are able to trigger the adenylate cyclase enzyme in the cell membrane and stimulate a rise in cAMP; it was therefore postulated that the block in cell growth caused by PGE1 was solely due to the increased intracellular concentration of cAMP (5). Since that time many investigators have shown that prostaglandins with an α,β unsaturated ketone ring structure inhibit cell growth (1,6–10) in normal and malignant cells. In this paper, we demonstrate using cell mutants that the growth inhibitory prostaglandins do not require cAMP or protein kinase mediated mechanism. In addition, we discuss the finding that inhibition of endogenous prostaglandin synthesis causes inhibition of osteoblast cell growth.KeywordsAdenylate CyclaseProstaglandin SynthesisCyclic MonophosphateEarly Gene ExpressionOsteoblast GrowthThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Modulation of beta-adrenergic receptor-stimulated lipolysis in the heart by prostaglandins.

The purpose of the present study was to investigate the contribution of prostaglandins to lipolysis elicited by beta-adrenergic receptor activation in the heart. We have studied the effect of prostaglandin E2 (PGE2), prostaglandin I2 (PGI2), and their precursor arachidonic acid (AA) in the presence and absence of a cyclooxygenase inhibitor, sodium meclofenamate, on glycerol output elicited by stimulation of beta-adrenergic receptors in the isolated rabbit heart with isoproterenol (ISOP). Bolus injections of ISOP (475 pmol) produced a constant increase in glycerol and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) output. Infusion of sodium meclofenamate (16 microM) reduced basal and attenuated ISOP-induced 6-keto-PGF1 alpha output and enhanced glycerol output. During inhibition of endogenous prostaglandin synthesis with meclofenamate, infusion of PGI2 or PGE2 (0.1-1 microM) inhibited ISOP-induced glycerol output. Infusion of AA (0.1-1 microM) increased 6-keto-PGF1 alpha and reduced glycerol output. Infusion of sodium meclofenamate abolished the effect of AA to increase 6-keto-PGF1 alpha and to decrease glycerol output. These data suggest that prostaglandins synthesized in the heart act as an inhibitory modulator of beta-adrenergic receptor-stimulated cardiac lipolysis.

Regulation of Plasminogen Activator in Rat Endometrial Stromal Cells: The Role of Prostaglandin E21

The rat endometrium undergoes decidualization, a tissue remodeling process, during embryo implantation. Plasminogen activator (PA), particularly the urokinase-type PA (uPA), has been implicated in tissue remodeling. The present study determined whether rat endometrial stromal cells secrete uPA during decidualization in vitro and, if so, whether the secretion is regulated by prostaglandins that are required in decidualization. Endometrial stromal cells were obtained from rats that had been treated with estrogen and progesterone to sensitize their uteri for decidualization, and the cells were cultured for up to 72 h in a serum-free medium. PA activity in the conditioned medium, as determined by a chromogenic assay, increased steadily during the 72-h culture period. PA secretion decreased when endogenous prostaglandin synthesis was inhibited by the addition of indomethacin to the cell cultures. The inhibitory effect of indomethacin on PA secretion was reversed by prostaglandin E2, and much less effectively by prostaglandin F2 alpha. PA activity in the medium was due primarily to uPA because 1) PA activity was inhibited by a uPA-specific inhibitor-amiloride-and by an anti-mouse uPA antibody, and 2) the predominant PA activity in the medium, as identified in zymography, had a molecular mass of approximately 40 kDa, similar to that reported for uPA. Northern blot analyses of RNA from the cultured cells demonstrated that the steady-state levels of mRNA for uPA, but not for tPA and plasminogen activator inhibitor-1, were decreased by indomethacin; this decrease was reversed by prostaglandin E2. Taken together, the data indicate that rat endometrial stromal cells secrete uPA during decidualization in vitro, and that prostaglandin E2 regulates uPA secretion by the decidualizing cells by directly increasing uPA gene transcription and/or stabilizing its transcripts. These findings may help to partially elucidate the mechanism of action of prostaglandin E2 in decidualization.

