Effects of selective and unselective cyclooxygenase inhibitors on prostanoid release from various rat organs.
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It has been assumed that cyclooxygenase-2 (COX-2) is solely responsible for inflammatory processes. Recently, this view has been challenged because COX-2-selective agents caused a delay of gastric ulcer healing and exacerbation of inflammation in rats. To further characterize organ-specific toxic effects of selective and nonselective COX inhibitors, we assessed the eicosanoid release from different rat organs ex vivo after oral administration of the COX-2-selective inhibitor NS-398 and the unselective COX inhibitors diclofenac, meloxicam, and ketorolac. Prostanoid and leukotriene release from tissue fragments of the stomach, kidney, lung, and brain were determined after ex vivo incubation of tissue fragments in Tyrode's solution for 10 min at 37 degrees C. Ketorolac (0.1, 0.3, and 0.9 mg/kg) inhibited prostanoid release from all organs most potently and led to a significant increase of leukotriene release from the lung. Effects of diclofenac and meloxicam (1, 3, and 9 mg/kg each) were similar for all organs tested. At 9 mg/kg, 6keto-prostaglandin F (PGF)(1alpha) release from gastric mucosa was reduced by 79.1 +/- 11.4 and 87.6 +/- 7.7% and PGE(2) release from rat kidney was inhibited by 60.4 +/- 6.8 and 78.6 +/- 16.6% by diclofenac and meloxicam, respectively. NS-398 did not reduce prostanoid release from the lung. Consistent with the reported constitutive expression of COX-2, prostanoid release from kidney and brain was reduced by 20 to 30%. The release of 6keto-PGF(1alpha) from gastric mucosa was reduced by 34.7 +/- 22.2% at 3 mg/kg and by 86.9 +/- 12.7% at 9 mg/kg. At these doses, NS-398 has been previously shown to be COX-2 selective. Because PGF(1alpha) is the stable breakdown product of PGI(2), these results suggest that COX-2 contributes to PGI(2) synthesis in the rat stomach. (+info)
Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart.
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OBJECTIVE: To assess whether the protective effect of ischaemic preconditioning (IPC) on endothelial function in coronary arteries of the rat involves prostaglandins. METHODS: Isolated rat hearts perfused under constant flow conditions were exposed to 30 min of partial ischaemia (flow-rate 1 ml/min) followed by 20 min of reperfusion, after which coronaries were precontracted with U-46619 0.1 microM, and the coronary response to the endothelium-dependent vasodilator, serotonin (5-HT, 10 microM), was compared to that of the endothelium-independent vasodilator, sodium nitroprusside (SNP, 3 microM). Prostaglandin production was blocked with a perfusion of indomethacin 10 microM started 15 min before IPC or a corresponding sham period and stopped just before the 20-min reperfusion period. RESULTS: In untreated hearts, ischaemia diminished selectively 5-HT-induced vasodilatation, compared to sham hearts. The vasodilatation by SNP was unaffected after ischaemia and reperfusion. IPC (5 min of zero-flow ischaemia followed by 10 min reperfusion before the 30-min partial ischaemia) preserved the vasodilatation produced by 5-HT. Enzymeimmunoassays showed an increased production of PGE2 in the IPC group. Treatment of hearts with indomethacin blocked the protective effect of IPC on the vasodilatation produced by 5-HT and decreased the production of PGE2. A 5-min perfusion with 3 nM PGE2 started 15 min before the partial ischaemia, protected the endothelium. This was blocked by 1 microM chelerythrine, but not by 0.3 microM glibenclamide. CONCLUSIONS: These results suggest that IPC affords protection to endothelial function in coronary arteries of the rat partially via the release of PGE2. Under our experimental conditions, the protective effect of PGE2 is mediated by PKC. (+info)
Aprotinin does not impair renal haemodynamics and function after cardiac surgery.
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Patients undergoing cardiac surgery with moderate hypothermic cardiopulmonary bypass (CPB) were allocated randomly to receive either saline (control group, n = 29) or a high-dose regimen of aprotinin (aprotinin group, n = 28). In both groups, CPB was associated with similar and transient increases in effective renal plasma flow (+54% in controls and +48% in aprotinin-treated patients) and in fractional excretion of sodium and potassium, but glomerular filtration rate remained unchanged. Plasma and urinary ratios of 6-keto-PGF1 alpha to thromboxane B2 (TxB2) increased significantly, indicating systemic and renal release of vasodilatory prostaglandins. Osmolar clearance correlated with urinary excretion of cyclic GMP (r = 0.79 and 0.86 in the control and aprotinin groups, respectively) and 6-keto-PGF1 alpha (r = 0.63 and 0.69 in the control and aprotinin groups, respectively). Compared with preoperative values, plasma atrial natriuretic peptide increased after weaning from CPB (+71% and +93% in the control and aprotinin groups, respectively). Aprotinin had no apparent adverse effect on renal function and it did not alter mechanisms involving prostanoids and atrial natriuretic peptide during cardiac surgery. (+info)
Effects of inhibitors of arachidonic acid turnover on the production of prostaglandins by the guinea-pig uterus.
