thromboxane-b2 and Body-Weight

This multicenter, double-blind, randomized, placebo-controlled, parallel-group study assessed renal function during dosing with etoricoxib 90 mg daily, celecoxib 200 mg twice daily, and naproxen 500 mg twice daily. Male and female subjects 60 to 81 years old (n = 85), in sodium balance on a controlled, normal sodium diet, were treated for 15 days. There were no clinically meaningful between-treatment differences in urinary sodium excretion, creatinine clearance, body weight, or serum electrolytes during the 2 weeks of treatment. Etoricoxib and celecoxib had no effect on the urinary thromboxane metabolite, 11-dehydrothromboxane B(2), while significantly decreasing the urinary prostacyclin metabolite, 2,3-dinor-6-keto PGF(1alpha). Decreases were greater for both metabolites following naproxen. Ambulatory systolic blood pressures were significantly higher than placebo for all treatments, with moderately greater increases for etoricoxib relative to other active treatments on day 14. Ambulatory diastolic blood pressures were significantly higher than placebo for etoricoxib and naproxen but not for celecoxib.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Celecoxib; Constipation; Creatinine; Diarrhea; Dose-Response Relationship, Drug; Double-Blind Method; Electrolytes; Etoricoxib; Female; Headache; Humans; Male; Middle Aged; Naproxen; Potassium; Prostaglandins; Pyrazoles; Pyridines; Sodium; Sulfonamides; Sulfones; Thromboxane B2

Aspirin resistance may be relatively common and associated with adverse outcome. Meta-analysis has clearly shown that 75 mg plain aspirin is the lowest effective dose; however, it is not known whether the recent increased use of enteric-coated aspirin could account for aspirin resistance. This study was designed to determine whether enteric-coated aspirin is as effective as plain aspirin in healthy volunteers.. Seventy-one healthy volunteers were enrolled in 3 separate bioequivalence studies. Using a crossover design, each volunteer took 2 different aspirin preparations. Five aspirin preparations were evaluated, 3 different enteric-coated 75-mg aspirins, dispersible aspirin 75 mg and asasantin (25-mg standard release aspirin plus 200-mg modified-release dipyridamole given twice daily). Serum thromboxane (TX) B2 levels and arachidonic acid-induced platelet aggregation were measured before and after 14 days of treatment.. All other aspirin preparations tested were inferior to dispersible aspirin (P<0.001) in their effect on serum TXB(2) level. Treatment failure (<95% inhibition serum TXB2 formation) occurred in 14 subjects, none of whom were taking dispersible aspirin. Mean weight for those demonstrating treatment failure was greater than those with complete TXB2 (>99%) inhibition (P<0.001). Using logistic regression analysis an 80-kg subject had a 20% probability of treatment failure. Asasantin was the most potent preparation in terms of inhibition of platelet aggregation.. Equivalent doses of the enteric-coated aspirin were not as effective as plain aspirin. Lower bioavailability of these preparations and poor absorption from the higher pH environment of the small intestine may result in inadequate platelet inhibition, particularly in heavier subjects.

Topics: Adult; Aspirin; Aspirin, Dipyridamole Drug Combination; Body Weight; Cross-Over Studies; Dipyridamole; Dose-Response Relationship, Drug; Drug Combinations; Humans; Logistic Models; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Reference Values; Tablets, Enteric-Coated; Therapeutic Equivalency; Thromboxane B2; Treatment Outcome

In addition to a variety of lipids, 2 products of the arachidonic acid cascade, prostacyclin and thromboxane, are involved in the pathogenesis of atherosclerosis as a result of their effects on platelet function and on the vascular endothelium. The aim of the present investigation was to ascertain if a sub-maximal 8 week endurance training period followed by a 4 week detraining period would have any effects on high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), triglycerides (TG), 2,3-dinor-6-keto-prostaglandin F(1alpha) (2,3-dinor-6-keto-PGF(1alpha)), the urinary metabolite of prostacyclin, 2,3-dinor-thromboxane B2 (2,3-dinor-TXB2), the urinary metabolite of thromboxane, and the ratios of TC to HDL-C and of 2,3 dinor-6-keto-PGF(1alpha) to 2,3-dinor-TXB2. Thirty-eight boys aged 10-14 were randomly divided into exercise (n = 21) and control (n = 17) groups. The exercise group trained on a bicycle ergometer 4 times/week, 1 h/session, at 80% of their physical working capacity at a heart rate of 170 beats/min (PWC(170)), for 8 weeks. The control group did not participate in any specific physical exercise program. The results showed that relative to the control group, the exercise group had a significant increase in HDL-C and 2,3-dinor-6-keto-PGF(1alpha) concentrations at the end of the 4th (p < 0.05 and p < 0.001, respectively) and the 8th week (p < 0.01 and p < 0.001) of training, respectively; a significant increase in the 2,3 dinor-6-keto-PGF(1alpha) - 2,3-dinor-TXB2 ratio (p < 0.05 and p < 0.01 at the same intervals); a significant decrease in TG at the end of the 8th week of training (p < 0.05); and a significant decrease in the TC--HDL-C ratio at the end of the 4th (p < 0.05) and 8th weeks of training (p < 0.001).

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Arachidonic Acid; Body Weight; Child; Cholesterol; Cholesterol, HDL; Heart Rate; Humans; Lipids; Longitudinal Studies; Male; Physical Endurance; Physical Exertion; Physical Fitness; Thromboxane B2; Triglycerides

The renin-angiotensin system plays a critical role in cardiovascular function, but little is known about the effects of specific cyclooxygenase 2 (COX-2) inhibition on this system in healthy humans under physiologic conditions.. Twenty-one healthy female volunteers received, in a randomized, double-blind, crossover study, celecoxib 200 mg twice a day, indomethacin 50 mg three times a day, or placebo for 4 days and a single dose, each, on day 5. On day 5 of each treatment, the following parameters were assessed with subjects in an upright position before and after administration of 20 mg furosemide intravenously: plasma renin activity (PRA), plasma aldosterone, serum and urine electrolytes, and creatinine. Index metabolites of prostanoids were analyzed by gas chromatography-tandem mass spectrometry in 24-hour urine on day 4 and in 2-hour urines before and after furosemide administration.. Baseline and furosemide-stimulated PRA were reduced to a similar degree by celecoxib and indomethacin. Plasma aldosterone and urinary excretion of potassium showed changes consistent with the alteration of PRA. Urinary excretion rates of prostaglandin E(2), (PGE(2)), 7alpha-hydroxy-5, 11-diketotetranor-prosta-1,16-dioic acid (PGE-M), and 2,3-dinor-thromboxane B(2) (TxB(2)) were not reduced by celecoxib, whereas indomethacin led to a decrease of 40%, 45%, and 80%, respectively. Both active treatments inhibited urinary excretion of 2,3-dinor-6-keto-PGF(1alpha) and 6-keto-PGF(1alpha) by 60% and 40%, respectively.. Renin-release in healthy humans with normal salt intake is COX-2 dependent. While COX-1 is critical for renal and systemic PGE(2) production, renal prostacyclin synthesis is apparently COX-2 dependent. Finally, the previously demonstrated shift of the thromboxane-prostacyclin balance toward prothrombotic thromboxane by specific COX-2 inhibition is confirmed.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aldosterone; Body Weight; Celecoxib; Creatinine; Cross-Over Studies; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Diuretics; Female; Furosemide; Humans; Indomethacin; Kidney; Potassium; Prostaglandins; Pyrazoles; Renin; Sodium; Sulfonamides; Thromboxane B2

The present study investigated whether the nitric oxide (NO) system is involved in cyclosporin A (CsA)-induced changes in cardiovascular and renal function in man.. Ten healthy volunteers were investigated twice--with and without intake of a single dose of CsA (8 mg/kg). N(G)-monomethyl-L-arginine (L-NMMA; 3 mg/kg) was injected 4 h after study start on each day.. There was no change in glomerular filtration rate (GFR) on the day without CsA. CsA alone did not change GFR, but after L-NMMA injection, GFR decreased significantly from 101 +/- 4 to 91 +/- 4 ml/min. L-NMMA increased renal vascular resistance with no difference between the two study days. CsA increased significantly the diastolic blood pressure (BP) by 8 +/- 2% and the heart rate (HR) by 30 +/- 4%, without changes in cardiac output L-NMMA further increased BP by around 8%, and decreased HR by 11% and cardiac output by 20% on both study days. L-NMMA decreased urinary flow rate by around 25% and renal sodium clearance from 1.1 to approximately 0.6 ml/min on both study days. CsA decreased plasma renin significantly and increased the urinary excretion rate of prostaglandin E2 (PgE2), 6-keto-prostaglandin F1alpha (6-keto-PgF1alpha) and thromboxane B2(TxB2) when compared to the control day. The urinary excretion rate of NOx and cGMP declined gradually on the control day. In contrast, there was a minor, non-significant increase in NOx and cGMP excretion after CsA, followed by a decrease (29 +/- 2 and 16 +/- 4%, respectively) after L-NMMA in parallel with the decrease in GFR.. The present findings suggest that NO does not play a major role during acute CsA-induced changes in cardiovascular function and renal haemodynamics in man. Renal NO synthesis, however, may attenuate the acute CsA-induced decrease in GFR.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Arachidonic Acid; Blood Pressure; Body Weight; Cardiovascular Physiological Phenomena; Cyclosporine; Dinoprostone; Enzyme Inhibitors; Female; Glomerular Filtration Rate; Humans; Kidney; Male; Nitrates; Nitric Oxide; Nitrites; omega-N-Methylarginine; Reference Values; Renin; Sodium; Thromboxane B2

To study the effects of a low dose of omega-3 fatty acids on platelet function and other cardiovascular risk factors in patients with non-insulin-dependent diabetes mellitus (NIDDM).. We performed a randomized, prospective, double-blind, controlled study of a low dose of omega-3 fatty acids (2.5 g/day) in 20 ambulatory subjects with NIDDM. Subjects ingested five 1-g fish oil capsules each containing 0.5 g omega-3 fatty acids or five 1-g safflower oil capsules per day for 6 weeks followed by a 6-week washout period.. Nine subjects completed the study in each group. Both groups exhibited moderate control of glucose levels; modest elevations in baseline total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels; and normal blood pressure values. In the fish oil group, plasma omega-3 fatty acid levels increased significantly. Fish oil significantly reduced the slope of the dose-response curves for collagen-induced platelet aggregation to one-third the value observed with safflower oil. No difference was observed in collagen-induced production of thromboxane A2 (TXA2, measured as the stable derivative TXB2), or in adenosine-5'-diphosphate- (ADP) induced platelet aggregation or TXA2 generation. Patients with high initial collagen-induced platelet TXA2 production showed a significantly larger drop after fish oil than safflower oil. Fish oil significantly reduced TG levels by 44 mg/dl and decreased upright systolic blood pressure (sBP) by 8 mmHg compared with safflower oil. Fish oil caused a significant but small increase in HbA1c (0.56%) and total cholesterol (20 mg/dl) but had no effect on fasting glucose, high-density lipoprotein cholesterol, or LDL-cholesterol levels.. Small doses of fish oil inhibit platelet aggregation and TXA2 production, reduce upright sBP and TG levels, and have only a small effect on glucose and cholesterol levels in patients with moderately controlled NIDDM. Small quantities of omega-3 fatty acids or dietary fish are safe and potentially beneficial in NIDDM patients.

Topics: Adult; Aged; Blood Platelets; Blood Pressure; Body Weight; Cardiovascular Diseases; Cholesterol; Diabetes Mellitus, Type 2; Dietary Fats; Double-Blind Method; Energy Intake; Fatty Acids, Omega-3; Fish Oils; Glycated Hemoglobin; Humans; Middle Aged; Platelet Aggregation; Posture; Prospective Studies; Risk Factors; Safflower Oil; Thromboxane B2; Time Factors

The pharmacokinetics and pharmacodynamics of AA-2414 [(+-)-7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptano+ ++ ic acid] were evaluated in 39 healthy male subjects after four different oral multiple-dosing regimens. Population pharmacokinetic analysis with NONMEM showed plasma concentration-time profiles of AA-2414 to be best characterized by a two-compartment open model with zero-order input and first-order elimination. The final estimates for oral clearance, volume of distribution, and steady-state volume of distribution were 10.7 ml/hr/kg, 92.8 ml/kg, and 280 ml/kg, respectively; the corresponding coefficients of variation for interindividual variability were 21%, 10%, and 9%. The pharmacokinetic parameters were associated only with body weight. The residual variability was 25%. The ex vivo platelet aggregation response to U-46619, a thromboxane A2 mimetic, was significantly inhibited by AA-2414. The effect was found to be linearly related to plasma concentration with population estimates of 2.3 mumol/L and 2.38 for the baseline effect and slope, respectively; the corresponding coefficients of variation for interindividual variability were 22% and 38%. The residual variability was 39%. The leukotriene B4, thromboxane B2, and anti-platelet aggregation factor activity measurements were not significantly affected by administration of AA-2414.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Administration, Oral; Adolescent; Adult; Benzoquinones; Body Weight; Double-Blind Method; Heptanoic Acids; Humans; Leukotriene B4; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandin Endoperoxides, Synthetic; Quinones; Receptors, Thromboxane; Thromboxane A2; Thromboxane B2

The pharmacokinetics of flurbiprofen (Ansaid Tablets, Upjohn Company of Canada, Don Mills, Ontario) were evaluated in both younger (40 to 60 years) and elderly (65 to 83 years) rheumatoid arthritic patients after both a 100-mg single-dose administration and at steady state during a 100-mg twice-a-day dosage regimen. Both flurbiprofen plasma concentration-time profiles and the urinary excretion of flurbiprofen and its major metabolites were evaluated. The results indicate that the pharmacokinetics of flurbiprofen are linear in both age groups based on only minor changes between single-dose and steady-state parameter determinations and the agreement between calculated and predicted accumulation values in plasma concentrations. Only minor differences in the pharmacokinetic parameters were observed between the younger and elderly patients. Only free flurbiprofen clearance was found to have a significant but variable correlation to patient age. The effect of flurbiprofen on the urinary excretion of two prostaglandins were also evaluated throughout this study. In both age groups, the maximum decrease in urinary excretion was observed after the first dose, and this effect was maintained throughout the remainder of the study. Percent decreases from baseline in urinary excretion during drug administration were similar for both age groups. Similar side-effect profiles were observed between age groups.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Age Factors; Aged; Aged, 80 and over; Arthritis, Rheumatoid; Body Weight; Female; Flurbiprofen; Humans; Male; Metabolic Clearance Rate; Middle Aged; Prospective Studies; Thromboxane B2

Little is known about the pathomechanism of pulmonary infections caused by

Topics: Acanthamoeba; Animals; Body Weight; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Host-Pathogen Interactions; Humans; Lung; Lung Diseases, Parasitic; Male; Mice, Inbred BALB C; Middle Aged; Organ Size; Thromboxane B2

Cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) play an important role in inflammatory bowel diseases (IBDs). We investigated the effects of flavocoxid, a dual COX/LOX inhibitor, in experimental colitis induced with either dinitrobenzenesulfonic acid (DNBS) or dextrane sulphate sodium (DSS) In the first model, colitis was induced in rats by a single intra-colonic instillation (25mg in 0.8ml 50% ethanol) of DNBS; after 24h animals were randomized to receive orally twice a day, flavocoxid (10mg/kg), zileuton (50mg/kg), or celecoxib (5mg/kg). Sham animals received 0.8ml of saline by a single intra-colonic instillation. Rats were killed 4 days after induction and samples were collected for analysis. In the second model, colitis was induced in rats by the administration of 8% DSS dissolved in drinking water; after 24h animals were randomized to the same above reported treatments. Sham animals received standard drinking water. Rats were killed 5 days after induction and samples were collected for analysis. Flavocoxid, zileuton and celecoxib improved weight loss, reduced colonic myeloperoxydase activity, macroscopic and microscopic damage, and TNF-α serum levels. Flavocoxid and celecoxib also reduced malondialdheyde, 6-keto PGF1α and PGE-2 levels while flavocoxid and zileuton decreased LTB-4 levels. In addition, flavocoxid treatment improved histological features and apoptosis as compared to zileuton and celecoxib; moreover only flavocoxid reduced TXB2, thus avoiding an imbalance in eicosanoids production. Our results show that flavocoxid has protective effect in IBDs and may represents a future safe treatment for inflammatory bowel diseases.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Apoptosis; Arachidonate 5-Lipoxygenase; Body Weight; Catechin; CD3 Complex; Celecoxib; Colitis; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Drug Combinations; Eating; Gene Expression Regulation; Hydroxyurea; Leukotriene B4; Lipid Peroxidation; Lipoxygenase Inhibitors; Male; Neutrophil Infiltration; Rats; Rats, Sprague-Dawley; Thromboxane B2; Tumor Necrosis Factor-alpha

In the rat, a high-fat (HF) plus fructose (F) diet produces cardiovascular and metabolic alterations that resemble human metabolic syndrome. Prostanoids (PR), cyclo-oxygenase-derived arachidonic acid metabolites, have vasoactive properties and mediate inflammation. The aim of this study was to analyse the effect of a HF+F diet on blood pressure (BP), metabolic parameters and mesenteric vascular bed PR production in male Sprague-Dawley rats. Four groups were studied over 9 weeks (n = 6 each): control (C), standard diet (SD) and tap water to drink; F+SD and 10% w/v F solution to drink; HF 50% (w/w) bovine fat added to SD and tap water; and HFF, both treatments. PR were determined by HPLC. Blood pressure was elevated in all experimental groups. Triglyceridaemia, insulinaemia and HOMA-IR were increased in the F and HF groups. HF+F animals showed elevated glycaemia, insulinaemia, HOMA-IR and triglyceridaemia. F decreased the vasodilator prostanoids PGI2 and PGE2 in the mesenteric vascular bed. Body weight was not significantly altered. In HFF, production of PGE2 , PGF2 alpha and TXB2 was elevated. The increased BP in HF and HFF could be partly attributed to the imbalance in vascular PR production towards vasoconstrictors. On the other hand, this dietary modification could induce inflammation, which would explain the elevation of PGE2 . In the F group, hypertension could be related to decreased vasodilator PRs. The simultaneous administration of HF and F in the rat produces deleterious effects greater than observed when treatments are applied separately.

Topics: Animals; Blood Glucose; Blood Pressure; Body Weight; Diet, High-Fat; Fructose; Insulin; Insulin Resistance; Male; Mesenteric Arteries; Metabolic Syndrome; Prostaglandins; Rats; Thromboxane B2; Triglycerides

Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E(-/-) mice. Urinary 11-dehydrothromboxane B2 (11-dTXB2) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p<0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.

Topics: Adult; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Body Mass Index; Body Weight; Case-Control Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Female; Gene Expression Regulation, Enzymologic; Hematocrit; Humans; Hypoxia; Male; Mice; Mice, Transgenic; Middle Aged; Pyrazoles; Risk Factors; Sleep Apnea, Obstructive; Thromboxane B2

An up-regulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-d-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signalling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanaesthetized rats that had been treated p.o. daily for 42 d with vehicle or a therapeutically relevant dose of LTG (10 mg/kg.d). Regional brain AA incorporation coefficients k* and rates J in, and AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and J in in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signalling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signalling are up-regulated in the post-mortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade.

Topics: Analysis of Variance; Animals; Arachidonic Acid; Autoradiography; Body Weight; Brain; Calcium Channel Blockers; Cyclooxygenase 2; Dinoprostone; Eicosanoids; Excitatory Amino Acid Agonists; Lamotrigine; Male; N-Methylaspartate; NF-kappa B; Protein Binding; Rats; Rats, Inbred F344; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Thromboxane B2; Triazines

Premature infants often develop serious clinical complications associated with respiratory failure and hyperoxic lung injury that includes lung inflammation and alterations in lung development. The goal of these studies is to test the hypothesis that there are differences in the course of lung injury in newborn mice exposed to 85% or >95% oxygen that provide models to address the differential effects of oxidation and inflammation. Our results indicate differences between the 85% and >95% O2 exposure groups by day 14 in weight gain and lung alveolarization. Inflammation, assessed by neutrophil counts, was observed in both hyperoxia groups by day 3 but was dramatically greater in the >95% O2-exposed groups by day 14 and associated with greater developmental deficits. Cytoplasmic phospholipase A2, cyclooxygenase-2, and 5-lipoxygenase levels were elevated but no patterns of differences were observed between exposure groups. Prostaglandins D2, E2, and F2alpha were increased in the tissues from mouse pups exposed to >95% O2 at 7 d indicating a differential expression of cyclooxygenase-2 products. Our data indicate that there are differences in the models of 85% or >95% O2 exposure and these differences may provide mechanistic insights into hyperoxic lung injury in an immature system.

Topics: Acute Lung Injury; Animals; Animals, Newborn; Arachidonate 5-Lipoxygenase; Body Weight; Cyclooxygenase 2; Disease Models, Animal; Group IV Phospholipases A2; Hyperoxia; Lung; Mice; Mice, Inbred C3H; Neutrophil Infiltration; Oxygen; Prostaglandins; Pulmonary Alveoli; Thromboxane B2; Time Factors; Up-Regulation

Certain polymorphisms reduce serotonin (5-HT) reuptake transporter (5-HTT) function and increase susceptibility to psychiatric disorders. Heterozygous (5-HTT(+/-))-deficient mice, models for humans with these polymorphisms, have elevated brain 5-HT concentrations and behavioral abnormalities. As postsynaptic 5-HT(2A/2C) receptors are coupled to cytosolic phospholipase A(2) (cPLA(2)), which releases arachidonic acid (AA) from membrane phospholipid, 5-HTT-deficient mice may have altered brain AA signaling and metabolism. To test this hypothesis, signaling was imaged as an AA incorporation coefficient k(*) in unanesthetized homozygous knockout (5-HTT(-/-)), 5-HTT(+/-) and wild-type (5-HTT(+/+)), mice following saline (baseline) or 1.5 mg/kg s.c. DOI, a partial 5-HT(2A/2C) receptor agonist. Enzyme activities, metabolite concentrations, and head-twitch responses to DOI were also measured. Baseline k(*) was widely elevated by 20-70% in brains of 5-HTT(+/-) and 5-HTT(-/-) compared to 5-HTT(+/+) mice. DOI increased k(*) in 5-HTT(+/+) mice, but decreased k(*) in 5-HTT-deficient mice. Brain cPLA(2) activity was elevated in 5-HTT-deficient mice; cyclooxygenase activity and prostaglandin E(2) and F(2alpha) and thromboxane B(2) concentrations were reduced. Head-twitch responses to DOI, although robust in 5-HTT(+/+) and 5-HTT(+/-) mice, were markedly fewer in 5-HTT(-/-) mice. Pretreatment with para-chlorophenylalanine, a 5-HT synthesis inhibitor, restored head twitches in 5-HTT(-/-) mice to levels in 5-HTT(+/+) mice. We propose that increased baseline values of k(*) in 5-HTT-deficient mice reflect tonic cPLA(2) stimulation through 5-HT(2A/2C) receptors occupied by excess 5-HT, and that reduced k(*) and head-twitch responses to DOI reflected displacement of receptor-bound 5-HT by DOI with a lower affinity. Increased baseline AA signaling in humans having polymorphisms with reduced 5-HTT function might be identified using positron emission tomography.

Topics: Amphetamines; Analysis of Variance; Animals; Arachidonic Acid; Autoradiography; Body Weight; Brain; Brain Mapping; Carbon Isotopes; Chromatography, Gas; Dinoprost; Dinoprostone; Fatty Acids; Fenclonine; Head Movements; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phospholipases A2, Cytosolic; Prostaglandin-Endoperoxide Synthases; Serotonin Antagonists; Serotonin Plasma Membrane Transport Proteins; Serotonin Receptor Agonists; Signal Transduction; Thromboxane B2; Wakefulness

Supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil may prevent development of heart failure through alterations in cardiac phospholipids that favorably impact inflammation and energy metabolism. A high-fat diet may block these effects in chronically stressed myocardium. Pathological left ventricle (LV) hypertrophy was generated by subjecting rats to pressure overload by constriction of the abdominal aorta. Animals were fed: (1) standard diet (10% of energy from fat), (2) standard diet with EPA+DHA (2.3% of energy intake as EPA+DHA), (3) high fat (60% fat); or (4) high fat with EPA+DHA. Pressure overload increased LV mass by approximately 40% in both standard and high-fat diets without fish oil. Supplementation with fish oil increased their incorporation into cardiac phospholipids, and decreased the proinflammatory fatty acid arachidonic acid and urine thromboxane B(2) with both the standard and high-fat diet. Linoleic acid and tetralinoloyl cardiolipin (an essential mitochondrial phospholipid) were decreased with pressure overload on standard diet, which was prevented by fish oil. Animals fed high-fat diet had decreased linoleic acid and tetralinoloyl cardiolipin regardless of fish oil supplementation. Fish oil limited LV hypertrophy on the standard diet, and prevented upregulation of fetal genes associated with heart failure (myosin heavy chain-beta and atrial natriuetic factor). These beneficial effects of fish oil were absent in animals on the high-fat diet. In conclusion, whereas treatment with EPA+DHA prevented tetralinoloyl cardiolipin depletion, LV hypertrophy, and abnormal genes expression with pressure overload, these effects were absent with a high-fat diet.

Topics: Animals; Aorta, Abdominal; Arachidonic Acid; Atrial Natriuretic Factor; Blood Pressure; Body Weight; Cardiolipins; Cardiotonic Agents; Constriction; Dietary Fats; Docosahexaenoic Acids; Echocardiography; Eicosapentaenoic Acid; Fish Oils; Hypertrophy, Left Ventricular; Linoleic Acid; Male; Myocardium; Myosin Heavy Chains; Organ Size; Phospholipids; Rats; Rats, Wistar; Thromboxane B2

ROMK null mice with a high survival rate and varying severity of hydronephrosis provide a good model to study type II Bartter syndrome pathophysiology (26). During the development of such a colony, we found that more male than female null mice survived, 58.7% vs. 33.3%. To investigate the possible mechanism of this difference, we compared the survival rates, renal functions, degree of hydronephrosis, as well as PGE(2) and TXB(2) production between male and female ROMK wild-type and null mice. We observed that female ROMK Bartter's mice exhibited lower GFR (0.37 vs. 0.54 ml.min(-1).100 g BW(-1), P < 0.05) and higher fractional Na(+) excretion (0.66% vs. 0.48%, P < 0.05) than male Bartter's. No significant differences in acid-base parameters, urinary K(+) excretion, and plasma electrolyte concentrations were observed between sexes. In addition, we assessed the liquid retention rate in the kidney to evaluate the extent of hydronephrosis and observed that 67% of male and 90% of female ROMK null mice were hydronephrotic mice. Urinary PGE(2) excretion was higher in both sexes of ROMK null mice: 1.35 vs. 1.10 ng/24 h in males and 2.90 vs. 0.87 ng/24 h in females. TXB(2) excretion was higher in female mice in both wild-type and ROMK null mice. The increments of urinary PGE(2) and TXB(2) were significantly higher in female null mice than males, 233.33% vs. 22.74% of PGE(2) and 85.67% vs. 20.36% of TXB(2). These data demonstrate a more severe Bartter phenotype in female ROMK null mice, and higher PGE(2) and TXB(2) production may be one of the mechanisms of this manifestation.

Topics: Age Factors; Animals; Bartter Syndrome; Body Weight; Dinoprostone; Female; Glomerular Filtration Rate; Hydronephrosis; Male; Mice; Mice, Knockout; Mice, Mutant Strains; Phenotype; Potassium; Potassium Channels, Inwardly Rectifying; Severity of Illness Index; Sex Characteristics; Sodium; Survival Rate; Thromboxane B2; Urine

The protective effect of Pycnogenol against cardiovascular diseases was clearly demonstrated. Nevertheless, little is known about its antithrombotic effect, especially in diabetes associated with enhanced thromboxane synthesis leading to severe vascular complications. Therefore, the main purpose of our study was to evaluate the effect of long-term Pycnogenol intake on synthesis of prothrombotic thromboxane A(2) (TXA(2)) in animal model of insulin-dependent diabetes. The levels of main plasma TXA(2) metabolite, thromboxane B(2) (TXB(2)), were assessed by enzyme-linked immunosorbent assay. Diabetes was induced in Wistar male rats by single injection of streptozotocin, resulting after 8 weeks in significant body weight reduction, increased plasma glucose concentrations, and decreased plasma C-peptide levels, compared to non-diabetic animals. There was no significant reduction of plasma glucose concentrations after Pycnogenol ingestion. It was found, however, that daily administration of either Pycnogenol (5mg/kg b.wt.) or acetylsalicylic acid (ASA, 10mg/kg b.wt.) significantly reduced plasma TXB(2) concentrations, and this inhibitory effect was higher in the latter case. Nonetheless, simultaneous administration of Pycnogenol and ASA did not improve effectiveness of ASA-mediated decrease in TXB(2) generation. The results of the present study suggest that Pycnogenol might have a beneficial antithrombotic effect when administered alone or as a supplementation of standard antiplatelet therapy in diabetic patients.

Topics: Animals; Aspirin; Blood Glucose; Body Weight; C-Peptide; Cyclooxygenase Inhibitors; Diabetes Mellitus, Experimental; Flavonoids; Male; Plant Extracts; Rats; Rats, Wistar; Thromboxane B2; Thromboxanes

Cysteinyl leukotrienes play a part in inflammatory processes such as inflammatory bowel diseases. The present study aimed to evaluate the effects of the cys-LT-1 receptor antagonist montelukast on a mild colitis model in rats. Colitis was induced by administrating 4% dextran sulphate sodium (DSS, MW 45,000) in drinking water for 9 days. Montelukast (10 mg/kg/day) or vehicle was given by gastric gavage once daily simultaneously with DSS administration. A healthy control group receiving water as drinking fluid and vehicle by gastric gavage was included. Body weight loss, consistency of faeces (loose/diarrhoea) and occult blood in the faeces/ gross bleeding were assessed on days 6 - 9. After sacrifice, the following were assessed: colonic histology, the expression of inducible nitric oxide synthase, macrophage/monocyte marker ED1, cyclooxygenase-1 and cyclooxygenase-2, as well as the production of leukotriene B(4) and E(4), prostaglandin E(2), its metabolite bicyclic-prostaglandin E(2) and thromboxane B(2) in the colonic tissue incubation in vitro. Rats receiving DSS exhibited bloody diarrhoea from day 6 onwards. Montelukast significantly reduced the occult blood in the faeces/ gross bleeding, maintained normal body weight gain and tended to decrease the ratio of leukotriene B(4)/ prostaglandin E(2) production in the colon in vitro. The results indicate that montelukast has some potential to ameliorate mild experimental colitis induced by DSS.