Role of prostaglandins in intestinal epithelial restitution stimulated by growth factors.

Mucosal integrity is reestablished after superficial injuries by a rapid resealing process, termed epithelial restitution, that is regulated by several growth factors and cytokines. Growth factors are also known to stimulate the synthesis of endogenous prostaglandins that mediate important functions in intestinal epithelial cells. Therefore, we examined the effect of endogenous eicosanoid production modulators, piroxicam, dexamethasone, and nordihydroguaiaretic acid (NDGA) on intestinal epithelial restitution using two cultured cell wound-resealing models, IEC-6 and Caco-2 cells. Epidermal growth factor, transforming growth factor-beta, hepatocyte growth factor, and fetal calf serum (FCS) accelerated intestinal epithelial restitution, and piroxicam significantly suppressed these stimulatory effects. Dexamethasone mimicked the action of piroxicam. No additive effect of piroxicam and dexamethasone was observed. NDGA did not affect epithelial restitution. Piroxicam abolished the increase in 6-ketoprostaglandin F1 alpha (PGF1 alpha) release induced by FCS. Furthermore, addition of a stable PGI2 analogue, OP-41483 [5(E)-6,9-deoxa-6,9-methylene-15-cyclopentyl-16,17,18,19,20-pen tanor-PGI2], reversed the slowing of epithelial restitution induced by piroxicam. These results suggest that endogenous prostaglandins play an important role in regulating intestinal epithelial restitution.

Regulation of Collagen Gene Expression by Prostaglandins and Interleukin-1beta in Cultured Chondrocytes and Fibroblasts.

To compare the modulatory effects of different prostaglandins on collagen gene expression in human chondrocytes, PGE(2), PGE(1), misoprostol (PGE(1) analog), and PGF(2alpha) (10, 50 and 100 ng ml(minus sign1)) were added to human chondrocytes with or without interleukin-1beta (IL-1beta) in the presence of indomethacin to inhibit endogenous prostaglandin synthesis and the effects evaluated on chondrocyte morphology, collagen synthesis, and procollagen mRNA levels. The effects of prostaglandins on the expression of collagen gene regulatory sequences were examined using transient transfection assays of reporter gene constructs in human chondrocytes and BALB/c3T3 fibroblasts, PGE(1), misoprostol, and PGF(2alpha), similar to PGE(2), inhibited type I collagen gene expression in fibroblasts and promoted type II collagen gene expression in chondrocytes. PGE(2), the major inflammatory prostaglandin produced by IL-1-activated chondrocytes and fibroblasts, and PGF(2alpha) were somewhat more potent than the anti-inflammatory prostaglandins PGE(1) and misoprostol in counteracting the IL-1-induced suppression of type II collagen gene expression by chondrocytes and stimulation of type I collagen gene expression by fibroblasts. Rather than promoting degradation of the cartilage matrix in joint diseases, prostaglandins may be somewhat protective, suppressing fibrosis, and maintaining or promoting appropriate cartilage repair.

Indomethacin inhibits cell proliferation and increases cell losses in rat gastrointestinal epithelium

Gastrointestinal cell proliferation was estimated in histological sections of rats treated with low and high doses of parenteral indomethacin for 3 to 60 days. Mitoses were arrested with vincristine and cells in S phase were labeled with tritiated thymidine. Short-term, low-dose treatments reduced the mitotic activity in the oxyntic and small intestinal epithelium, whereas moderate doses restored the mitotic index and high doses increased the proliferative activity and produced epithelial hyperplasia. Long-term, low-dose treatments increased cell proliferation in the small intestine and reduced the number of villous cells. Indomethacin did not affect the proliferative response elicited by refeeding in the oxyntic mucosa, but the simultaneous administration of prostaglandin E2 analog increased the number of arrested mitoses. The turnover of labeled cells was accelerated by indomethacin, particularly in the small intestine. These findings indicate that prostaglandins are regulators of the cell kinetics of the gastrointestinal epithelium but, at the same time, they disclose the presence of trophic mechanisms that are independent of the synthesis of endogenous prostaglandins.

