thromboxane-b2 and Disease-Models--Animal

Most available nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both the constitutive cyclooxygenase-1 (COX-1) and the inducible cyclooxygenase-2 (COX-2), resulting in inhibition of prostaglandin (PG) and thromboxane (TX) biosynthesis. The inhibition of COX-2 might be the cause of the favourable anti-inflammatory, analgesic and antipyretic effects of NSAIDs, whereas that of COX-1 might result in unwanted gastrointestinal, renal and possibly other side-effects. Nimesulide is a sulfonanilide compound with anti-inflammatory properties. Its pharmacological profile (better inhibition of PG synthesis in inflammatory areas than in gastric mucosa), suggested that it might be a selective inhibitor of COX-2. In several in vitro assays using either purified COX-2 and COX-1 preparations or cell preparations (both from animal and human origins) expressing COX-1 or COX-2, ten out of eleven different groups have demonstrated that nimesulide selectively inhibits COX-2. The COX-2/ COX-1 inhibitory ratio varies, according to the assay preparation, from about 0.76 to 0.0004 i.e. a 1.3 to 2,512-fold higher selectivity for COX-2 than for COX-1. Moreover, an in vivo whole blood assay performed on healthy volunteers demonstrated a significant fall in COX-2 PGE2 production without any effect on COX-1 TXB2 production in subjects treated with nimesulide (100 mg b.i.d. for 2 weeks) versus no effect on COX-2 PGE2 and an almost total suppression of COX-1 TXB2 in subjects treated with aspirin (300 mg t.i.d. for 2 weeks). Nimesulide can thus be considered a relatively selective COX-2 inhibitor. At the recommended dosage of 100 mg b.i.d., it is as effective an analgesic and anti-inflammatory agent as classical NSAIDs, and a well-tolerated drug with few side-effects according to large-scale open studies and a global evaluation of a large number of controlled and non-controlled comparative trials.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Humans; Inflammation; Isoenzymes; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Sulfonamides; Thromboxane B2

The cardioprotective and antithrombotic activity of molsidomine, a novel therapeutic agent for the treatment of coronary heart disease, was investigated in a series of animal models of myocardial ischemia. Molsidomine given to dogs with marked ST segment elevation (epicardial electrogram), induced by a reduction of left descending coronary artery (LAD) flow to 20% to 30% of the original value, resulted within 40 minutes in complete normalization of ECG changes. In another animal model molsidomine given either before or after occlusion of the LAD significantly reduced infarct size. All these molsidomine effects were accompanied by a marked lowering of preload, resulting in a reduction of extravascular coronary artery resistance and in increased blood flow toward the ischemic zones. In a model of myocardial ischemia and reperfusion in the anesthetized dog, molsidomine had a marked protective effect against the incidence of spontaneous ventricular fibrillation. This effect could also be attributed to the anti-ischemic activity of molsidomine, which would reduce the disparity between the refractory periods in normal and ischemic areas and thus increase ventricular stability. The antithrombotic activity of molsidomine was investigated in dogs in which the left circumflex coronary artery was electrically stimulated, a procedure that leads to thrombotic occlusion. Molsidomine in a dose-dependent manner prevented coronary thrombotic occlusion and reduced thrombus wet weight and the size of the resulting infarction. These effects of molsidomine were not related to its hemodynamic activity, since nitroglycerin and isosorbide dinitrate had similar hemodynamic effects but did not prevent coronary thrombosis. The antithrombotic activity of molsidomine is probably related to its ability to lower coronary venous blood thromboxane levels.

Topics: Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Dogs; Electric Stimulation; Molsidomine; Nitroglycerin; Oxadiazoles; Sydnones; Thromboxane B2; Vasodilator Agents; Ventricular Fibrillation