Topics: Acetates; Administration, Oral; Animals; Blotting, Western; Body Weight; Bridged Bicyclo Compounds; Colitis; Colon; Cyclooxygenase 1; Cyclooxygenase 2; Cyclopropanes; Dextran Sulfate; Dinoprostone; Immunochemistry; Immunoglobulin G; Leukotriene Antagonists; Leukotriene B4; Male; Nitric Oxide Synthase Type II; Occult Blood; Quinolines; Rats; Rats, Wistar; Severity of Illness Index; Sulfides; Thromboxane B2

Previously, we observed that alloxan-induced in vitro cytotoxicity and apoptosis in an insulin secreting rat insulinoma, RIN, cells was prevented by prior exposure to prostaglandin (PG) E(1), PGE(2), PGI(2), PGF(1)(alpha), and PGF(3)(alpha) (P<0.05 compared to alloxan), whereas thromboxane B(2) (TXB(2)) and 6-keto-PGF(1)(alpha) were ineffective. In an extension of these studies, we now report that prior intraperitoneal administration of PGE(1), PGE(2), PGF(1)(alpha), and PGF(3)(alpha) prevented alloxan-induced diabetes mellitus in male Wistar rats, whereas PGI(2), TXB(2), and 6-keto PGF(1)(alpha) were not that effective. PGE(1), PGE(2), PGF(1)(alpha), and PGF(3)(alpha) not only attenuated chemical-induced diabetes mellitus but also restored the antioxidant status to normal range in red blood cells and pancreas. These results suggest that PGE(1), PGE(2), PGF(1)(alpha), and PGF(3)(alpha) can abrogate chemically induced diabetes mellitus in experimental animals and attenuate the oxidant stress that occurs in diabetes mellitus.

Topics: Alloxan; Alprostadil; Animals; Antioxidants; Blood Glucose; Body Weight; Catalase; Ceruloplasmin; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Dinoprostone; Erythrocytes; Glutathione Peroxidase; Glutathione Transferase; Injections, Intraperitoneal; Insulin; Lactic Acid; Lipid Peroxides; Male; Malondialdehyde; Nitric Oxide; Pancreas; Prostaglandins; Prostaglandins F; Rats; Rats, Wistar; Superoxide Dismutase; Thromboxane B2

This study examined whether targeted disruption of the genes for the prostacyclin receptor (IP) or the thromboxane A2 receptor (TP) confers a susceptibility to salt-dependent hypertension.. Eight female IP- or TP-deficient mice were examined. Baseline systolic blood pressure (SBP) did not differ between TP(-/-) and TP(+/+), but was significantly lower in the IP(-/-) group than in the IP(+/+). With a high salt diet, SBP in IP(-/-) gradually increased. In contrast, SBP in the IP(+/+), TP(-/-), or TP(+/+) groups remained unchanged.. The prostacyclin receptor may participate in the maintenance of baseline BP. With salt loading, BP adaptation may take place, at least in part, via IP mediated signals.

Topics: Animals; Blood Pressure; Body Weight; Female; Heart Rate; Heterozygote; Homozygote; Mice; Mice, Inbred C57BL; Mice, Knockout; Receptors, Epoprostenol; Receptors, Thromboxane A2, Prostaglandin H2; Reverse Transcriptase Polymerase Chain Reaction; Sodium, Dietary; Thromboxane B2

The aims of the present study were to analyse the effects of an oral daily dose (10 mg/kg) of the dietary flavonoid quercetin for five weeks in two-kidney, one-clip (2K1C) Goldblatt (GB) hypertensive rats. The evolution of systolic blood pressure was followed by weekly measurements, and morphological variables, proteinuria, plasma nitrates plus nitrites (NOx) and thiobarbituric acid reactive substances (TBARS), liver oxidative stress markers and endothelial function were determined at the end of the experimental period. Quercetin treatment reduced systolic blood pressure of GB rats, producing no effect in control animals. It also reduced cardiac hypertrophy and proteinuria developed in GB hypertensive rats. Decreased endothelium-dependent relaxation to acetylcholine of aortic rings from GB rats was improved by chronic quercetin treatment, as well as increased endothelium-dependent vasoconstrictor response to acetylcholine and overproduction of TXB2 by aortic vessels of GB rats, being without effect in normotensive animals. Increased plasma NOx and TBARS, and decreased liver total glutathione (GSH) levels and glutathione peroxidase (GPX) activity were observed in GB hypertensive rats compared to the control animals. Normalisation of plasma NOx and TBARS concentrations and improvement of the antioxidant defences system in liver accompanied the antihypertensive effect of quercetin. We conclude that chronic oral treatment with quercetin shows both antihypertensive and antioxidant effects in this model of renovascular hypertension.

Topics: Animals; Antioxidants; Aorta; Blood Pressure; Body Weight; Diet; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Glutathione; Glutathione Peroxidase; Hypertension, Renovascular; Kidney; Liver; Male; Nitrates; Nitrites; Organ Size; Oxidative Stress; Potassium Chloride; Proteinuria; Quercetin; Rats; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Time Factors

The mechanisms involved in development of cardiovascular complications associated with diabetes mellitus are not well elucidated. Among the vasoactive factors that may play a role in development of these complications are angiotensin II and thromboxane B2 (TXB2). We hypothesized that diabetes increases renal production of TXB2 through stimulation of angiotensin type-1 receptor.. We used a microdialysis technique to monitor changes in renal interstitial fluid (RIF) TXB2 in conscious streptozotocin-induced diabetes rat model. The RIF levels of angiotensin II and TXB2 were monitored before and during 6 weeks after development of diabetes and during treatment with the angiotensin type-1 receptor blocker valsartan at 10 mg/kg. Measurement of the urinary albumin excretion (UAE) was used to monitor the development and progression of diabetic nephropathy.. The UAE was 81.62 +/- 1.31 ng/min, 184.75 +/- 9.41 ng/min (P < .01), and 229.84 +/- 4.49 ng/min (P < .0001) at baseline, week 3, and week 6, respectively, after induction of diabetes. Basal levels of RIF angiotensin II were 4.28 +/- 0.02 pg/mL and significantly increased to 6.24 +/- 0.31 pg/mL (P < .001) and 7.66 +/- 0.05 pg/mL (P < .001) at 3 and 6 weeks after development of diabetes. Similarly, basal RIF TXB2 was 197 +/- 27 pg/mL and increased to 488 +/- 80 pg/mL (P < .01) and 703 +/- 130 pg/mL (P < .01) at 3 and 6 weeks after development of diabetes. Valsartan caused further increase in RIF angiotensin II levels. In contrast, valsartan decreased RIF TXB2 levels at baseline to 85 +/- 11 pg/mL (P < .01), at 3 weeks to 141 +/- 17 pg/mL (P < .01), and at 6 weeks to 255 +/- 45 pg/mL (P < .01) after development of diabetes.. These results demonstrate that diabetes mellitus is accompanied by increased renal production of angiotensin II and TXB2. The increase in TXB2 is mediated through stimulation of angiotensin type-1 receptor.

Topics: Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Extracellular Fluid; Kidney; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Tetrazoles; Thromboxane B2; Valine; Valsartan

We investigated the hypothesis that thromboxane A2 (TxA2)-prostaglandin H2 receptors (TP-Rs) mediate the hemodynamic responses and increase in reactive oxygen species (ROS) to ANG II (400 ng x kg(-1) x min(-1) sc for 14 days) using TP-R knockout (TP -/-) and wild-type (+/+) mice. TP -/- had normal basal mean arterial blood pressure (MAP) and glomerular filtration rate but reduced renal blood flow and increased filtration fraction (FF) and renal vascular resistance (RVR) and markers of ROS (thiobarbituric acid-reactive substances and 8-isoprostane PGF2alpha) and nitric oxide (NOx). Infusion of ANG II into TP +/+ increased ROS and thromboxane B2 (TxB2) and increased RVR and FF. ANG II infusion into TP -/- mice reduced ANG I and increased aldosterone but caused a blunted increase in MAP (TP -/- : +6 +/- 2 vs. TP +/+: +15 +/- 3 mmHg) and failed to increase FF, ROS, or TxB2 but increased NOx and paradoxically decreased RVR (-2.1 +/- 1.7 vs. +2.6 +/- 0.8 mmHg x ml(-1) x min(-1) x g(-1)). Blockade of AT1 receptor of TP -/- mice infused with ANG II reduced MAP (-8 mmHg) and aldosterone but did not change the RVR or ROS. In conclusion, during an ANG II slow pressor response, AT1 receptors activate TP-Rs that generate ROS and prostaglandins but inhibit NO. TP-Rs mediate all of the increase in RVR and FF, part of the increase in MAP, but are not implicated in the suppression of ANG I or increase in aldosterone. TP -/- mice have a basal increase in RVR and FF associated with ROS.

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Angiotensin I; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Body Weight; Dinoprost; Electrolytes; Epoprostenol; Female; Heart Rate; Hematocrit; Hypertension, Renal; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitrates; Nitrites; Organ Size; Receptor, Angiotensin, Type 1; Receptors, Thromboxane A2, Prostaglandin H2; Renal Circulation; Specific Pathogen-Free Organisms; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Urine; Vascular Resistance; Vasoconstrictor Agents

To determine cytochrome P450 (CYP450) and cyclooxygenase (COX) expression and metabolite regulation and renal damage in the early stages of obesity-related hypertension and diabetes.. Obese and lean Zucker rats at 10 to 12 weeks of age were studied. Blood pressure was measured in the conscious state using radiotelemetry. Blood glucose levels and body weight were measured periodically. Protein expression of CYP450 and COX enzymes in the kidney cortex, renal microvessels, and glomeruli was studied. The levels of CYP450 and COX metabolites in urine were measured, and urinary albumin excretion, an indicator of kidney damage, was measured.. Body weight and blood glucose averaged 432 +/- 20 grams and 105 +/- 5 mg/dl, respectively, in obese Zucker rats as compared with 320 +/- 8 grams and 91 +/- 5 mg/dl, respectively, in age-matched 10- to 12-week-old lean Zucker rats. Renal microvascular CYP4A and COX-2 protein levels were increased 2.3- and 17.0-fold, respectively, in obese Zucker rats. The protein expression of CYP2C11 and CYP2C23 was decreased 2.0-fold in renal microvessels isolated from obese Zucker rats when compared with lean Zucker rats. The urinary excretion rate of thromboxane B(2) was increased significantly in obese Zucker as compared with lean Zucker rats (22.0 +/- 1.8 vs. 13.4 +/- 1.0 ng/d). Urinary albumin excretion, an index of kidney damage, was increased in the obese Zucker rat at this early age.. These results suggest that increased CYP4A and COX-2 protein levels and decreased CYP2C11 and CYP2C23 protein levels occur in association with microalbuminuria during the onset of obesity-related hypertension and type 2 diabetes.

Topics: Albuminuria; Animals; Aryl Hydrocarbon Hydroxylases; Blood Glucose; Body Weight; Cyclooxygenase 2; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Diabetes Mellitus, Type 2; Hypertension; Isoenzymes; Kidney; Kidney Cortex; Kidney Glomerulus; Male; Microcirculation; Obesity; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Zucker; Steroid 16-alpha-Hydroxylase; Thromboxane B2

To investigate the effects of celecoxib on fetal growth, and placental prostanoid and nitric oxide (NO) production in fetal rabbits, pregnant rabbits received celecoxib (30 mg/kg per day) from 13 to 20 days (Cel-A), from 13 to 28 days (Cel-B), or vehicle from 13 to 28 days gestation. Fetal body and organ weights, and measurements of linear growth were recorded. The placentas were weighed and analyzed for prostaglandins (PGs), NO oxidation products (NOx), and total cellular protein levels. Placental prostaglandin E2 (PGE2) and NOx levels increased (P < or = 0.05), while thromboxane B2 levels were suppressed (P < or = 0.01) in Cel-B group. Tail length and brain weight were greater, while lung weights were lower in the Cel-B group (P < or = 0.05). Maternal administration of celecoxib appears to preferentially increase placental vasodilators and decrease placental TxA2, suggesting that the drug may increase uteroplacental perfusion without adverse fetal outcome.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Female; Isoenzymes; Nitric Oxide; Organ Size; Perfusion; Placenta; Pregnancy; Pregnancy, Animal; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pyrazoles; Rabbits; Sulfonamides; Thromboxane B2; Time Factors

There is a well-known association between diabetes and atherosclerosis. Platelets are involved in the development of atherosclerotic vascular diseases and play a key role in atherosclerotic complications. Diabetes mellitus is related to alteration in the homeostasis of selenium and the protective role of selenium against lipid peroxidation in diabetes is reported. In the present study, thrombin-induced platelet aggregation and thromboxane A2 (TxA2) formation in diabetes and the effect of sodium selenite were evaluated.. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ) in Wistar rats (n = 21). Thirty of them were used as control rats. A week after streptozotocin injection, 11 of the control rats and 12 of the diabetics were injected with 5 micromol/kg/day of sodium selenite for 4 weeks. Thrombin-induced aggregation of the platelets was evaluated by optical technique. Thromboxane B2 (TxB2), TxA2 metabolite, was measured by enzyme-linked immunoassay (EIA) in thrombin-induced platelets.. The platelet aggregation and TxB2 level increased in diabetic rats. Sodium selenite reversed the increase in platelet aggregation and TxB2 and caused a small but significant (p < 0.05) decrease in the glucose level. The hyperaggregability of platelets in STZ-induced diabetic rats was thought to be related to the enhanced TxA2 formation of platelets. Increase in TxA2 formation implies lipid peroxidation. Sodium selenite decreased the TxA2 formation. Besides its antioxidative effect, further studies are needed to establish the insulin-like effect of selenite because of a small decrease in blood glucose.

Topics: Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Insulin; Lipid Peroxidation; Platelet Activation; Platelet Aggregation; Rats; Rats, Wistar; Sodium Selenite; Streptozocin; Thrombin; Thromboxane A2; Thromboxane B2

Chronic infusion of angiotensin-(1-7) [Ang-(1-7)] lowers blood pressure in salt-induced and spontaneously hypertensive (SHR) rats. In the present study, we have examined the acute effect of Ang-(1-7) in salt-induced hypertension using Dahl salt-sensitive rats placed on low (0.3%) or high (8.0% NaCl) salt diets for 2 weeks. Rats fed a high salt diet showed a greater rise in BP than those fed a low salt diet. Ang-(1-7) (24 microg/kg) reduced mean arterial pressure (MAP), enhanced the release of prostacyclin and nitric oxide, and suppressed thromboxane A(2) levels. A-779 (48 microg/kg, i.v), a selective Ang-(1-7) antagonist, partially blocked these effects of Ang-(1-7). The Ang-(1-7)-induced depressor response observed in these animals was related to an increase in vasodilatory prostanoids, a decrease in the constrictor prostanoid thromboxane A(2), and an increase in nitric oxide levels in both plasma and isolated aortic rings.