Isoproterenol-induced gastric mucosal protection from bile acid

Topical isoproterenol is a potent protective agent against bile acid-induced gastric mucosal injury in hypotensive and normotensive rats. This study was undertaken to ascertain what role endogenous prostaglandins and gastric mucosal blood flow play in isoproterenol-induced protection. Accordingly, anesthetized, fasted rats were given the cyclooxygenase inhibitor, indomethacin (5 mg/kg subcutaneously), 30 min prior to topical pretreatment with 3 ml of intragastric saline, isoproterenol (3 microM), or 16,16-dimethyl prostaglandin E2 (3 microM) for 15 min. Gastric injury was induced with topical 5 mM acidified taurocholate and damage assessed by measuring net transmucosal ion fluxes, the appearance of DNA into the gastric lumen, and histology of the gastric epithelium. In a separate set of experiments, the effects of topical isoproterenol on gastric mucosal blood flow (laser Doppler flowmetry) and luminal PGE2 concentrations (125I radioimmunoassay) were examined. Pretreatment with topical isoproterenol or 16,16-dimethyl prostaglandin E2 significantly decreased bile acid-induced net luminal ion fluxes and DNA accumulation, suggesting mucosal protection. The protective effect of isoproterenol, but not 16,16-dimethyl prostaglandin E2, was negated by indomethacin (corroborated by histology). Further, isoproterenol did not significantly alter gastric mucosal blood flow, but did augment luminal PGE2 concentrations, an effect also abolished by indomethacin. Thus, isoproterenol appears to protect the gastric mucosa from the damaging effects of bile acid through a mechanism that requires the synthesis and release of cytoprotective endogenous prostaglandins.

5,6-EET inhibits ion transport in collecting duct by stimulating endogenous prostaglandin synthesis

We examined the mechanism by which the cytochrome P-450 metabolite of arachidonate, 5,6-epoxyeicosatrienoic acid (5,6-EET), modulates electrogenic transport in the rabbit cortical collecting duct (CCD). 5,6-EET depolarized transepithelial voltage (VT) in a concentration-dependent manner with a maximal effect at 1 microM. None of the other EET regioisomers (8,9-, 11,12-, or 14,15-EET; all at 1 microM) affected VT, This action was also stereoselective, with 5(S),6(R)-EET producing a 2.5-fold greater effect on VT than 5(R),6(S)-EET (1 microM each). Like basolateral prostaglandin E2 (PGE2), both luminal and basolateral 5,6-EET increased cytosolic Ca2+ concentration ([Ca2+]i) in the rabbit CCD. Pretreatment with cyclooxygenase inhibitors (10 microM ibuprofen or 5 microM indomethacin) completely blocked both the [Ca2+]i increase and the change in VT. Neither 5,6-epoxy-PGE1 nor 5-hydroxy-PGI1, cyclooxygenase metabolites of 5,6-EET, affected VT. However, when added to primary cultures of rabbit CCDs, 5,6-EET stimulated endogenous PGE2 synthesis. We propose that 5,6-EET stimulates endogenous prostaglandin synthesis, which inhibits electrogenic ion transport in the CCD.