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterized by nephritis, in which mortality is largely influenced by the severity of renal involvement. As there are evidences that thromboxane (TX)A2 plays an important role in the pathogenesis of lupus nephritis, we decided to assess the effects of long-term suppression of TXA2 synthesis on the progression of the disease, by designing a study of TXA2-synthase inhibition having adequate size to detect an effect on mortality as the primary end-point. Thus, we randomized 362 NZBxNZW mice (11-week-old at entry) to one of the following treatments: a TXA2 synthase inhibitor, FCE 22178 (300 mg/kg daily), saline or cyclophosphamide (5 mg/mouse weekly x 4 weeks) used as reference treatment. The TXA2 synthase inhibitor suppressed TXA2 biosynthesis, as reflected by urinary TXB2 and 2,3-dinor-TXB2 excretion (by 78% and 90%, respectively) and significantly reduced mortality (death rate: 34% vs. 61% in controls, at 37 weeks, P < 0.01). A significant reduction in proteinuria (9 +/- 1.6 vs. 17.3 +/- 2.4 mg/24 hr in FCE 22178 vs. saline, P < 0.01) and glomerular lesions was observed up to 30 weeks but not at 37 weeks. In contrast, cyclophosphamide prevented the development of proteinuria and histologic lesions, and reduced mortality to 8% at 37 weeks. Renal plasma flow and glomerular filtration rate were lower (by 29% and 52%, respectively) in 37-week-old as compared to young NZBxNZW mice. These parameters were further depressed by cyclophosphamide (by 48% and 45% vs. age-matched controls, respectively, P < 0.01) but were not altered significantly by FCE 22178.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cyclophosphamide; Disease Models, Animal; Female; Fluorescent Antibody Technique; Glomerular Filtration Rate; Imidazoles; Lupus Nephritis; Mice; Mice, Inbred NZB; Naphthalenes; Proteinuria; Survival Rate; Thromboxane B2; Thromboxane-A Synthase

Our previous study demonstrated the types of platelet dysfunction varied at early stage (∼3 h) in trauma-induced coagulopathy (TIC) caused by different types of injuries. And arachidonic acid (AA)-dependent pathway inhibition in platelet seemed to be specific for TIC caused by multiple injury (MI). The aim of this research was to further study AA-dependent pathway inhibition in platelets in a rat model of TIC caused by MI and to explore its potential mechanisms.. Sprague-Dawley rat model of TIC caused by MI was established. We used thrombelastography with platelet mapping as a measure of platelet function to assess the inhibitory extent of AA-dependent activation pathway. Flow cytometry was used to determine the expression of activation-dependent granular protein P-selectin (CD62P). In addition, the plasma levels of 6-Keto-prostaglandin F1 alpha (6-Keto-PGF1α), Prostaglandin E2, and Thromboxane B2 were assessed by enzyme-linked immuno sorbent assay.. The inhibition rate of AA-dependent pathway after injury was significantly higher than that of control. The maximum amplitude decreased in the MI group, compared with that of control. The percentage of CD62P expression in the MI group was remarkably lower than that of control after AA treatment. The plasma concentrations of 6-Keto-PGF1α and PGE2 increased in the MI group.. Platelets inhibition was observed in TIC caused by MI at early stage after injury, which might be partially attributed to AA-dependent activation pathway dysfunction. The increase of plasma Prostacyclin and PGE2 levels may contribute to the inhibition process.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Blood Coagulation Disorders; Blood Platelets; Dinoprostone; Disease Models, Animal; Epoprostenol; Male; Multiple Trauma; P-Selectin; Platelet Activation; Platelet Function Tests; Rats; Rats, Sprague-Dawley; Thrombelastography; Thromboxane B2

Lead (Pb) is a heavy metal with a proven neurotoxic effect. Exposure is particularly dangerous to the developing brain in the pre- and neonatal periods. One postulated mechanism of its neurotoxicity is induction of inflammation. This study analyzed the effect of exposure of rat pups to Pb during periods of brain development on the concentrations of selected cytokines and prostanoids in the forebrain cortex, hippocampus and cerebellum.. Administration of 0.1% lead acetate (PbAc) in drinking water ad libitum, from the first day of gestation to postnatal day 21, resulted in blood Pb in rat pups reaching levels below the threshold considered safe for humans by the Centers for Disease Control and Prevention (10 µg/dL). Enzyme-linked immunosorbent assay (ELISA) method was used to determine the levels of interleukins IL-1β, IL-6, transforming growth factor-β (TGF-β), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2). Western blot and quantitative real-time PCR were used to determine the expression levels of cyclooxygenases COX-1 and COX-2. Finally, Western blot was used to determine the level of nuclear factor kappa B (NF-κB).. In all studied brain structures (forebrain cortex, hippocampus and cerebellum), the administration of Pb caused a significant increase in all studied cytokines and prostanoids (IL-1β, IL-6, TGF-β, PGE2 and TXB2). The protein and mRNA expression of COX-1 and COX-2 increased in all studied brain structures, as did NF-κB expression.. Chronic pre- and neonatal exposure to Pb induces neuroinflammation in the forebrain cortex, hippocampus and cerebellum of rat pups.