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin I; Angiotensin II; Animals; Blood Pressure; Body Weight; Cyclic GMP; Dinoprostone; Epoprostenol; Hypertension; Male; Nitric Oxide; Peptide Fragments; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Dahl; Rats, Inbred SHR; Salts; Thromboxane A2; Thromboxane B2; Time Factors

Although it is well known that dietary lipids affect the course of glomerulonephritis in rats and humans, the precise mechanisms involved have not been fully elucidated. The aim of this study was to investigate the effects of different types of dietary lipids (fish oil and vegetable oil) on daunomycin (DM)-induced nephropathy in mice fed on soybean oil (SO) or cod liver oil (CLO). Urinary protein excretion, serum albumin, creatinine, total cholesterol, and TG were measured, and glomerular histological changes were evaluated. Antioxidant enzymes were also measured, along with the levels of lipid peroxide, GSH, thromboxane (Tx) B2, and 6-keto prostaglandin F1alpha in renal cortical tissue. Dietary CLO significantly reduced urinary albumin excretion and ameliorated the histological changes induced by DM. The increase of tissue lipid peroxide levels seen in SO-fed mice was suppressed in CLO-fed mice, whereas CLO-fed mice showed higher GSH levels than SO-fed mice throughout the experiment. In addition, renal tissue GSH peroxidase activity was significantly higher at 72 h after DM injection in CLO-DM mice than in SO-DM mice. Both renal cortical TxB2 and 6-keto PGF1alpha levels were significantly lower in CLO-DM mice than in SO-DM mice. These results suggest that inhibition of oxidative damage by dietary CLO played an important role in the prevention of DM nephropathy in this mouse model. The effect of CLO was closely associated with the inhibition of Tx synthesis.

Topics: Albuminuria; Animals; Body Weight; Cod Liver Oil; Daunorubicin; Dietary Fats; Dinoprost; Glutathione; Kidney; Kidney Diseases; Lipid Peroxides; Male; Mice; Mice, Inbred Strains; Soybean Oil; Thromboxane B2

Amtolmetin guacyl (CAS 873344-06-7, MED 15) is a non-steroidal anti-inflammatory drug (NSAID) which has shown gastroprotective effects attributable to capsaicin receptor stimulation through the presence of a vanillic moiety in its molecular structure. The present paper further defines the anti-inflammatory activity of the product in an exudative rat model and in an arthritic rat model. The results obtained from both studies demonstrate anti-inflammatory effects comparable to those of the traditional NSAIDs in use. This study also demonstrated that amtolmetin guacyl possesses high antiaggregatory activity comparable to acetylsalicylic acid (CAS 50-78-2), when expressed as inhibition of blood thromboxane synthesis; the in vitro antiaggregatory activity was decidedly superior to that expressed by either acetylsalicylic acid or tolmetin (CAS 26171-23-3) (a traditional NSAID and metabolite of amtolmetin guacyl). The characteristics of gastroprotection along with control of inflammation and platelet aggregation render amtolmetin guacyl recommendable in the treatment of inflammatory and thromboembolic conditions where long-term therapy is required.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anti-Ulcer Agents; Arthritis; Body Weight; Bone Density; Carrageenan; Dose-Response Relationship, Drug; Exudates and Transudates; Glycine; In Vitro Techniques; Indomethacin; Male; Piroxicam; Platelet Aggregation; Platelet Aggregation Inhibitors; Pleurisy; Pyrroles; Rats; Thromboxane B2

In an investigation of the involvement of prostanoids in the pathogenesis of nephropathy in type 2 diabetes, we repeatedly measured the urinary excretion of prostanoids in both diabetic and healthy rats as the rats aged. Seven rats of the Otsuka Long-Evans Tokushima Fatty strain were used as rats with a model of type 2 diabetes and seven rats of the Long-Evans Tokushima Otsuka strain were used as rats without diabetes. Thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1alpha, the amounts of which reflect renal production of TXA2 and PGI2, respectively, and PGE2 in urine collected in metabolic cages were assayed when rats were 14, 30, 46, and 54 weeks old. Plasma glucose and urinary protein excretion also were measured periodically. The mean plasma glucose concentration of the diabetic rats was higher than that of the healthy rats throughout the study. At 30 weeks and later, urinary protein excretion by the diabetic rats was greater than that of the healthy rats, and it increased with age. Urinary excretion of TXB2 by the diabetic rats was higher than that of the healthy rats at 14 weeks (52.4+/-23.5 vs. 27.0+/-2.6 ng/day; mean +/- SD, P = .015) and the difference continued to the end of the experiment. Urinary excretion of 6-keto-PGF1alpha by the diabetic rats was high at 14 weeks (52.3+/-12.8 vs. 26.9+/-4.6 ng/day; mean +/- SD, P<.001) but decreased with age and was the same as that of the healthy rats at 54 weeks. The urinary excretion of PGE2 by the two groups of rats was not significantly different. These results suggest that altered renal production of TXA2 and PGI2 is involved in the pathogenesis of diabetic nephropathy in rats with type 2 diabetes.

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Blood Glucose; Body Weight; Creatinine; Diabetes Mellitus, Type 2; Dinoprostone; Disease Models, Animal; Kidney; Male; Prostaglandins; Rats; Rats, Inbred OLETF; Rats, Long-Evans; Thromboxane B2; Thromboxanes

Atherosclerosis involves a complex array of factors, including leukocyte adhesion and platelet vasoactive factors. Aspirin, which is used to prevent secondary complications of atherosclerosis, inhibits platelet production of thromboxane (Tx) A(2). The actions of TxA(2) as well as of other arachidonic acid products, such as prostaglandin (PG) H(2), PGF(2alpha), hydroxyeicosatetraenoic acids, and isoprostanes, can be effectively antagonized by blocking thromboxane (TP) receptors. The purpose of this study was to determine the role of platelet-derived TxA(2) in atherosclerotic lesion development by comparing the effects of aspirin and the TP receptor antagonist S18886. The effect of 11 weeks of treatment with aspirin (30 mg. kg(-1). d(-1)) or S18886 (5 mg. kg(-1). d(-1)) on aortic root atherosclerotic lesions, serum levels of intercellular adhesion molecule-1 (ICAM-1), and the TxA(2) metabolite TxB(2) was determined in apolipoprotein E-deficient mice at 21 weeks of age. Both treatments did not affect body or heart weight or serum cholesterol levels. Aspirin, to a greater extent than S18886, significantly decreased serum TxB(2) levels, indicating the greater efficacy of aspirin in preventing platelet synthesis of TxA(2). S18886, but not aspirin, significantly decreased aortic root lesions as well as serum ICAM-1 levels. S18886 also prevented the increased expression of ICAM-1 in cultured human endothelial cells stimulated by the TP receptor agonist U46619. These results indicate that inhibition of platelet TxA(2) synthesis with aspirin has no significant effect on atherogenesis or adhesion molecule levels. The effects of S18886 suggest that blockade of TP receptors inhibits atherosclerosis by a mechanism independent of platelet-derived TxA(2), perhaps by preventing the expression of adhesion molecules whose expression is stimulated by eicosanoids other than TxA(2).

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta; Apolipoproteins E; Arteriosclerosis; Aspirin; Body Weight; Cell Adhesion; Cholesterol; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Naphthalenes; Platelet Aggregation Inhibitors; Propionates; Receptors, Thromboxane; Tetrahydronaphthalenes; Thromboxane A2; Thromboxane B2; U937 Cells; Umbilical Veins; Vasoconstrictor Agents

1. Endothelial dysfunction has been described with ageing but the mechanisms responsible have not been clearly elucidated and might be different from one vessel to the other. This study assesses the relative contribution of endothelial nitric oxide (NO) and cyclo-oxygenase (COX) metabolites in relaxation to acetylcholine with ageing in the aorta and the small mesenteric artery of the rat. 2. In the aorta and branch II or III of superior mesenteric artery (SMA), endothelium-dependent relaxation to acetylcholine was not different between 12 - 14 (adult) and 32-week-old rats whereas it was reduced at 70 - 100 (old) weeks of age. 3. Despite an increased endothelial NO-synthase protein expression, the NO-synthase inhibitor, N(G)-nitro-L-arginine-sensitive component of relaxation decreased with ageing. 4. In old rats, exposure to the COX inhibitor, indomethacin, but not the selective COX-2 inhibitor, NS-398, potentiated response to acetylcholine. The thromboxane A(2)/prostaglandin H(2) receptor antagonist, GR 32191B enhanced relaxation to acetylcholine in aorta but it had no effect in SMA. Furthermore, acetylcholine increased thromboxane B(2) production (enzymeimmunoassay) in aorta but not in SMA. Finally, Western blot analysis showed enhanced expression of COX-1 and 2 in the two arteries with ageing. 5. These results suggest that the decrease in acetylcholine-induced relaxation with ageing involves reduced NO-mediated dilatation and increased generation of vasoconstrictor prostanoids most likely from COX-1. They also point out vascular bed heterogeneity related to the nature of prostanoids involved between the aorta (i.e., thromboxane A(2)) and the SMA (unidentified) arteries even though increased expression of COX occurs in both vessels.

Topics: Acetylcholine; Aging; Animals; Aorta; Blood Pressure; Blotting, Western; Body Weight; Cyclooxygenase 1; Cyclooxygenase 2; Eicosanoids; Endothelium, Vascular; Isoenzymes; Male; Membrane Proteins; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Thromboxane B2; Vasodilation

Cyclosporine (CsA) (45 mg/kg/day for 7 days) administration in female Wistar rats induced significant decrease in creatinine clearance (Ccr) and body weight loss (BWL). Urine volume (V) was not altered and proteinuria (PU) not provoked. These changes were associated with increased urinary endothelin 1 (ET-1) and thromboxane B(2)(TXB(2)) concentrations, and decreased urinary ratios of prostaglandin (6ketoPGF(1 alpha)and PGE(2)) to TXB(2)excretions. Nifedipine (NFD) (0.1 mg/kg/day for 7 days), a calcium channel blocker, administrated in addition to CsA, to another group of animals, significantly augmented Ccr and urine V but did not prevent BWL in comparison to CsA-only treated rats. The urinary ET-1 and TXB(2)concentrations displayed significant and non-significant decrease respectively, while the urinary excretion ratios of 6ketoPGF(1 alpha)/TXB(2)and PGE(2)/TXB(2)were significantly enhanced.These observations indicate that the partial protection of NFD in CsA-induced nephrotoxicity could be attributed to augmented urinary prostanoid ratios of renal vasodilators (6ketoPGF(1 alpha)and PGE(2)) to vasoconstrictor (TXB(2)) excretions, and also to reduced release of rather renal origin ET-1, the most potent mamalian vasoconstrictor peptide known to date. In a previous study, we found that NFD only slightly prevented structural renal damage, induced by CsA. So, the NFD protection refers only to functional toxicity and not to structural damage, mediated at least in part by the preservation of relatively high renal TXB(2)levels. However, other nephrotoxic factors and additional mechanisms could also be implicated in this CsA-induced syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Calcium Channel Blockers; Creatinine; Cyclosporine; Dinoprostone; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Enzyme Inhibitors; Female; Immunoassay; Kidney; Nifedipine; Proteinuria; Rats; Rats, Wistar; Spectrophotometry; Thromboxane B2; Urine

Nitric oxide (NO) has been identified as an effective vascular relaxant. This study analyses the contribution of the precursor L-arginine (L-arg) by oral administration in two kidney-two clip hypertension in the rat (2K-2C). Two groups were studied: sham (SH, n=21) and hypertensive (HT, n=15). After 4 weeks of surgery, a group of rats remained as controls (SHc and HTc, respectively), while others were supplemented with L-arg (1.25 g/L) in drinking water (SHa and HTa) for 3 weeks. Blood pressure was significantly increased in 2K-2C rats but remained unchanged after L-arg treatment. Plasma nitrite/nitrate concentrations were not different among groups. The contractile response of aorta to KCl, serotonin and the protein kinase C (PKC) stimulant, phorbol 12,13-dibutyrate (PDBu) was also evaluated. Higher contractile responses to PDBu (p<0.001) and lower relaxation to acetylcholine (Ach 10(-6) M, p<0.05 and 10(-5)M, p<0.02) were observed in aortic rings of HTc vs SHc; L-arg supplementation significantly diminished tension development to all agonists (p<0.05) but failed to modify the lower relaxation to Ach in HTa. Thromboxane (TxA(2)) - synthesis in rings of HTc was higher than in SHc under basal conditions (p<0.05). In the groups with supplement of L-arg, PDBu significantly stimulated prostacyclin (PGI(2)) synthesis more in HTa rats than in SHa ones (p<0.05). To conclude: 1) L-arg fails to modify hypertension development in 2K-2C rats; and 2) L-arg exerts a beneficial effect on the vascular wall, by reducing contractility in rings from HTa rats; it also improved PGI(2) synthesis under PDBu stimulation. 3) greater PKC activation and TxA(2) production rather than lower NO availability might result in systemic hypertension in 2K-2C rats.

Topics: Acetylcholine; Administration, Oral; Animals; Arginine; Blood Pressure; Body Weight; Epoprostenol; Hypertension; Isotonic Solutions; Kidney; Male; Muscle, Smooth, Vascular; Nitrates; Nitrites; Organ Size; Phorbol 12,13-Dibutyrate; Potassium Chloride; Protein Kinase C; Rats; Rats, Sprague-Dawley; Serotonin; Thromboxane B2; Time Factors

1. The metabolic processes that occur around the tendon during mechanical loading and exercise are undescribed in man. These processes are important for understanding the development of overuse inflammation and injury. 2. A microdialysis technique was used to determine interstitial concentrations of glycerol, glucose, lactate, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) as well as to calculate tissue substrate balance in the peritendinous region of the human Achilles tendon. Recovery of 48-62 % (range) at rest and 70-77 % during exercise were obtained for glycerol, glucose and PGE2. 3. Six young healthy humans were studied at rest, during 30 min of intermittent static plantar flexion of the ankle at a workload corresponding to individual body weight, and during 60 min of recovery. Microdialysis was performed in both legs with simultaneous determination of blood flow by 133Xe washout in the same area, and blood sampling from the radial artery. 4. With exercise, the net release of lactate as well as of glycerol from the peritendinous space of the Achilles tendon increased 2-fold (P < 0.05). Furthermore a 100 % increase in interstitial concentration of PGE2 and TXB2 was found, but it was only significant for TXB2(P < 0.05). As peritendinous blood flow increased 2- to 3-fold during intermittent static contractions, this indicates also that the output of these substances from the tissue increased during exercise. 5. This study indicates that both lipid and carbohydrate metabolism as well as inflammatory activity is accelerated in the peritendinous region of the human Achilles tendon with dynamic loading.

Topics: Achilles Tendon; Adult; Ankle Joint; Body Weight; Dinoprostone; Exercise; Female; Glucose; Glycerol; Humans; Lactates; Male; Microdialysis; Regional Blood Flow; Thromboxane B2; Xenon Radioisotopes

Omega-3 (omega-3) fatty acid rich-fish oil (FO) and vitamin E (vit-E) may delay the progress of certain autoimmune diseases. The present study examined the mechanism of action of omega-3 and omega-6 lipids and vit-E on the serum cytokines and lipid mediators in autoimmune-prone MRL/lpr mice (a model for rheumatoid arthritis, RA). The lpr (lymphoproliferative) gene is overexpressed in these mice causing extensive lymphoproliferation, lupus-like symptoms and accelerated aging.. Weanling female MRL/lpr and congenic control MRL/++ mice were fed 10% corn oil (CO, omega6) or FO-based semipurified diets containing two levels of vitamin E (vit-E-75, I.U. and vit-E-500 I.U./Kg diet) for four months. At the end of the experiment, serum anti-DNA antibodies, cytokines and lipid mediators levels were determined.. The appearance of enlarged lymph nodes was delayed in the mice fed FO, and the FO-500 IU vit-E diet offered further protection against enlargement of lymph nodes. The MRL/lpr mice exhibited significantly higher levels of serum anti-dsDNA antibodies. The FO-fed mice had significantly lower serum IL-6, IL-10, IL-12, TNF-alpha, PGE2, TXB2 and LTB4 levels compared with CO-fed mice. In mice fed 500 IU vit-E diets, the serum IL-6, IL-10, IL-12 and TNF-alpha levels were significantly lower and serum IL-1beta was significantly higher compared to 75 IU-vit-E-fed mice in CO/FO or both. The levels of anti-DNA antibodies, IL-4, IL-6, TNF-alpha, IL-10 and IL-12 were higher in the sera of MRL/lpr mice. The FO diet lowered the levels of these cytokines (except IL-4) and lipid mediators. Adding 500 IU of vit-E to the FO diet further lowered the levels of IL-6, IL-10, IL-12, and TNF-alpha.. It is clear from our observations that the beneficial effects of FO can be enhanced by the addition of 500 IU of vit-E in the diet. The FO diet containing 500 IU of vit-E may specifically modulate the levels of IL-6, IL-10, IL-12 and TNF-alpha and thereby may delay the onset of autoimmunity in the MRL/lpr mouse model. The observations from this study may form a basis for selective nutrition intervention based on specific fatty acids and antioxidants in delaying the progress of RA.