Adaptive cytoprotection in cultured rat gastric mucus-producing cells role of mucus and prostaglandin synthesis

In cultured gastric mucosal cells, we investigated whether: (1) adaptive cytoprotection was associated with stimulation of endogenous prostaglandin synthesis; (2) prostaglandins given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage; and (3) a relationship existed between cytoprotection and mucus release. Cytolysis was quantified by measuring 51Cr release from prelabeled cells. Mucus release was determined by measurement of [3H]glucosamine release. Concentrations of ethanol > 12% caused cell damage and increased 51Cr release dose dependently. Pretreatment with low concentrations of ethanol (0.5-1.5%) decreased ethanol-induced 51Cr release, but also decreased prostaglandin E2 synthesis. Prostaglandin E2 and 16,16-dimethyl prostaglandin E2 given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage. Treatment with low concentrations of ethanol (1.5%) increased mucus release from cultured gastric mucosal cells. However, prostaglandin E2 and 16,16-dimethyl prostaglandin E2 did not affect mucus release. We conclude that in cultured gastric mucus-producing cells: (1) adaptive cytoprotection occurs without stimulation of endogenous prostaglandin synthesis but with increase in mucus release; and (2) exogenous prostaglandins are cytoprotective against ethanol-induced gastric mucosal cell damage without stimulating mucus release in vitro. We postulate that adaptive cytoprotection in cultured gastric mucus-producing cells is not mediated by prostaglandin, but by mucus released in response to a mild irritant.

Glucocorticoid delays intestinal epithelial restitution by inhibiting endogenous prostaglandin synthesis: [formula omitted], Y. Shinomura, T. Kiyohara, S. Kanayama, T. Minami, M. Sugimachi, Y. Matsuzawa. Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan

Glucocorticoid delays intestinal epithelial restitution by inhibiting endogenous prostaglandin synthesis: [formula omitted], Y. Shinomura, T. Kiyohara, S. Kanayama, T. Minami, M. Sugimachi, Y. Matsuzawa. Second Department of Internal Medicine, Osaka University Medical School, Osaka, Japan

Mediation of hyperglycemia-evoked gastric slow-wave dysrhythmias by endogenous prostaglandins

Background/Aims : Antral hypomotility and gastric dysrhythmias occur in diabetic gastroparesis. This study tested the hypothesis that acute hyperglycemia suppresses fed antral contractions and disrupts slow-wave rhythmicity via prostaglandin pathways. Methods : Six normal volunteers underwent electrogastrography and antroduodenal manometry under control, hyperglycemic clamp, and euglycemic, hyperinsulinemic clamp conditions before and after administration of indomethacin (50 mg orally three times daily for 3 days). Results : Hyperglycemic clamping to 230 mg/dL evoked a 4-fold increase in tachygastric activity and a 2.6-fold increase in arrhythmic activity ( P < 0.05), whereas 140 and 175 mg/dL did not induce dysrhythmias. Antral motility indexes were reduced by 58% ± 14% at 175 mg/dL and 70% ± 8% at 230 mg/dL after a 750-kcal meal. Euglycemic, hyperinsulinemic clamping to insulin levels observed with the highest glucose infusions did not produce tachyarrhythmias or hypomotility. After indomethacin, hyperglycemic clamping to 230 mg/dL did not induce tachyarrhythmias. In contrast, indomethacin did not prevent the reduction in motility evoked by hyperglycemic clamping. Conclusions : Acute hyperglycemia, but not hyperinsulinemia, inhibits fed antral motility and induces gastric dysrhythmias at higher plasma glucose levels. Induction of dysrhythmias, but not hypomotility, is dependent on endogenous prostaglandin synthesis. These findings offer insight into the myoelectric disturbances of diabetic gastroparesis and suggest a possible therapeutic role for prostaglandin synthesis inhibitors for gastric dysrhythmias in this condition.

The effects of 1,25-dihydroxyvitamin D 3 on osteoclast formation in fetal mouse metatarsal organ cultures