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The supply of free arachidonic acid from phospholipids is generally regarded as the rate-limiting step for prostaglandin (PG) synthesis by tissues. Two enzymes involved in arachidonic acid uptake into, and release from, phospholipids are acyl-CoA:lysophospholipid acyltransferase (ACLAT) and phospholipase A2 (PLA2), respectively. PGF2 alpha produced by the endometrium induces luteolysis in several species including guinea-pigs. Thimerosal, an inhibitor of ACLAT, and aristolochic acid, an inhibitor of PLA2, both reduced, in a concentration-dependent manner, the output of PGF2 alpha from guinea-pig endometrium cultured for 24 h on days 7 and 15 of the oestrous cycle. This study showed that the continual production of PGF 2 alpha by guinea-pig endometrium is not only dependent upon the activity of PLA2 for releasing free arachidonic acid for PGF2 alpha synthesis, but also on the incorporation of arachidonic acid into the phospholipid pool by the activity of ACLAT. The inhibitory effects of thimerosal and aristolochic acid on the outputs of PGE2 and 6-keto-PGF1 alpha were less marked, particularly on day 7 when the low output of PGE2 was unaffected and the output of 6-keto-PGF1 alpha was increased at the lower concentrations of thimerosal. This finding indicates that there are different pools of arachidonic acid bound as phospholipid for the syntheses of PGF2 alpha and 6-keto-PGF1 alpha by guinea-pig endometrium. (+info)
The induction of cyclooxygenase-2 in IL-1beta-treated endothelial cells is inhibited by prostaglandin E2 through cAMP.
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Prostaglandins (PGs) have numerous cardiovascular and inflammatory effects. Cyclooxygenase (COX), which exists as COX-1 and COX-2 isoforms, is the first enzyme in the pathway in which arachidonic acid is converted to PGs. Prostaglandin E2 (PGE2) exerts a variety of biological activities for the maintenance of local homeostasis in the body. Elucidation of PGE2 involvement in the signalling molecules such as COX could lead to potential therapeutic interventions. Here, we have investigated the effects of PGE2 on the induction of COX-2 in human umbilical vein endothelial cells (HUVEC) treated with interleukin-1beta (IL-1beta 1 ng/ml). COX activity was measured by the production of 6-keto-PGF1alpha, PGE2, PGF2alpha and thromboxane B2 (TXB2) in the presence of exogenous arachidonic acids (10 microM for 10 min) using enzyme immunoassay (EIA). COX-1 and COX-2 protein was measured by immunoblotting using specific antibody. Untreated HUVEC contained only COX-1 protein while IL-1beta treated HUVEC contained COX-1 and COX-2 protein. PGE2 (3 microM for 24h) did not affect on COX activity and protein in untreated HUVEC. Interestingly, PGE2 (3 microM for 24h) can inhibit COX-2 protein, but not COX-1 protein, expressed in HUVEC treated with IL-1beta. This inhibition was reversed by coincubation with forskolin (100 microM). The increased COX activity in HUVEC treated with IL-1beta was also inhibited by PGE2 (0.03, 0.3 and 3 microM for 24h) in a dose-dependent manner. Similarly, forskolin (10, 50 or 100 microM) can also reverse the inhibition of PGE2 on increased COX activity in IL-1beta treated HUVEC. The results suggested that (i) PGE2 can initiate negative feedback regulation in the induction of COX-2 elicited by IL-1beta in endothelial cells, (ii) the inhibition of PGE2 on COX-2 protein and activity in IL-1beta treated HUVEC is mediated by cAMP and (iii) the therapeutic use of PGE2 in the condition which COX-2 has been involved may have different roles. (+info)
The effect of acute ingestion of a large dose of alcohol on the hemostatic system and its circadian variation.