Topics: Animals; Antibodies, Antinuclear; Arthritis, Rheumatoid; Body Weight; Cytokines; Dietary Fats, Unsaturated; Dinoprostone; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Female; Interleukins; Kidney; Leukotriene B4; Mice; Thromboxane B2; Tumor Necrosis Factor-alpha; Vitamin E; Weaning

The main adverse effect of cyclosporine A (CyA) is nephrotoxicity. CyA increases urinary concentrations of thromboxane A2 (TXA2), a potent vasoconstrictor that can be involved in kidney failure induced by CyA. Furthermore, it has been postulated that a relationship exists between oxygen free radicals and the synthesis of arachidonate metabolites in experimental models of CyA nephrotoxicity. We studied the effect of vitamin E (VitE), an oxygen free radical scavenger, on renal function, on glomerular synthesis of thromboxane B2 (TXB2), and on free radicals in rats treated with CyA. Four groups of male Wistar rats were studied: (1) a control group; (2) a group given VitE at 0.05 mg/dl in drinking water for 25 days; (3) a group given CyA at 50 mg/kg body weight/day orally for 10 days; and (3) a group given Vit E + CyA, in which rats were provided with drinking water containing VitE for 15 days and afterwards were treated with VitE and CyA for 10 days. Renal function parameters and glomerular synthesis of TXB2, superoxide anion (02.-), malondialdehyde (MDA), and hydrogen peroxide (H202) were evaluated. CyA decreased body weight, caused deterioration of kidney function and increased glomerular synthesis of TXB2, O2.-, MDA, and H202. Pretreatment with VitE prevented the effects of CyA on kidney function and decreased glomerular synthesis of these mediators. In conclusion, CyA induced glomerular synthesis of reactive oxygen species (ROS) and TxB2. Pretreatment with VitE inhibited acute renal failure induced by CyA, probably by scavenging free radicals and by inhibiting the synthesis of TXB2.

Topics: Animals; Body Weight; Cyclosporine; Free Radical Scavengers; Hydrogen Peroxide; Kidney Diseases; Kidney Glomerulus; Lipid Peroxides; Male; Rats; Rats, Wistar; Reactive Oxygen Species; Superoxides; Thromboxane A2; Thromboxane B2; Vitamin E

Severe Mg deficiency changed mineral homeostasis, induced membrane damage, increased lipid peroxidation and cytokine concentrations, and reduced immunocompetence. In order to investigate whether the pathobiochemical effects correlate directly with the degree of Mg deficiency or whether there might be a threshold with no detectable effects above, diets with 70, 110, 208, 330 and 850 ppm Mg were fed to growing Wistar rats. After feeding the diets for 0, 10, 20 and 30 days parameters of free radical action (malondialdehyde and vitamin E content), mineral content (Mg, Ca, Fe) in various tissues (liver, spleen, heart, kidney, muscle) and plasma parameters (Mg, Ca, Fe, alanine- and aspartate-aminotransferase) were measured. After 30 days 6-keto-prostaglandin F1 alpha, thromboxane B2, tumor necrosis factor-alpha, and immunoglobulins (IgG, IgM, IgA) were additionally analyzed. Tissue Mg content was either unchanged or only slightly reduced in severe Mg deficiency. Tissue Fe content rose when the extracellular Mg concentration was below 0.25 mM. There was a close positive correlation between tissue Fe and malondialdehyde content, and malondialdehyde was negatively correlated with vitamin E content. Below a threshold of about 0.25 mM plasma Mg concentration, transaminases increased in plasma. The same threshold could be observed for the increase of tissue Ca content, except in the kidney where calcifications were found already in mild Mg deficiency. Tumor necrosis factor-alpha and 6-keto-prostaglandin F1 alpha were increased when the plasma Mg concentration was below 0.15 mM, and thromboxane B2 was increased when plasma was lower than 0.25 mM. IgG and IgA were significantly reduced below 0.25 mM plasma Mg and IgM below 0.4 mM plasma Mg. Mild Mg deficiency, therefore, can be compensated and might not lead to pathological symptoms if not combined with other pathobiological conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Animals; Aspartate Aminotransferases; Body Weight; Electrolytes; Erythrocytes; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Magnesium Deficiency; Male; Malondialdehyde; Rats; Rats, Wistar; Thromboxane B2; Tumor Necrosis Factor-alpha; Vitamin E

The effects of fasting for 4 days on the isometric developed tension (IDT) and on the metabolism of labelled glucose and arachidonic acid in uteri from intact and spayed (25 days) rats, were explored. Starvation produces a fall in the contractile activity of intact rats, while in ovariectomized ones, no differences can be seen with respect to their controls. Fasting produces a fall in the glucose metabolism of both intact and ovariectomized rats, being more noticeable in the former group. Indomethacin (5 x 10(-6) M) increases the metabolism of labelled glucose in all experimental groups, significantly. The metabolism of exogenous arachidonic acid into different eicosanoids, PGE2, PGF2 alpha, 6-keto-F1 alpha and TXB2, shows that total food deprivation diminishes significantly the production of PGE2 in intact rats. In contrast, in ovariectomized starved rats, PGE2 increases markedly. The rest of the metabolites studied are not influenced by fasting. These results show that the effects of fasting on the contractile activity and on the release of some metabolites from arachidonic acid by the uteri isolated from intact rats are not seen in ovariectomized animals.

Topics: 6-Ketoprostaglandin F1 alpha; Alprostadil; Animals; Arachidonic Acid; Body Weight; Carbon Dioxide; Dinoprost; Fasting; Female; Glucose; Indomethacin; Isometric Contraction; Ovariectomy; Rats; Thromboxane B2; Uterine Contraction; Uterus

The effects of a soybean oil diet and a high-cholesterol oil (HC) diet, and an HC diet with eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) supplementation, on basal and postpreservative cardiac function of the hearts and on postpreservative renal function of the kidneys from older rats were examined.. Groups 1 through 4 of 100-week-old rats were fed either soybean oil, HC, HC with EPA, or HC with DHA, respectively, for 12 weeks. Blood was collected for analysis of plasma fatty acids, and the heart and left kidney were removed from the rat. In experiment 1, the heart was perfused on a Langendorff apparatus. After evaluation of the cardiac function of each rat, the heart was stored in histidine-tryptophan-ketoglutarate solution for 8 hr at 4 degrees C. The heart was reperfused and the recovery of cardiac function was evaluated. The coronary perfusate during reperfusion was collected to measure 6-keto prostaglandin F1alpha and thromboxane B2. Coronary flow (CF) perfused with Krebs-Henseleit bicarbonate (KHB) solution containing 5-hydroxytryptamine (5-HT) and nitroglycerin were evaluated in the Langendorff mode with atrial pacing (330 beats/min). In experiment 2, the excised left kidney was immediately flushed and preserved with University of Wisconsin solution for 8 hr at 4 degrees C. The kidney was then reperfused with KHB solution and renal function was evaluated.. The plasma and cardiac EPA levels in group 3 were significantly higher than the levels found in the other groups. The plasma and cardiac ratios of EPA to arachidonic acid were significantly higher in groups 3 and 4 than in groups 1 and 2. There were no significant differences in basal cardiac function among any of the diet-fed rats. The percentage values of the recovery of aortic flow, cardiac output (CO), and left ventricular max dp/dt in group 3 and CO in group 4 were significantly higher than in group 2. In addition, the recovery of CF in group 3 tended to be higher than in group 2 (P=0.07). The percentage values of the recovery of aortic flow, CF, CO, and left ventricular max dp/dt in group 1 were significantly lower than in the other dietary groups. CF reperfused with KHB solution containing 5-HT was significantly higher in group 3 than in groups 1 and 2. CF reperfused with KHB solution containing 5-HT was significantly higher in group 4 than in group 1. CF reperfused with KHB solution containing nitroglycerin in group 3 tended to be higher than in groups 1 and 2 (P=0.07). The thromboxame B2 concentrations in the coronary perfusate during reperfusion in groups 3 and 4 were significantly lower than in groups 1 and 2. Fractional sodium reabsorption in group 3 was significantly higher than in group 2. Inulin clearance in groups 3 and 4 was significantly higher than in group 1. The postpreservative urinary flow in group 3 was significantly higher than in groups 1 and 2. The urinary flow was significantly higher in group 4 than in group 1.. These results suggest that EPA administration may attenuate preservation and reperfusion injury and improve the recovery of cardiac and renal functions in hyperlipidemic and older rats. DHA administration may also show beneficial effects on kidney preservation in hyperlipidemic rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Cholesterol, Dietary; Dietary Fats, Unsaturated; Eating; Fatty Acids, Omega-3; Female; Glucose; Heart; Hyperlipidemias; Kidney; Lipids; Nitroglycerin; Organ Preservation; Rats; Rats, Wistar; Reperfusion; Serotonin; Thromboxane B2; Tromethamine

To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin.. Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration.. Eighteen 6-month-old male Beagles, 6 in each group.. After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs. TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F1a (PGF1a) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF(in)-to-TXB2, ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs.. Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis.. Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis.

Topics: Animals; Body Weight; Creatinine; Diet; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Eating; Enzyme Inhibitors; Fatty Acids, Omega-3; Food, Fortified; Gentamicins; Glomerular Filtration Rate; Kidney Cortex; Kidney Diseases; Male; Potassium; Prostaglandins; Protein Synthesis Inhibitors; Pyridines; Random Allocation; Sodium; Thromboxane B2; Thromboxane-A Synthase

Nonsteroidal anti-inflammatory drugs (NSAIDs) have well-characterized inhibitory effects on gastric ulcer healing. A new class of gastrointestinal-sparing, nitric oxide-releasing NSAID derivatives has been recently described. This study was performed to determine if one of these compounds (nitrofenac) would influence healing of a preexisting ulcer.. Seven days after induction of gastric ulcer with serosal acetic acid, daily oral treatment with antiinflammatory doses of diclofenac, nitrofenac, or vehicle was started. After 7 days of treatment, the ulcer area was measured. The effects of misoprostol and two drugs that show in vitro selectivity for inhibiting cyclooxygenase 2 (nabumetone and L745,337) were also assessed.. Diclofenac, nabumetone, and L745,337 had no effect on ulcer healing when compared with vehicle. Only diclofenac significantly decreased hematocrit and weight gain. On the other hand, nitrofenac significantly accelerated healing. Glyceryl trinitrate also significantly and dose dependently accelerated healing. Nitrofenac suppressed cyclooxygenase 1 activity to a similar extent as diclofenac.. These results show that an NO-releasing NSAID derivative and an NO donor could accelerate ulcer healing, whereas a standard NSAID, misoprostol, and two inhibitors of cyclooxygenase 2 had no effect. In addition to sparing the gastrointestinal tract, NO-releasing NSAIDs, despite suppressing cyclooxygenase activity, are capable of accelerating tissue repair.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cyclooxygenase Inhibitors; Diclofenac; Gastric Acid; Hematocrit; Male; Misoprostol; Rats; Rats, Wistar; Stomach Ulcer; Thromboxane B2

1. Patients with obstructive jaundice are especially susceptible to acute renal failure. We have previously observed that in rats with bile duct ligation impaired renal function is associated with increased urinary thromboxane excretion. 2. In the present study we therefore investigated, in rats with bile duct ligation, renal function, urinary thromboxane excretion and thromboxane B2 synthesis by isolated glomeruli as well as the effects of the thromboxane A2/prostaglandin H2 receptor antagonist Daltroban on renal function in rats with bile duct ligation as compared with sham-operated rats. 3. On the fourth day after bile duct ligation (n = 7 rats) endogenous creatinine clearance as an estimate of glomerular filtration rate was significantly reduced to 0.74 +/- 0.05 (SEM) as compared with 1.06 +/- 0.09 ml min-1 g-1 kidney weight in sham-operated rats (n = 7, P < 0.01). In rats with bile duct ligation, urine volume was slightly increased, whereas urinary sodium (Na+) (P < 0.001) and potassium (K+) (P < 0.01) excretion as well as urine osmolarity (P < 0.05) were significantly reduced and lower than in sham-operated rats. 4. Urinary thromboxane excretion was significantly higher in rats with bile duct ligation than in sham-operated rats: 116.6 +/- 22.3 versus 56.8 +/- 10.2 pmol 24 h-1 100 g-1 body weight (P < 0.05). Thromboxane B2 synthesis in glomeruli isolated from rats with bile duct ligation was also significantly higher than in sham-operated rats: 12.6 +/- 2.0 versus 6.4 +/- 0.9 pmol h-1 mg-1 protein (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Animals; Blood Pressure; Body Weight; Cholestasis; Female; Kidney; Kidney Glomerulus; Ligation; Organ Size; Phenylacetates; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sulfonamides; Thromboxane A2; Thromboxane B2

Plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 levels were determined to evaluate their role as predictive indicators for the development and progression of coronary atherosclerosis in young hypercholesterolemic swine. 32 young swine were randomly assigned to the control or atherogenic diet group for 10, 30, 90, or 180 days. Lipid profiles were obtained at the onset and repeated throughout the study. Radioimmunoassays of plasma 6-keto-prostaglandin F1 alpha and thromboxane B2 were recorded at 10 day intervals in the 10 and 30 day subjects and at 30 day intervals in the 90 and 180 day subjects. Sections from the proximal left anterior descending coronary artery were classified based on their histological evidence of atherosclerosis by light microscopy. Hypercholesterolemia was positively correlated with development of coronary atherosclerosis (r = 0.704). However, plasma 6-keto-prostaglandin F1 alpha, thromboxane B2, and the thromboxane B2:6-keto-prostaglandin F1 alpha ratio were not found to be predictive indicators (p > 0.05) for the development or early progression of coronary atherosclerosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteriosclerosis; Body Weight; Diet, Atherogenic; Disease Models, Animal; Epoprostenol; Female; Hematocrit; Hypercholesterolemia; Lipids; Male; Random Allocation; Risk Factors; Swine; Thromboxane A2; Thromboxane B2