We have previously described a model system, using 15-day fetal mouse metatarsals cultured in serumless medium, in which osteoclasts and their precursors develop from in situ progenitors in a mariner which is similar, both temporally and spatially, to that which occurs in vivo. In this report we evaluate the role of the osteotropic hormone 1,25-dihydroxyvitamin D 3 (1,25-D3) on osteoclast formation in this model system by characterizing its effects on proliferation, differentiation, and fusion of cells of the osteoclast lineage. Morphologic evaluation was used to enumerate osteoclast precursors, mono- and multinucleate osteoclasts, and osteoclast nuclei in serial paraffin sections. Dose response data reveal a significant stimulation of osteoclast formation by 1,25-D3 in the range of 0.6 nM to 40 nM, and kinetic analyses suggest that these effects are on proliferation of osteoclast progenitors as well as on differentiation of precursors to form osteoclasts. A single 48 h exposure between day 4 and 6 of culture is necessary and sufficient to induce maximal osteoclast formation, while continuous exposure beyond this “critical period” inhibits multinucleate osteoclast formation. Simultaneous treatment with indomethacin inhibits the effects of 1,25-D3, while treatment with PGE 2 stimulates osteoclast formation without significantly increasing precursor numbers, or inhibiting multinucleate osteoclast formation. These results suggest that the effect of 1,25-D3 to induce differentiation of precursors to form mono- and multinucleate osteoclasts is mediated by endogenous prostaglandin synthesis. On the other hand, the inhibition of polykaryon formation observed with continuous 1,25-D3 treatment, does not appear to be a prostaglandin mediated phenomena. However, the difference between the effects of exogenous PGE 2 compared to that produced endogenously in response to 1,25-D3, suggest that endogenous prostaglandins other than PGE 2 may mediate some of the effects of 1,25-D3 on osteoclast formation.

Role of gastric mucosal blood flow in gastroprotective effect of novel xanthine derivative.

The effect of 3-ethyl-1-(6-hydroxy-6-methylheptyl)-7-propylxanthine (A90 6119) on 40% ethanol-induced gastric lesions and gastric mucosal blood flow was investigated in rats. Gastric mucosal blood flow was measured by the hydrogen gas clearance technique and the test compounds and vehicle were administered intraduodenally. A90 6119 dose-dependently increased gastric mucosal blood flow and decreased gross and histologic gastric mucosal injury induced by 40% ethanol. Both the gastric mucosal blood flow and protective effects of A90 6119 were completely attenuated by pretreatment with indomethacin. The findings demonstrate that A90 6119 protects against ethanol-induced gastric injury, and this effect involves stimulation of endogenous prostaglandin synthesis and an increase in gastric mucosal blood flow.

Comparison of the effects of 3,5,3′-triiodothyroacetic acid and triiodothyronine on bone resorption in cultured fetal rat long bones and neonatal mouse calvariae

Thyroid hormones can stimulate bone resorption both directly and indirectly by increasing endogenous prostaglandin (PG) synthesis. Because 3,5,3'-triiodothyroacetic acid (Triac, Tiratricol) can bind to nuclear thyroid hormone receptors with high affinity, we compared the effects of Triac and 3,5,3'-triiodothyronine (T3) on bone resorption. 45Ca release was measured at 2, 5, and 8 days from 19-day-old-fetal rat long bones in the presence or absence of calcitonin, indomethacin, aphidicolin (APC), cortisol, or interleukin-1 receptor antagonist (IL-1ra). Both Triac and T3 stimulated 45Ca release in a dose-dependent manner. The maximal treated/control ratio (T/C) for Triac (10(-7) M) was 1.6 +/- 0.1 at 2 days and 2.5 +/- 0.1 at 5 days and, for T3 (10(-7) M), 1.5 +/- 0.1 at 2 days and 2.6 +/- 0.1 at 5 days. These responses were smaller and slower than that to PTH. Significant stimulation of resorption was observed at 10(-8), 10(-9), and 10(-10) M for Triac but only at 10(-8) and 10(-9) M for T3. Indomethacin (10(-6) M) and IL-1ra (1 microgram/ml) did not decrease the effects of Triac or T3. In contrast, calcitonin (10(-9) M), APC (30 microM), and cortisol could all block the response to these hormones. These results indicated that the resorptive responses were not mediated by endogenous PG or IL-1 but were osteoclast mediated and dependent on DNA synthesis, suggesting that these hormones acted by stimulating replication of osteoclast precursors or other supporting cells. Thyroid hormones were less effective in 7-day-old neonatal mouse calvariae.(ABSTRACT TRUNCATED AT 250 WORDS)