Topics: Animals; Animals, Newborn; Biomarkers; Cerebellum; Dinoprostone; Disease Models, Animal; Encephalitis; Female; Hippocampus; Interleukin-1beta; Interleukin-6; Lead; Male; Pregnancy; Prenatal Exposure Delayed Effects; Prosencephalon; Rats; Thromboxane B2; Transforming Growth Factor beta

The present study was designed to explore the regulatory mechanisms and influences of cotinine on deep vein thrombosis (DVT) in rats via the toll-like receptor 4/nuclear factor κ binding (TLR-4/NF-κB) pathway.. In this experimental study, 30 SD rats were randomly assigned to control group, sham operation group, model group, cotinine (10 μg/kg) group, and model + cotinine (10 μg/kg) group. The thromboxane B2 (TXB2), 6-keto-PGF1α, plasminogen activator inhibitor (PAI), tissue plasminogen activator (t-PA), TLR4, NF-κB, and p65 mRNA and protein expression and tissue changes were analyzed by ELISA, Hematoxylin-Eosin (HE) staining, RT-PCR, and Western blot.. There was no significant difference between the control and sham operation groups (P>0.05). The model and cotinine groups showed significantly higher mRNA and protein levels of TXB2, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), PAI, TLR-4, and NF-κB, and significantly lower levels of 6-keto-PGF1α and t-PA than the control and sham operation groups (P<0.05), and the model + cotinine group showed significantly higher mRNA and protein levels of TXB2, IL-6 and TNF-α, PAI, TLR-4, and NF-κB and significantly lower levels of 6-keto-PGF1α and t-PA than the model group (P<0.05).. Cotinine can aggravate thrombus and inflammation in rats with DVT, and the mechanism may be associated with the activation of the TLR-4/NF-κB inflammatory signaling pathway.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Cotinine; Disease Models, Animal; Fibrinolytic Agents; Male; NF-kappa B; Rats, Sprague-Dawley; Signal Transduction; Thromboxane B2; Toll-Like Receptor 4; Venous Thrombosis

This study aims to test the hypothesis that vitamin D deficiency can influence long-chain polyunsaturated fatty acid metabolism through alterations in the one-carbon cycle. Wistar rats (n = 8 per group) were given either a control (1,000 IU D3/kg diet) or a vitamin D deficient (VDD) (0 IU D3/kg diet) diet from pre-pregnancy to delivery. On day 20 of gestation, pregnant female rats were delivered by C-section to collect placenta and blood. VDD group demonstrated high serum parathyroid hormone, low serum phosphate, low plasma folate, higher plasma homocysteine, and higher plasma malondialdehyde levels (P < 0.05 for all) as compared to control. Lower protein levels of placental cystathionine-β-synthase enzyme (P < 0.05) were observed in the VDD group as compared to control. VDD group demonstrated higher placental mRNA levels of the enzymes phospholipase A

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcium; Cyclooxygenase 2; Cystathionine beta-Synthase; Disease Models, Animal; Female; Folic Acid; Gene Expression Regulation; Group II Phospholipases A2; Homocysteine; Humans; Malondialdehyde; Parathyroid Hormone; Phosphates; Placenta; Pregnancy; Rats; Rats, Wistar; Signal Transduction; Thromboxane B2; Vitamin B 12; Vitamin D Deficiency

Although several studies have revealed the role of different lipid mediators in colitis, the comprehensive analysis of their production across different phases of colitis remained unclear. Here, we performed the following analysis in the dextran sodium sulfate (DSS)-induced colitis model using LC-MS/MS. Oral administration of 2% DSS in mice for 4 days resulted in severe intestinal inflammation by day 7, which gradually subsided by day 18. Based on the disease scoring index (assigned on the basis of fecal condition and weight loss), we defined the phases of colitis as induction (days 0-4), acute inflammation (days 4-7), recovery (days 7-9), and late recovery (days 9-18). Across all phases, 58 lipid mediators were detected in the inflamed colon tissue. In the induction phase, the production of n-6 fatty acid-derived prostaglandin E

Topics: Administration, Oral; Animals; Chromatography, Liquid; Colitis; Dextran Sulfate; Dinoprostone; Disease Models, Animal; Inflammation; Leukotrienes; Lipids; Male; Mice; Mice, Inbred C57BL; Tandem Mass Spectrometry; Thromboxane B2