Dietary protein restriction ameliorates the decrease in GFR and renal plasma flow that occurs 24 hours after the onset of bilateral ureteral obstruction (BUO). The vasoactive hormones, prostaglandins (PGs) and thromboxane (Tx), have a role in the changes in renal function described above. Thus, we evaluated the effect of dietary protein restriction on the production of PGE2. 6-keto PGF1 alpha and TxB2 and on the activities of cyclooxygenase and phospholipases A2 and C in glomeruli isolated from sham-operated control (SOC) and BUO rats fed a low (6% casein) or a normal protein (23% casein) diet for approximately four weeks. A normal protein diet compared to a low protein diet significantly increased the glomerular production of PGE2, 6-keto PGF1 alpha and TxB2 in SOC rats. Glomeruli of rats with BUO fed a normal protein diet had further increased production of eicosanoids when compared to glomeruli of SOC rats ingesting the same diet. The production rates of eicosanoids correlated well with the activity of cyclooxygenase in the two groups of rats. On the other hand, a low protein diet completely abolished the increase in glomerular eicosanoid production seen in rats with BUO. The synthetic levels of eicosanoids were comparable in low protein-fed SOC and BUO rats, indicating normalization of glomerular eicosanoid production in BUO rats fed a low protein diet. Moreover, there were no significant differences in the activities of cyclooxygenase and phospholipases A2 and C between the SOC and BUO rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Dietary Proteins; Dinoprostone; Eicosanoids; Female; Kidney Glomerulus; Organ Size; Phospholipases; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Thromboxane B2; Ureteral Obstruction

The effects of exercise training on eicosanoid levels were studied in male Wistar rats. One-month-old rats were trained on a drum exerciser at an intensity of around 70% of maximal oxygen consumption for 10 weeks (60 min day-1, 5 days week-1) after familiarization. Some animals of the same age did not exercise and served as a control. Two days after training, several blood vessels, including thoracic aortae, inferior vena cavae, external iliac arteries, external iliac veins, common carotid arteries and jugular veins, were excised and incubated for 10 min. Basal release of prostacyclin from these vessels was determined using [125I]radio-immunoassay (RIA) of 6-keto-PGF1 alpha. The levels of plasma prostacyclin and urinary metabolites of prostacyclin and thromboxane were also determined by RIA. Our results showed that trained animals had lower body weight and urine 11-dehydro-thromboxane B2 levels than the controls (P < 0.001 and P < 0.05, respectively). In contrast, urinary 2,3-dinor-6-keto-PGF1 alpha level was elevated after training (P < 0.05). Nonetheless, prostacyclin levels in plasma and from various dissected vessel segments, except thoracic aorta, did not change significantly after training. These findings suggest that exercise training may affect endogenous eicosanoid levels by increasing the basal release of prostacyclin and reducing the basal thromboxane level.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Cell Count; Body Weight; Epoprostenol; Male; Muscle, Smooth, Vascular; Oxygen Consumption; Physical Exertion; Pulmonary Gas Exchange; Rats; Rats, Wistar; Thromboxane B2; Thromboxanes

The ability of thromboxane synthetase inhibition to reverse acute cyclosporin A (CsA)-induced nephrotoxicity in the rat was investigated. CsA administration (50 mg/kg/day p.o. for 14 days) to male Sprague-Dawley rats caused a significant 50% decline in creatinine clearance rates, an increase in N-acetyl-beta-D-glucosaminidase (NAG) enzymuria and renal tubulointerstitial damage by day 14. These changes were associated with a 5-6-fold increase in urinary thromboxane B2 excretion (from pretreatment values of 28.1 +/- 7.9 to 122.6 +/- 38.9 and 165.8 +/- 39.0 eta g/24 hr body weight on days 7 and 14, respectively). Excretion rates of 6-keto-prostaglandin F1 alpha and prostaglandin E2 were, however, unaffected by CsA administration. Co-treatment with a thromboxane synthetase inhibitor (CGS 12970; 8-[3-methyl-2-(3-pyridyl)-1-indolyl]-octanoic acid) from day 7 (10 mg/kg/day) normalized thromboxane B2 excretion, resulted in creatine clearance rates which were similar to pretreatment values on days 10 and 14, reduced NAG enzymuria on day 10 and prevented acute proximal tubular vacuolation. However, the severity of chronic CsA nephrotoxicity, namely chronic tubular damage and microcalcification at the corticomedullary junction, was not diminished by the thromboxane synthetase inhibition. These results demonstrate that (i) elevated thromboxane synthesis plays an important role in the development of acute CsA nephrotoxicity and (ii) that different and/or additional mechanisms are involved in the pathogenesis of chronic nephrotoxicity.

Topics: Animals; Body Weight; Cyclosporine; Enzyme Inhibitors; Kidney Diseases; Male; Prostaglandins; Pyridines; Rats; Rats, Sprague-Dawley; Thromboxane B2; Thromboxane-A Synthase

The effect of highly purified eicosapentaenoic acid ethyl ester (EPA-E) on colitis was investigated using a guinea pig model. The technique for preparing a degraded carrageenan with a molecular weight of about 30,000 from commercial iota-carrageenan was first refined. When this degraded carrageenan was fed to guinea pigs, localized ulcerations occurred in the cecum with infiltration of numerous mononuclear phagocytes. Oral administration of 300 mg.kg-1.day-1 of EPA-E for 3 weeks significantly prevented the development of colitis. The amounts of prostaglandin E2, thromboxane B2, and leukotriene B4 released from the cecal mucosa were also measured. The release of prostaglandin E2 and thromboxane B2 was significantly decreased in the animals fed EPA-E compared with those given olive oil or a vehicle alone. In addition, there was a positive correlation between the amounts of these eicosanoids and the degree of ulcer formation. However, there was no difference in the amount of leukotriene B4 among various experimental groups of animals. Furthermore, EPA-E feeding induced a significant decrease in the level of arachidonic acid and a significant increase in that of EPA in peritoneal macrophages. These results suggest that EPA has a prophylactic effect on the development of carrageenan-induced colitis, which may be ascribed in part to reduced eicosanoid production.

Topics: Animals; Body Weight; Carrageenan; Cecal Diseases; Colitis; Dinoprostone; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Fatty Acids; Guinea Pigs; Leukotriene B4; Macrophages; Male; Occult Blood; Thromboxane B2; Ulcer

1. To investigate possible mechanisms of increased systolic blood pressure after 1 weeks treatment with dexamethasone and its amelioration by fish oil feeding, we have examined the reactivity of aortic rings and perfused mesenteric resistance vessels. 2. Thirty six Sprague-Dawley rats were initially divided into two groups and fed a semisynthetic diet containing either (10% by weight) hydrogenated coconut oil and safflower oil mixture (HCO/S) (24 rats) or fish oil (12 rats) for 5 weeks. From the end of the fourth week, dexamethasone (1.25 mg ml-1) in drinking water, was given to half the rats on hydrogenated coconut oil (HCO/S+Dex) and to the fish oil-fed group (fish oil+Dex). 3. One week of dexamethasone treatment raised systolic blood pressure in the HCO/S+Dex rats but not in the fish oil+Dex group. 4. Endothelium-dependent relaxation to acetylcholine (ACh) was decreased in aortic rings taken from HCO/S+Dex rats compared to rats on HCO/S alone. Relaxant responses to ACh of aortic rings from rats given fish oil+Dex were intermediate between the three groups. Aortic endothelium-independent responses to sodium nitroprusside (SNP) were unchanged between the groups, while aortic contractile responses to noradrenaline were similar in all the groups. 5. In the perfused mesenteric resistance artery, sensitivity to noradrenaline was decreased in rats given fish oil and dexamethasone compared to the other two groups. There were no differences in resistance vessel relaxation to ACh or SNP between groups. 6. Serum corticosterone levels, used as a marker of dexamethasone absorption, were substantially suppressed in dexamethasone-treated rats but levels were higher in rats on fish oil than on HCO/S diets. 7. We suggest that the glucocorticoid-induced rise in systolic blood pressure may be due in part to decreased aortic compliance as a consequence of impaired endothelium-dependent relaxation and perhaps reduced nitric oxide synthesis. Fish oil feeding may ameliorate this rise in blood pressure through (i) changes in dexamethasone absorption, (ii) decrease in reactivity to noradrenaline of perfused mesenteric resistance arteries, (iii) an increase in endothelium-dependent relaxation to ACh or a combination of these three factors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Corticosterone; Dexamethasone; Electrolytes; Endothelium, Vascular; Fatty Acids; Fish Oils; Glucocorticoids; Hypertension; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Rats; Rats, Sprague-Dawley; Splanchnic Circulation; Thromboxane B2; Vascular Resistance

The glomerular functional and structural changes in a murine model (MRL-lpr/lpr) of progressive lupus nephritis were studied. Animals were grouped into three age categories. (I, 14 wk; II, 20 wk; and III, 26 wk). GFR fell with age (257 +/- 43, 178 +/- 50, and 150 +/- 40 microL/min for Groups I through III, respectively). Similarly, the ultrafiltration coefficient (Kf) measured on isolated glomeruli fell with time (0.030 +/- 0.006, 0.023 +/- 0.006, and 0.013 +/- 0.002 nL/s/mm Hg, respectively). Both indomethacin and a selective thromboxane receptor antagonist L-670,596 significantly improved GFR in Group II animals to values seen in Group I animals. Neither agent had any effect to increase GFR in older group III animals. L-670,596 had no effect on Kf in Group II or III animals. Glomerular morphometric evaluation demonstrated a progressive rise in glomerular tuft volume, mesangial matrix expansion, proliferation in cells, and a reduction in open capillary loops and epithelial filtration slits with age. However, because of the increase in glomerular volume, calculated surface area remained well preserved over the three respective groups (61 +/- 18, 76 +/- 15, and 71 +/- 13 microns2 x 10(3)). Therefore, the fall in Kf is likely due to a fall in hydraulic permeability (Lp). The ultrastructural component of the glomerular capillary wall that correlated best with Lp was the epithelial filtration slit number per micrometer of glomerular basement length (r = 0.73; P < 0.0001), which suggests that the structural correlate Kf is in the filtration slit length (FSL). Despite the cell proliferation and mesangial matrix expansion in early disease (Group II), the overall FSL remains stable because of a slight increase in filtration surface area and a slight reduction in epithelial slits per micrometer of glomerular basement membrane. The fall in GFR appears to be hemodynamically mediated by thromboxane A2. In older Group III animals, the fall in GFR appears to be due to a 40% reduction in FSL rather than being hemodynamically based. Thus, the early improvement in function with pharmacological agents is deceptive because considerable disease may be present because of adaptive structural changes. Eventually, with disease progression, compensating hemodynamic and structural factors fail to maintain GFR within normal limits.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Carbazoles; Female; Glomerular Filtration Rate; Hematocrit; Indomethacin; Kidney Glomerulus; Lupus Nephritis; Mice; Mice, Inbred Strains; Mice, Mutant Strains; Organ Size; Renal Circulation; Thromboxane B2

This study investigated whether hemostatic function can be modified by both the consumption of fish oil and the level of dietary selenium. Male Sprague-Dawley rats were fed for 8 wk semipurified diets containing 7% corn oil (by wt) or 5.5% fish oil (MaxEPA) plus 1.5% corn oil with or without selenium supplementation. Consumption of the four diets caused no difference in weight gain, food intake or plasma malondialdehyde content. The selenium-supplemented rats had significantly higher levels of selenium and glutathione peroxidase activity in plasma. Fish oil feeding decreased ADP-induced platelet aggregation and increased bleeding time. The level of dietary selenium and type of oil interacted to influence the production of 6-keto-prostaglandin F1 alpha: more was produced when corn oil was fed in the selenium-deficient diets. These data suggest that the effect of dietary selenium on hemostatic function and the production of eicosanoids is minor.

Topics: Administration, Oral; Animals; Arachidonic Acids; Body Weight; Dietary Fats; Fish Oils; Lipids; Male; Malondialdehyde; Organ Size; Platelet Aggregation; Rats; Rats, Inbred Strains; Selenium; Thromboxane B2

To examine the effects of endogenous thromboxane A2 on the development of diabetic nephropathy, we administered OKY-046, an inhibitor of thromboxane synthesis, to streptozotocin-induced diabetic rats. Animals were divided into three groups; nondiabetic control, diabetic, and diabetic with OKY-046, and were sacrificed 16 weeks after experimental procedures. The chronic oral administration of OKY-046 to diabetic rats significantly decreased plasma and urinary thromboxane B2 levels. Urinary protein excretion and serum glucose levels were significantly lower in the OKY-046-treated diabetic rats than in the untreated diabetics (60.8 +/- 23.2 vs. 94.1 +/- 33.4 mg/day in the 16th week, p less than 0.05 and 424.4 +/- 93.3 vs. 614.4 +/- 102.3 mg/dl in the 16th week, p less than 0.01, respectively). Platelet aggregation was inhibited by OKY-046. Blood urea nitrogen was unaffected. Ultrastructural examination revealed that the thickness of glomerular basement membrane was markedly thinner in the OKY-046-treated diabetic rats than in the untreated diabetics (197.4 +/- 29.6 vs. 288.6 +/- 46.9 nm, p less than 0.01). These results suggest that thromboxane A2 may play an important role in the development and progression of diabetic nephropathy in rats.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Insulin; Kidney; Male; Methacrylates; Microscopy, Electron; Platelet Aggregation; Proteinuria; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Eicosanoids are modulators of defensive and inflammatory processes in the gut mucosa, and may be involved in the pathogenesis of chronic inflammatory lesions of the bowel. As omega-3 fatty acids compete with the omega-6 as precursors of eicosanoid synthesis, we compared the effects of dietary supplementation with either sunflower (source of omega-6) or cod liver (source of omega-3) oil on the development of chronic granulomatous lesions in the rat colon. After four weeks on the supplemented diets, plasma omega-6 fatty acid content was significantly higher in the sunflower group, while omega-3 fatty acids predominated in the cod liver group. Inflammatory colitis was then induced by intracolonic administration of trinitrobenzene sulphonic acid. Luminal eicosanoid release, as measured by radioimmunoassay of intracolonic dialysis fluid, increased significantly after the challenge in both groups. Generation of prostaglandin E2 (PGE2) and leucotriene B4 (LTB4) peaked by day 3 and thereafter declined; thromboxane B2 (TXB2), instead, continued to increase from day 3 to 20 in sunflower fed rats, whereas this change was blunted in cod liver animals. The rats were killed 20, 30, or 50 days after the induction of colitis, and the colonic lesions were scored macroscopically (adhesions to surrounding tissues, strictures, ulcerations, and wall thickness) and histologically (ulceration, inflammation, depth of the lesions, and fibrosis). In cod liver animals, the damage score was markedly reduced by day 30, and inflammation and ulceration were almost absent by day 50. In conclusion, a fish oil diet prevents the increase in thromboxane in the chronic state of inflammation and shortens the course of the colonic disease by diminishing both the severity of the lesions and their progression to chronicity.