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BACKGROUND AND PURPOSE: Heavy binge drinking may trigger the onset of embolic stroke and acute myocardial infarction, but the underlying mechanisms are unclear. The effects of binge drinking on the hemostatic system and its circadian variation have not been investigated. We investigated the effects of an acute intake of a large dose of alcohol (1.5 g/kg). METHODS: Twelve healthy, nonsmoking men participated in sessions where they were served ethanol in fruit juice or served fruit juice alone and, lying in a supine position, were followed up for 12 to 24 hours. The treatments were randomized and separated from each other by a 1-week washout period. Blood and urine were collected for hemostatic measurements. RESULTS: The urinary excretion of the platelet thromboxane A(2) metabolite 2, 3-dinor-thromboxane B(2) was significantly (P<0.05) greater during the night after an evening intake of alcohol than during the control night. A smaller increase was observed during the daytime after an intake of alcohol in the morning. The effects on the endothelial prostacyclin metabolite 2,3-dinor-6-ketoprostaglandin F(1alpha) excretion were negligible. A 7-fold increase in plasminogen activator inhibitor 1 activity was observed after both morning (P<0. 05) and evening (P<0.01) intakes of alcohol. CONCLUSIONS: This is the first study to suggest that acute ingestion of a relatively large but tolerable dose of alcohol transiently enhances thromboxane-mediated platelet activation. The observations also demonstrate alcohol-induced changes in the normal circadian periodicity of the hemostatic system in subjects not accustomed to consumption of alcohol. (+info)
An imbalance in plasma prostanoids in patients with Raynaud's phenomenon and pulmonary vasospasm.
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Raynaud's phenomenon has been suggested as a predisposing factor for pulmonary vasospasm which may lead to pulmonary hypertension, but the occurrence of cold stimulus-induced pulmonary vasospasm has been inconsistent. Such inconsistent pulmonary vascular responses may be caused by differences in the production of endogenous vasodilators and vasoconstrictors among patients. Fourteen patients with Raynaud's phenomenon associated with mixed connective tissue disease (n=10) or systemic sclerosis (n=4) participated in the study. Right heart catheterization was performed before and after a cold pressor test, immersing a hand in cold water (15 degrees C) for 5 min. Plasma levels of 6-keto prostaglandin (PG)F1alpha, thromboxane (TX)B2 and endothelin (ET)-1 in the mixed venous blood were measured. Mean pulmonary artery pressure increased after the cold pressor test in five of 14 patients, and the patients were divided into those with pulmonary vasospasm (responders) and those without vasospasm (nonresponders). After the cold pressor test, levels of 6-keto PGF1alpha increased significantly in nonresponders (p<0.01) and decreased significantly in responders (p<0.05). The ratios of 6-keto PGF1alpha to TXB2 significantly increased in nonresponders (p<0.01) but not in responders and the difference between responders and nonresponders after the cold pressor test was also statistically significant (p<0.05). No significant change in plasma ET-1 levels occurred in either responders or nonresponders. The results suggest that an impaired production of prostaglandin I2 and an imbalance between prostaglandin I2 and thromboxane A2 are associated with the occurrence of pulmonary vasospasm induced by Raynaud's phenomenon. (+info)
Areca nut extract up-regulates prostaglandin production, cyclooxygenase-2 mRNA and protein expression of human oral keratinocytes.
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There are about 600 million betel quid (BQ) chewers in the world. BQ chewing is associated with increased incidence of oral cancer and submucous fibrosis. In this study, areca nut (AN) extract (200-800 microg/ml) induced the prostaglandin E(2) (PGE(2)) production by 1. 4-3.4-fold and 6-keto-PGF(1 alpha) production by 1.1-1.7-fold of gingival keratinocytes (GK), respectively, following 24 h of exposure. Exposure of GK to AN extract (>400 microg/ml) led to cell retraction and intracellular vacuoles formation. At concentrations of 800 and 1200 microg/ml, AN extract induced cell death at 21-24 and 32-52% as detected by MTT assay and cellular lactate dehydrogenase release, respectively. Interestingly, AN-induced morphological changes of GK are reversible. GK can still proliferate following exposure to AN extract. Cytotoxicity of AN extract cannot be inhibited by indomethacin (1 microM) and aspirin (50 microM), indicating that prostaglandin (PG) production is not the major factor responsible for AN cytotoxicity. PGE(2) exhibited little effect on the growth of GK at concentrations ranging from 100-1000 pg/ml. Stimulating GK production of PGs by AN extract could be due to induction of cyclooxygenase-2 (COX-2) mRNA expression and protein production. These results suggest that AN ingredients are critical in the pathogenesis of oral submucous fibrosis and oral cancer via their stimulatory effects on the PGs, COX-2 production and associated tissue inflammatory responses. AN cytotoxicity to GK is not directly mediated by COX-2 stimulation and PG production. (+info)