Prostaglandin modulation of the gastric vasculature and mucosal integrity in cirrhotic rats

Gastric bleeding is a frequent occurrence in cirrhotic patients and may be related to altered microcirculatory responses to luminal irritants and/or vasoactive mediators. Because gastric prostaglandin synthesis has been reported to be altered in cirrhosis, we have examined the role of prostaglandins in modulating gastric perfusion velocity and mucosal integrity in cirrhotic rats. Cirrhosis was induced by bile duct ligation. Gastric perfusion velocity was measured in an ex vivo gastric chamber preparation by laser-Doppler flowmetry. The responsiveness of the mucosa to topical application of 20% ethanol was assessed. Effects of pretreatment with indomethacin or misoprostol were also determined. Gastric and hepatic prostaglandin E2 syntheses were significantly depressed (by approximately 60%) in cirrhotic vs. normal rats. Administration of indomethacin (7.5 mg/kg) to normal rats did not significantly affect gastric perfusion velocity, but in cirrhotic rats it caused a 45% reduction (P < 0.05). Topically applied misoprostol produced significantly greater (2- to 5-fold) increases in gastric perfusion velocity in cirrhotics than in controls. Cirrhotic rats were significantly more susceptible to gastric injury induced by topically applied 20% ethanol than were controls. These results suggest that gastric perfusion velocity in cirrhotic rats is modulated by endogenous prostaglandins to a much greater degree than in controls. Gastric vascular hyperresponsiveness to misoprostol may be attributable to an adaptive response to depressed endogenous prostaglandin synthesis in the cirrhotic animals.

Indomethacin, an inhibitor of prostaglandin synthesis attenuates alteration in spinal cord evoked potentials and edema formation after trauma to the spinal cord: An experimental study in the rat

The potential efficacy of indomethacin (a potent inhibitor of endogenous prostaglandin synthesis) on spinal cord-evoked potentials and edema formation occurring after a focal trauma to the spinal cord was examined in a rat model. The spinal cord evoked potentials were recorded in urethane-anesthetized male rats using monopolar electrodes placed epidurally over the T 9 (rostral) and T 12 (caudal) segments after stimulation of the ipsilateral right tibial and sural nerves. Reference electrodes were placed in the corresponding paravertebral muscles. The spinal cord evoked potential consisted of a small positive peak followed by a broad and high negative peak. Amplitudes and latencies of the maximal positive peak and the maximal negative peak were measured. The latencies and amplitudes 30 min before injury were used as references (100%). A complete loss was denoted as 0%. All the potentials were quite stable during 30 min of recording before injury. Infliction of trauma to the T 10–T 11 segments of the spinal cord with a sterile scalpel blade (about 5 mm longitudinal and 2 mm deep incision into the right dorsal horn extending to Rexed's laminae VII) in untreated animals resulted in an immediate depression of the rostral maximal negative peak amplitude (60–100%) which persisted during 5 h of recording. The latencies of the rostral as well as caudal maximal negative and positive peaks increased successively from 2 h post-trauma. In this group of animals, 5 h after injury the spinal cord water content in the traumatized segments was increased by more than 6% as compared with a group of uninjured animals. Pretreatment with indomethacin (10 mg/kg body weight i.p. 30 min before injury) markedly attenuated the immediate decrease in the maximal negative peak amplitude after injury, but did not influence the successive latency increase. However, the increase in the water content of the traumatized cord after 5 h was less pronounced compared with untreated injured rats. Our results show a beneficial effect of indomethacin on trauma-induced spinal cord evoked potential changes and edema formation. Prostaglandins may thus influence early bioelectrical changes occurring in traumatized spinal cord not reported earlier. The findings support the view that early recording of spinal cord evoked potential may be useful to predict the outcome in some forms of spinal cord injuries.