Zhi-Xiong Capsules (ZXC) involving Hirudo, Ligusticum chuanxiong, Salvia miltiorrhiza, Leonurus artemisia, and Pueraria lobata, is an empirical prescription used in Chinese clinics applied for treating cerebral arteriosclerosis and blood-stasis in clinic. However, the mechanism of its antithrombotic activity has not been investigated until now. The present study was designed to investigate its antithrombotic effects, the mechanism of ZXC on anti-thrombus action and to identify the main chemical composition of ZXC using HPLC-DAD-ESI-IT-TOF-MS. Two animal models were used to evaluate the antithrombotic effect of ZXC, the arterial thrombosis model and a venous thrombosis model. ZXC prolonged the plasma recalcification time (PRT), the activated partial thromboplastin time (APTT), the thrombin time (TT) and the prothrombin time (PT) and clearly reduced the content of fibrinogen (FIB) obviously in the arterial thrombosis model. Furthermore, it markedly suppressed the level of TXB

Topics: Acute Disease; Animals; Anticoagulants; Antithrombins; Aspirin; Blood Coagulation; Capsules; Carotid Arteries; Chlorides; Disease Models, Animal; Drug Evaluation, Preclinical; Drugs, Chinese Herbal; Ferric Compounds; Fibrinolysis; Heparin; Lung; Mice; Platelet Activation; Platelet Aggregation; Prostaglandins F; Pulmonary Embolism; Rabbits; Rats, Sprague-Dawley; Thrombolytic Therapy; Thrombosis; Thromboxane B2

Nowadays, bronchial asthma is still a severe disease threatening human health, and it is incumbent upon us to seek effective therapeutic drugs. Mahuang decoction (MHD), a classic famous Chinese prescription, has been used for thousands of years to prevent phlegm from forming, stop coughing and relieve asthma, but the relevant mechanism has not been thoroughly clarified. This study aims to investigate the anti-airway inflammation effect of MHD and the possible molecular mechanism underlying IL21/STAT3 signaling pathway, so as to provide guidance for the treatment of MHD on bronchial asthma.. Specific pathogen free SD rats were randomly divided into 6 groups: normal control group, model group, positive group (Compound methoxyphenamine), MHD-treated groups at doses of 10 ml/kg, 5 ml/kg and 2.5 ml/kg, 10 rats in each group. Except for the normal control group, rats in other groups were sensitized with ovalbumin via introperitoneal injection and challenged with ovalbumin inhalation to trigger asthma model. At 24 h after the last excitation, bronchoalveolar lavage fluid (BALF) of every rat was drawn and the number of inflammatory cells was analyzed using cell counting method. ELISA method was performed to determine the concentrations of TXB. MHD intervention demonstrated a strong inhibitory action on the secretion of inflammatory mediators as well as the inflammatory cell infiltration in pulmonary tissues of asthmatic rats, and also depressed the protein expressions of IL-21, IL-21R, STAT3 and p-STAT3 in pulmonary tissues. MHD effectively mitigates airway inflammation and regulates the IL-21/STAT3 signaling pathway in rat asthma model.

Topics: 6-Ketoprostaglandin F1 alpha; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Ephedra sinica; Leukocyte Count; Lung; Matrix Metalloproteinase 9; Ovalbumin; Phytotherapy; Plant Preparations; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor; Thromboxane B2; Tissue Inhibitor of Metalloproteinase-1

To examine the microvascular pathological characteristics and changes in related injury\ factors in a rat model of acute blood stasis.. A total of 75 Sprague-Dawley rats were divided randomly and equally into a control group\ and four experimental groups assessed at different times after the induction of stasis (0, 1, 3 or 6 h after\ stasis) (n = 15). The acute blood stasis model was established through rat tail-vein injection of\ high-molecular-weight dextran. After Electrocardiograph (ECG) detection at predetermined times (0,\ 1, 3 and 6 h after induction of stasis), the rats were sacrificed and blood and cardiac samples were harvested\ for analysis. Hematoxylin-eosin (HE) staining and transmission electron microscopy were used\ for histopathological detection; an enzyme linked immunosorbent assay (ELISA) was used to detect\ thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-Keto-PGF1α) concentrations; a real-time\ polymerase chain reaction (PCR) reaction system was used to detect intercellular adhesion molecule\ 1 (ICAM-1) and vascular cell adhesion molecule1 (VCAM-1) mRNA expression; western blotting was\ used to detect vascular endothelial cadherin (VE-cadherin) protein expression.. The ST segment in the ECG showed gradual elevation after induction of stasis and continued\ elevation at a high level at 3 and 6 h. The HE staining showed changes in myocardial cell necrosis\ and tissue dissociation after the induction of stasis, along with inflammatory infiltration. Results of\ transmission electron microscopy showed immediate changes in blood stasis and lumen occlusion in\ the microvasculature, along with endothelial cell swelling. After the induction of stasis, TXB2 concentrations\ gradually increased while 6-Keto-PGF(1α) concentrations were immediately significantly reduced.\ The TXB(2)/6-Keto-PGF(1α) ratio was maintained at a high level. ICAM-1 mRNA expression showed\ an unstable elevation while VCAM-1 mRNA expression was significantly reduced after the induction\ of stasis. Compared with the control group, VE-cadherin protein expression increased at 0 and 3 h after\ the induction of stasis, while no change occurred at 1 and 6 h.. The pathological manifestations of acute blood stasis are microvascular blood retention,\ lumen stenosis and even occlusion. The condition is also called "blood coagulation and weep" in\ Traditional Chinese Medicine. The blood stasis model resulted in the injury and necrosis of endothelial\ cells and cardiomyocytes, along with the presence of an imbalance of vasomotor factor levels, platelet\ activation, and increases in the expression of adhesion molecules and endothelial barrier dysfunction,\ which corresponds to "blood failed to nourish" in Traditional Chinese Medicine.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Adhesion Molecules; Disease Models, Animal; Electrocardiography; Heart; Humans; Intercellular Adhesion Molecule-1; Male; Microvessels; Myocardial Infarction; Myocardium; Rats; Rats, Sprague-Dawley; Thromboxane B2; Vascular Cell Adhesion Molecule-1