Topics: Animals; Body Weight; Cod Liver Oil; Crohn Disease; Dietary Fats; Dinoprostone; Fatty Acids; Fatty Acids, Omega-3; Fish Oils; Helianthus; Leukotriene B4; Male; Plant Oils; Rats; Rats, Inbred Strains; Thromboxane B2; Trinitrobenzenesulfonic Acid

The vasodepressor responses to intravenous injections of arachidonic acid, and the formation of its metabolites, were studied in rats made diabetic 1 or 2 weeks after a 1-dose alloxan treatment. Arachidonic acid dose-dependently decreased the diastolic blood pressure in normal animals, but this hypotensive effect was significantly weaker in 2-week postalloxan-treated rats. Indometacin abolished arachidonic-acid-induced depressor responses in both normal and diabetic animals. Hypotension induced by sodium nitroprusside was of the same magnitude in non-diabetic and insulin deficient rats. Plasma levels of thromboxane B2 were significantly increased in both the 1- and 2-week diabetic rats, being greater in the latter group; those of 6-keto-PGF1 alpha remained unchanged during the 2-week diabetic period. It is concluded that the attenuation by diabetes of depressor responses to arachidonic acid could be due to changes in the thromboxane/prostacyclin balance, with thromboxane formation being elevated whereas prostacyclin generation remains unaffected.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Male; Nitroprusside; Rats; Rats, Inbred Strains; Thromboxane A2; Thromboxane B2

We examined the relationship between glomerular filtration rate (GFR), as assessed by inulin clearance, and glomerular prostaglandin and thromboxane production as a function of glycemic control in control rats and rats that had had streptozocin-induced diabetes for 2 months. In severely hyperglycemic (plasma glucose level 644 +/- 40 mg/dl) rats with streptozocin-induced diabetes that had not been treated with insulin, GFR was reduced to values below those in control rats by 2 months, whether data were expressed as milliliters per minute or as a function of kidney weight. By contrast, treatment of the diabetic rats with insulin to maintain moderate hyperglycemia (plasma glucose concentration 398 +/- 40 mg/dl) resulted in a persistent elevation of GFR compared with values in control rats. Basal production of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), the stable metabolic product of prostaglandin I2 (PGl2), by glomeruli isolated from the moderately hyperglycemic rats was higher than corresponding values of glomeruli from control rats. Differences in PGE2 and 6-keto-PGF1 alpha production by glomeruli from moderately hyperglycemic and control rats were abolished by addition of arachidonate to the incubation mixture, supporting a role for enhanced availability of arachidonate in the mediation of altered vasodilatory prostaglandin production. By contrast, glomerular production of thromboxane B2 (TXB2), the stable metabolic product of thromboxane A2 (TXA2), was not different in moderately hyperglycemic rats compared with controls. Thus, enhanced production of vasodilatory prostaglandins by glomeruli from moderately hyperglycemic rats was associated with an increase in GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Dinoprostone; Female; Glomerular Filtration Rate; Insulin; Kidney Glomerulus; Organ Size; Prostaglandins; Rats; Rats, Inbred Strains; Streptozocin; Thromboxane B2; Thromboxanes

Furosemide causes both diuretic and non-diuretic changes in renal function. We compared responses to intravenous furosemide 0.5 mg.kg-1 in 38 subjects (30 males, 8 females) aged 18 to 30 with those in 14 subjects (9 males, 5 females) aged 50 and over. There were no consistent differences attributable to gender. Older persons showed greater natriuresis (47 percent in males and 26 percent in females) but their increment in plasma renin activity was markedly reduced. The urinary excretion of thromboxane B2 was elevated in older subjects (58 +/- 10 vs. 30 +/- 4 ng/4 h, p less than 0.05 for males; 48 +/- 7 vs. 29 +/- 4 ng/4 hr, p less than 0.05 for females) while that of 6-keto prostaglandin F1 alpha was not different. While differences in the diuretic response to furosemide may be due to pharmacokinetic differences, the non-diuretic response differences may reflect age related changes in renal prostaglandin synthesis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aging; Blood Pressure; Body Weight; Diuresis; Female; Furosemide; Heart Rate; Humans; Injections, Intravenous; Kidney; Male; Middle Aged; Prostaglandins; Renin; Thromboxane B2

Measurements were made of PGE2, PGF2 and TXB2 in the urine of male and female Munich-Wistar rats. Initial urine were collected in the awake state in metabolic cages and were followed by collections of ureteral urine during surgery and anesthesia both before and during cyclooxygenase inhibition with indomethacin. The excretion rate of all eicosinoids in the awake state was similar between the sexes. PGE2 excretion remained unaffected after anesthesia/surgery in both sexes indicating that providing plasma volume is maintained, the PGE2 system is not activated by the stress of anesthesia/surgery. Near complete inhibition of PGE2 was observed during indomethacin administration in both sexes. TXB2 excretion rates rose in both males and females with anesthesia/surgery and were slightly suppressed during indomethacin in males only. PGF2 excretion rose following surgery/anesthesia and was statistically significant in female rats. During indomethacin, TXB2 excretion was moderately reduced in male rats and unaffected in the female. Near complete inhibition of PGF2 was observed during indomethacin in both sexes. The urinary eicosinoid responses to indomethacin seen in these studies failed to provide an explanation for our earlier observations of a fall in renal vascular resistance in the female rat, studied under anesthesia and during indomethacin administration.

Topics: Anesthesia; Animals; Body Weight; Dinoprost; Dinoprostone; Eicosanoic Acids; Female; Male; Rats; Rats, Inbred Strains; Sex Factors; Surgical Procedures, Operative; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Weight; Creatinine; Cyclosporins; Dinoprostone; Kidney; Prostaglandins E; Pyridines; Rats; Thromboxane B2; Thromboxane-A Synthase

1. Dietary suppression of prostanoid synthesis with fish oils has had little effect on blood pressure in models of experimental hypertension in rats. However, a pressor effect of dietary fish oils was observed in spontaneously hypertensive rats (SHR) subject to 1 week of salt loading. 2. Animals were allocated to semisynthetic diets containing either 10% by weight Max EPA fish oil or a control diet of coconut oil, and studied after receiving 1.5% saline for 4 weeks. 3. Within the first week of salt loading, SHR-fed fish oil showed an increase in blood pressure (mean = 9 mmHg) relative to controls. This effect was transient, and after the first week of salt loading there was little difference in blood pressure between the two dietary groups. 4. Following dietary treatment there were substantial changes in plasma fatty acid composition with a 48% decrease in arachidonic acid content of fish oil-fed rats compared with control animals. Rats on the fish oil diet showed a threefold decrease in serum thromboxane generation. Prostacyclin production by incubated segments of aorta was reduced by more than 50% compared with the coconut oil-fed control group. 5. SHR on the fish oil diet showed increased urine volume and sodium excretion, presumably due to increased fluid and salt intake. 6. This study shows that dietary suppression of prostacyclin synthesis is associated with only a minor effect on blood pressure in long-term salt loading of SHR.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Weight; Chromatography, Gas; Diet; Eicosanoids; Fatty Acids, Nonesterified; Fish Oils; Hypertension; Male; Platelet Activating Factor; Potassium; Rats; Rats, Inbred SHR; Sodium; Thromboxane B2; Urodynamics

The lamprey (Entosphenus japonicus Martens) has been recommended in Japan as an efficacious diet for curing some of chronic inflammatory disorders. Fresh lamprey is rich in n-3 unsaturated fatty acids (e.g., eicosapentaenoic and docosahexaenoic acids) with minimal seasonal variation. The dietary effect of lamprey oil on acute myocardial ischemia was therefore investigated. Rats were fed a control diet or a diet supplemented with 5% safflower oil (SO) or 5% lamprey oil (LO) for 4 weeks. After coronary artery ligation, rats fed the LO diet demonstrated a higher 24-h survival rate and a reduced loss of creatine kinase activity from ischemic myocardium when compared with rats fed the control or SO diet. Moreover, the intracellular redistribution of lysosomal enzyme activity in the ischemic myocardium was significantly suppressed in the LO diet group. Analysis of the fatty acid composition of myocardial phospholipids in rats fed LO showed marked elevation of n-3 fatty acids, whereas arachidonic acid (n-6) content was significantly reduced. Hence, the n-3/n-6 ratio of myocardial phospholipids was markedly increased in the LO diet group. In addition, there was more than a 77% reduction in TXB2 synthetic capacity in whole blood in rats fed the LO diet when compared with rats fed either the control or SO diet. In conclusion, dietary supplementation with LO prevents sudden cardiac death and limits the extension of cellular damage from acute myocardial ischemia in rats. Both changes in thromboxane generation and altered membrane fatty acid composition may be involved in the observed reduction of ischemic damage in the heart.

Topics: Animals; Body Weight; Coronary Disease; Dietary Fats, Unsaturated; Fatty Acids; Fish Oils; Heart; Hematologic Tests; Lampreys; Male; Organ Size; Rats; Rats, Inbred Strains; Thromboxane B2

1. The effects of jaundice on renal and circulatory function were investigated in chronic bile duct ligated (CBDL) rats 6 days after surgery. Sham operated (SO) animals served as controls. 2. Body weight was significantly reduced, whereas blood pressure remained unaltered, 6 days after bile duct ligation when serum bilirubin had risen to 169 +/- 18 (SEM) as compared with 2.8 +/- 0.3 mumol/l in SO rats. When compared with control values before surgery, urinary volume had significantly increased and absolute excretion of sodium, potassium, chloride and phosphate had decreased on day 6 after CBDL. Endogenous creatinine clearance was markedly depressed when compared with SO rats. Whereas fractional excretion of potassium remained unaltered, fractional excretion of sodium and of phosphate was significantly increased. 3. Except for a significant increase in urinary thromboxane B2 (TXB2) excretion in CBDL rats, no significant changes were observed in urinary excretion of prostaglandin (PG) E2, in the synthesis of PGE2, 6-keto-PGF1 alpha and TXB2 by isolated aortic tissue in vitro, nor in renal and cardiac adenosine triphosphatase activities or renal cortical mitochondrial function. 4. The adenosine triphosphate content of kidney cortex and cardiac mitochondrial function were significantly depressed in CBDL rats. 5. The results demonstrate that jaundice in CBDL rats is associated with functional and metabolic disturbances of the kidney and cardiac muscle, which may contribute to the renal and haemodynamic characteristics observed in jaundiced animals and humans.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Body Weight; Cholestasis; Dinoprostone; Female; Heart; Kidney; Myocardium; Prostaglandins E; Rats; Rats, Inbred Strains; Sodium-Potassium-Exchanging ATPase; Thromboxane B2

Monocrotaline pyrrole (MCTP) causes pulmonary endothelial cell injury and pulmonary hypertension in rats. Damage to endothelial cells in culture has been associated with altered prostacyclin (PGI2) production; therefore, it was of interest to determine if MCTP affected pulmonary PGI2 production. Release of the stable metabolites of PGI2 and thromboxane A2, 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) and thromboxane B2 (TxB2), respectively, was examined in isolated, buffer-perfused lungs from MCTP-treated rats at times when elevated pulmonary arterial pressure is first observed (day 7) and when the pulmonary hypertensive state has existed for some time (day 14), 6-keto PGF1 alpha release was not affected by MCTP treatment 7 or 14 days after a single intravenous injection of MCTP. TxB2 release was also unaffected at day 7, however 14 days after treatment TxB2 release was greater in lungs from MCTP-treated rats compared to controls. The concentration of both 6-keto PGF1 alpha and TxB2 increased when arachidonic acid was infused into lungs from control or treated rats. These data indicate that MCTP treatment increases the release of TxB2 from isolated lungs at a time when pulmonary hypertension is well-established, but not during early development of pulmonary hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Body Weight; Hydrostatic Pressure; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Organ Size; Perfusion; Pyrrolizidine Alkaloids; Rats; Thromboxane B2; Time Factors

1. This study investigated the effects of dietary modification of prostaglandin (PG) synthesis on blood pressure regulation in DOCA/salt-treated rats. 2. After an initial 4 week period on either a 2-series PG 'inhibitory' diet of fish oil (Max EPA), A 'stimulatory' diet of safflower oil or a control diet of saturated fat, three groups of rats were placed on a DOCA/salt regimen for a further 4 weeks. Another group on the saturated fat diet continued their diet without DOCA/salt administration. 3. All the DOCA-treated groups showed a marked increase in blood pressure. However, both polyunsaturated fat (PUFA)-fed groups had blood pressures significantly lower then the saturated fat control. 4. Rats on the Max EPA showed impaired ability to generate prostanoids in vitro (serum, aorta and kidney) and in vivo (urinary PG excretion). DOCA administration increased urinary PGE2 excretion. 5. Thus, dietary suppression of 2-series PG is not accompanied by accelerated DOCA/salt hypertension. The reduction in blood pressure observed in both the safflower and Max EPA-fed groups may be due to PUFA-induced changes in cell membrane fluidity.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Weight; Desoxycorticosterone; Dietary Fats; Electrolytes; Hypertension; Kidney; Lipids; Male; Prostaglandins; Rats; Rats, Inbred Strains; Renin; Sodium Chloride; Thromboxane B2

A selective inhibitor of thromboxane synthase, Ro 22-3581 has been shown to be a useful tool for investigating the relationship between hyperinsulinemia and obesity. These studies have established that the pharmacologic normalization of the hyperinsulinemia associated with elevated weights in genetically obese and diet-induced obese rats resulted in decreased weight gain or weight loss. This effect was shown to be reversible, partially independent of the suppression of food intake, dependent on a functional endocrine pancreas, and not diabetogenic. However, these studies have not established a cause and effect relationship between the inhibition of thromboxane synthase activity by Ro 22-3581 and its suppression of insulin secretion and circulating insulin levels.

Topics: Animals; Body Weight; Diabetes Mellitus, Experimental; Imidazoles; Insulin; Obesity; Rats; Rats, Zucker; Thromboxane B2; Thromboxane-A Synthase

Vitamin E and linoleate, both of which are found in high concentrations in sunflower seed oil, were examined independently for their influence on general and blood-vascular parameters in vitamin E-deficient common marmosets. A vitamin E-deficient diet (-E, 4 micrograms/g) was supplemented with either 40 micrograms/g vitamin E (+E), vitamin E stripped sunflower oil (+10% SSO-E), or SSO (+10% SSO w/w) in a 2 x 2 factorial designed experiment, and the diets fed for 9 months to 4 even groups of common marmosets. Vitamin E deficiency was associated in marmosets with a loss of skeletal muscle mass and of body weight, enhanced peroxidative haemolysis of erythrocytes, increased white blood cell counts, and in the SSO-E group a relative neutrophilia. Platelet reactivity was increased with vitamin E deficiency, and to a greater degree with the SSO-E group. Aortic prostacyclin production was significantly increased by the addition of vitamin E, linoleate and both as SSO to the deficient diet, the effects being additive. Fatty acid changes associated with the different treatments reflected the influence of high linoleate and vitamin E treatments. The platelet and aortic arachidonate value in the SSO-E group showed the lowest and most variable value, and this was associated with greatest platelet aggregability. An adequate vitamin E intake is essential for stabilising high PUFA diets and biomembranes and enhancing the protective role of prostacyclin in blood vessels against thrombogenesis.

Topics: Animals; Aorta; Blood Platelets; Body Weight; Callithrix; Dietary Fats, Unsaturated; Fatty Acids; Female; Hemolysis; Leukocyte Count; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Muscles; Organ Size; Plant Oils; Platelet Aggregation; Prostaglandins; Prostaglandins F; Sunflower Oil; Thromboxane B2; Vitamin E; Vitamin E Deficiency

Reduction of renal mass in the rat results in an increased glomerular prostaglandin (PG) and thromboxane (TX) formation that modulates renal hemodynamics. To evaluate whether dietary protein intake could exert effects on renal PG and TX formation after reduction of approximately 70% of renal mass, rats with remnant kidneys were placed on either a high-protein (HP) or a low-protein (LP) diet. After 2 wk on the diet, proteinuria, glomerular filtration rate (GFR), urinary PGE2 excretion, and glomerular PGE2, 6-keto PGF1 alpha, and TxB2 biosynthesis were significantly greater in the rats on HP diets. Two-wk administration of the thromboxane synthesis inhibitor UK 38485 reduced renal TxB2 formation by approximately 70%. In addition, chronic UK 38485 treatment significantly inhibited papillary PGE2 production. Neither chronic nor bolus administration of UK 38485 had an effect on proteinuria or GFR in rats on HP diets. Chronic UK 38485 treatment, however, reduced GFR and proteinuria in rats on LP diets. The bolus administration of UK 38485 did not alter GFR in animals receiving a LP diet. The cyclooxygenase inhibitor indomethacin reduced GFR only in rats on HP diets. The data demonstrate that HP intake stimulates renal prostanoid formation. The increased prostaglandin formation on HP intake modulates GFR in these rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Body Weight; Dietary Proteins; Dinoprostone; Imidazoles; Indomethacin; Inulin; Kidney Glomerulus; Organ Size; Prostaglandins; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2

Male weanling F-344 rats were maintained on selenium-supplemented or -deficient diets and were exposed to fresh cigarette smoke daily for 28 weeks. The deficient status of animals was demonstrated by a significant reduction in the pulmonary and hepatic glutathione peroxidase (GSH-Px) activity of rats on selenium-deficient diet. Sham and smoke treatment did not influence the GSH-Px activity in either diet group. Elevated levels of blood carboxyhemoglobin and pulmonary aryl hydrocarbon hydroxylase activity in the smoke-exposed rats of both diet groups indicated effective inhalation of cigarette smoke by animals. Studies of the extracellular release of arachidonate metabolites by pulmonary alveolar macrophages (PAMs) indicated that resting cells released small amounts of prostaglandin E2 (PGE2), thromboxane B2 (TXB2) and leukotriene B4 (LTB4). Upon phagocytic challenge by opsonized zymosan particles, the release of the three metabolites was substantially increased in all diet and treatment groups. While the release of cyclooxygenase products, PGE2 and TXB2, remained unaffected by cigarette smoke, an inhibition of approximately 50% in the release of lipoxygenase product, LTB4, was observed in cells from selenium-fed animals. In selenium-deficient animals, cigarette smoke almost completely inhibited (greater than 80%) the zymosan-stimulated release of LTB4 by PAMs and additionally caused about 50% reduction in TXB2 release. These results suggest a specific inhibition of lipoxygenase pathway by cigarette smoke in PAMs of selenium-fed rats and suggest that cigarette smoke may additionally impair enzymes of the cyclooxygenase pathway in PAMs of selenium-deficient animals.

Topics: Administration, Oral; Animals; Arachidonic Acid; Arachidonic Acids; Body Weight; Cyclooxygenase Inhibitors; Dinoprostone; Glutathione Peroxidase; Leukotriene B4; Lipoxygenase; Lipoxygenase Inhibitors; Liver; Lung; Macrophages; Male; Nicotiana; Phagocytosis; Plants, Toxic; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Pulmonary Alveoli; Rats; Rats, Inbred F344; Selenium; Smoke; Thromboxane B2

In order to assess the pathophysiological role of the renal Thromboxane (Tx)A2 in genetic hypertension, the urinary excretion of its stable metabolite: the TxB2 was followed in groups of 12 hypertensive (LH), normotensive (LN) and low blood pressure (LL) female rats of the Lyon strains at the ages of 5, 9, 21 and 32 weeks. In the 3 strains studied, the urinary TxB2 excretion markedly decreased between 5 and 9 weeks of age and did change thereafter. In addition, 5 and 9 weeks old rats exhibited an increased urinary TxB2 output compared to LN and LL controls. Since TxA2 is a potent vasoconstrictor, it seems likely to hypothesize that the early increase observed in the renal TxA2 biosynthesis could be one of the primary events occurring during the development of hypertension in this rat model.

Topics: Aging; Animals; Body Weight; Female; Hypertension; Kidney; Rats; Thromboxane A2; Thromboxane B2

1. Lean (ln/ln) and obese (ob/ob) mice were given diets containing a fat source of 100 g evening primrose (Oenothera biennis) oil (fatty acids 18:2n-6, 18:3n-6; EPO) or 100 g cod liver oil (20:5n-3, 22:6n-3; CLO)/kg diet. 2. Weight gain was lower in the ob/ob mice fed on CLO, an effect unrelated to food intake. 3. In the ob/ob mice fed on CLO, thromboxane synthesis by clotting platelets was reduced compared with that in ob/ob mice fed on EPO. 4. The ob/ob CLO-fed mice had lower arachidonic acid but higher levels of n-3 fatty acids in liver, brown adipose tissue and white adipose tissue. 5. The n-3 fatty acids in CLO therefore replaced the n-6 fatty acids in tissue lipids and reduced synthesis of '2 series' prostaglandins in addition to causing lower weight gain in the CLO-fed ob/ob mice.

Topics: Animals; Body Weight; Fatty Acids; Fatty Acids, Essential; Lipids; Male; Mice; Mice, Inbred C57BL; Obesity; Phospholipids; Thromboxane B2

Lewis lung primary carcinomas have been extracted for eicosanoids, and the findings examined in relation to lung metastases. The order of the 5 compounds measured was PGE2 greater than PGE1 greater than PGF2 alpha greater than 6-keto-PGF1 alpha greater than TXB2. On the basis of the observation that the balance of PGI2 and TXA2 is altered in metastasis (Honn et al., 1983), the effects of Nafazatrom, a PGI2 enhancing agent, and imidazole, a thromboxane synthetase inhibitor, were tested. The experimental approach taken was to study spontaneous lung metastases after removal of the primary tumour at 13 days after tumour cell inoculation. Both Nafazatrom and imidazole decreased the lung weight when given during the period either before or after the excision of the primary tumour. There was a general trend toward an increase in the number of small lung nodules (greater than 2 mm) and a decrease in large lung nodules (greater than 2 mm) as a result of the chemotherapy. Mean survival time of the mice was significantly different among the five groups, with the mice surviving the longest in the group treated with Nafazatrom after the excision of the primary tumour.

Topics: Animals; Body Weight; Carcinoma; Imidazoles; Lung; Lung Neoplasms; Mice; Neoplasm Metastasis; Organ Size; Prostaglandins; Prostaglandins E; Prostaglandins F; Pyrazoles; Pyrazolones; Thromboxane B2

A semisynthetic diet containing adequate amounts of vitamin E and 10% (w/w) of a mixture of polyunsaturated oils subjected to heating and characterized by elevated indexes of thermal alteration (polar component, dimer triglyceride, altered triglyceride contents and reduced alpha-tocopherol levels) was fed to growing male rats for a period of eight weeks. It resulted in a selective alteration of the production of vascular eicosanoids (elevation of platelet thromboxane formation and decrease of vascular prostacyclin release) compared to the values found in rats fed a diet containing a fresh mixture of polyunsaturated oils. Major nutritional parameters, plasma lipids and the fatty acid profiles of plasma, liver and heart lipids were not different in the two groups of animals. Supplementation of an excess vitamin E (300 mg/kg) to the diet containing heated fat neutralized the adverse effects of heated fat on vascular eicosanoid production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Platelets; Body Weight; Cooking; Diet; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Hot Temperature; In Vitro Techniques; Lipids; Male; Nutritional Physiological Phenomena; Organ Size; Platelet Aggregation; Rats; Thromboxane B2; Thromboxanes; Time Factors; Vitamin E

This study was designed to examine the effect of dexamethasone treatment on tissue and urinary prostanoids, and to determine whether inhibition of prostaglandin biosynthesis by manipulation of dietary fatty acids accelerates the development of glucocorticoid hypertension. Forty-eight rats were placed on either a 2-series prostaglandin 'inhibitory' diet (cod liver oil/linseed oil) or a control diet of saturated fat for an initial period of 4 weeks. The groups were then divided into two so that half of each received dexamethasone in their drinking water (2.5 mg/l) for 1 week whilst continuing their respective dietary regimens. Rats on the cod liver oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid, and significantly impaired ability to generate serum thromboxane B2 (33%), aortic 6-oxo-prostaglandin F1 alpha (44%), renal homogenate prostaglandin E2 (45%) and 6-oxo-prostaglandin F1 alpha (74%) and urinary prostaglandin E2 (84%) and 6-oxo-prostaglandin F1 alpha (79%). Despite the diminished levels of vasodilator 2-series prostaglandins, the cod liver oil diet prevented the development of glucocorticoid induced hypertension. Relative to their respective dietary controls, dexamethasone treatment resulted in decreased serum thromboxane B2 (20%) but increased aortic 6-oxo-prostaglandin F1 alpha (186%), renal homogenate prostaglandins (127-230%) and urinary excretion of prostaglandin E2 (640-860%) and 6-oxo-prostaglandin F1 alpha (230-365%) in both dietary groups. It therefore seems unlikely that glucocorticoid induced hypertension is a consequence of inhibition of vasodilator prostaglandin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arachidonic Acids; Body Weight; Dexamethasone; Dietary Fats; Dinoprostone; Fatty Acids; Fish Oils; Hypertension; Kidney; Male; Phospholipids; Prostaglandin Antagonists; Prostaglandins E; Rats; Rats, Inbred Strains; Renin; Thromboxane B2

Urinary prostaglandins (PGs) and thromboxane excretion, measured by radioimmunoassay, were examined in male Wistar rats made diabetic with streptozotocin, 70 mg/kg. In addition, immunoreactive (i) 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) production by aortic rings was studied as well as conversion of [14C] arachidonic acid (AA) by aortic rings, polymorphonuclear leukocytes, and macrophages isolated from diabetic and age-matched control rats. The profile of urinary eicosanoid excretion changed after induction of diabetes. iPGF2 alpha excretion transiently increased, reaching a peak at 7 days and declining to control values by 48 days. iPGE2 excretion declined with time after induction of diabetes while marked increases in i thromboxane B2 and i6-keto-PGF1 alpha excretion occurred within 48 h and were maintained for the duration of the study, up to 176 days. However, serum i thromboxane B2 levels were similar in control and diabetic rats. Formation of i6-keto-PGF1 alpha by aortic rings obtained from diabetic rats was approximately one-half that of aortic rings from control rats. Similarly, conversion of [14C]AA revealed a diminished capacity of aortic rings from diabetic rats to synthesize prostacyclin (PGI2) measured as 6-keto-PGF1 alpha. Conversion of [14C]AA by polymorphonuclear leukocytes and macrophages obtained from diabetic rats did not differ from those obtained from control rats. In conclusion, experimental diabetes mellitus is accompanied by temporal alterations in AA metabolism, the functional significance of which is unknown at this time.

Topics: Animals; Aorta; Arachidonic Acid; Arachidonic Acids; Body Weight; Diabetes Mellitus, Experimental; Kidney; Macrophages; Male; Neutrophils; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2; Thromboxanes

Indomethacin and sulindac were used as tools to study the role of renal and/or systemic prostaglandins in the pharmacological response to atenolol. Patients receiving chronic treatment with atenolol 100 mg received indomethacin 50 mg twice daily or sulindac 200 mg twice daily in a randomised crossover trial. Indomethacin significantly reduced the antihypertensive action of atenolol while sulindac had no effect. The role that systemic and/or renal prostaglandins may play in the antihypertensive action of atenolol is discussed with reference to renal PGI2 production and inhibition of platelet cyclo-oxygenase.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Atenolol; Blood Pressure; Body Weight; Drug Interactions; Female; Humans; Hypertension; Indenes; Indomethacin; Male; Middle Aged; Random Allocation; Renin; Sulindac; Thromboxane B2

Intramuscular administration to female rabbits of 2 mg/kg ethinylestradiol every other day for 10 days increased the uptake and incorporation of [14C]arachidonic acid into platelet lipids, and increased the proportion of [14C]arachidonic acid released from platelets after stimulation by thrombin. The conversion of [14C]arachidonic acid to thromboxane B2 did not differ between the control and ethinylestradiol-treated groups. Thus, the results of this study indicate that the major site in the prostaglandin metabolic pathway influenced by estrogen is the incorporation and release of arachidonic acid in platelet phospholipids.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Platelets; Body Weight; Ethinyl Estradiol; Female; Lipids; Prostaglandins; Rabbits; Thromboxane B2

To study the influence of dietary modification on prostaglandin synthesis and on blood pressure regulation, the effects of dietary enrichment with linolenic or linoleic acid was compared with standard rat chow in 3 groups of 13 rats before and after renal artery constriction and contralateral nephrectomy. Before renal artery constriction 4 weeks supplementation with 40 en% linseed oil (53% linolenic acid) increased renal linolenic acid, decreased arachidonic acid, and suppressed synthesis of 6-keto-PGF1 alpha and PGE2 by renal homogenates (33% and 38% respectively, p less than 0.01) compared with standard diet. Rats fed on 40 en % sunflower seed oil (63% linoleic acid) increased renal prostaglandin synthesis (p less than 0.05) compared with linseed oil, but not compared with standard diet. Seven weeks after renal artery constriction renal and aortic 6-keto-PGF1 alpha and PGE2 were suppressed 30% to 50% (p less than 0.05) by linseed oil supplements compared with sunflower seed oil and standard diets. In the sunflower seed oil group aortic 6-keto-PGF1 alpha correlated (r = 0.75, p less than 0.02) with final systolic blood pressure. Final systolic blood pressures were similar in linseed oil (152.9 mm Hg +/- se 3.3, sunflower oil (155.1 +/- se 6.6) and standard diet group (159.0 +/- se 4.2). Thus dietary linseed oil suppressed renal and aortic prostaglandin synthesis but did not accentuate renal hypertension, and linoleic acid supplementation did not protect against 1 kidney 1 clip renal hypertension.

Topics: Animals; Aorta, Abdominal; Body Weight; Dietary Fats; Fatty Acids; Fatty Acids, Unsaturated; Hypertension, Renal; Kidney; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Preincubation of rat platelet-rich plasma (PRP) with ethanol resulted in dose-dependent inhibition of the formation of endoperoxide metabolites (EPM) when the PRP was aggregated by collagen suspension. The inhibition was manifested at concentrations normally attainable in blood of rats or humans by tolerable amounts of ethanol ingestion. Paradoxically, chronic ingestion of ethanol caused enhanced synthesis of EPM in platelets, indicating that the inhibitory effect of ethanol would be temporary, and that it can be reversed as soon as ethanol is eliminated. The level of arachidonic acid in platelet phospholipids of rats fed the ethanol diet was not different from that of the control, indicating that availability of immediate precursor acid would not be a factor for the enhanced synthesis of EPM in the ethanol group. This result suggested that platelets from rats subjected to chronic ethanol ingestion become hyperactive in synthesizing EPM through an unknown mechanism. When citrated whole blood was incubated in the presence of collagen suspension, amounts of EPM synthesized in the ethanol group were not different from those of the control group, but this was due to significant reduction of platelet counts in the ethanol group. Whether the effect of ethanol on other tissues would be similar to that on platelets is unknown. It is tempting to speculate that some of the pathological changes resulting from alcoholism might be mediated through the effect of ethanol on EPM formation.

Topics: Animals; Arachidonic Acids; Blood Platelets; Body Weight; Collagen; Dose-Response Relationship, Drug; Ethanol; Fatty Acids; In Vitro Techniques; Male; Phospholipids; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rats; Thromboxane B2

Topics: Animals; Aorta; Arachidonic Acids; Blood Platelets; Body Weight; Columbidae; Estradiol; Estrone; Female; Lipids; Platelet Aggregation; Prostaglandins; Prostaglandins E; Prostaglandins F; Testosterone; Thromboxane B2