Astaxanthin (ASTX) is a xanthophyll carotenoid that reduces hemostasis in hyperlipidemic organisms. Its antihemostatic mechanisms remain unclear.. The effects of ASTX on coagulation, the fibrinolytic system and platelet aggregation were investigated in hyperlipidemic rats.. Different doses of ASTX (5, 10 and 30 mg/kg/day, p.o.) were administered for four weeks to high-fat diet-induced hyperlipidemic rats. Serum lipid and lipoprotein levels were measured with an automatic biochemical analyzer. The prothrombin time (PT), activated partial thromboplastin time (APTT) and maximum platelet aggregation rate (MAR) were determined by a coagulation analyzer. The activities of the tissue-type plasminogen activator (t-PA), type-1 plasminogen activator inhibitor (PAI-1) and endothelial nitric oxide synthase (eNOS), as well as the levels of thromboxane B(2) [TXB(2)], 6-keto prostaglandin F(1α) [6-keto-PGF(1α)] and platelet granule membrane protein (GMP-140), were measured with enzyme-linked immunosorbent assay kits. Gene and protein expression levels were analyzed by reverse transcriptase polymerase chain reaction and Western blot, respectively.. ASTX (30 mg/kg) treatment in hyperlipidemic rats reduced serum TG (0.58 ± 0.14 versus 1.12 ± 0.24 mmol/L), serum TC (1.77 ± 0.22 versus 2.24 ± 0.21 mmol/L), serum LDL-C (1.13 ± 0.32 versus 2.04 ± 0.48 mmol/L), serum MDA (69%), plasma MAR (55%), serum TXB2/6-keto-PGF1α (34%) and serum GMP-140 levels (25%), plasma PAI-1 activity (48%) and downregulated the mRNA (33%) and protein (23%) expression of aorta eNOS, the mRNA (79%) and protein (72%) expression levels of aorta PAI-1. However, ASTX (30 mg/kg/d) treatment increased serum SOD activity (2.1 fold), serum GPx activity (1.8 fold), plasma PT (1.3 fold), plasma APTT (1.7 fold), serum NO (1.4-fold), serum 6-keto-PGF1α (1.3 fold).. ASTX reduced blood coagulation and platelet aggregation and promoted fibrinolytic activity in hyperlipidemic rats. These activities were closely correlated with ASTX, maintaining the balance of t-PA/PAI-1, NO/ROS and TXA2/PGI2 in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticoagulants; Biomarkers; Blood Coagulation; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Fibrinolysis; Fibrinolytic Agents; Hyperlipidemias; Lipid Peroxidation; Lipids; Male; Nitric Oxide; Nitric Oxide Synthase Type III; P-Selectin; Partial Thromboplastin Time; Plasminogen Activator Inhibitor 1; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Prothrombin Time; Rats, Sprague-Dawley; Thromboxane B2; Time Factors; Tissue Plasminogen Activator; Xanthophylls

In diabetes-related states of chronic hyperglycaemia elevated concentrations of glucose may alter the functioning of platelet enzymes involved in arachidonic acid metabolism, including prostaglandin H2 synthase (cyclooxygenase) (PGHS, COX). Therefore, the principal aim of this study was to assess the effects of experimental chronic hyperglycaemia on platelet PGHS-1 (COX-1) expression and activity. Blood platelet activation and reactivity were assessed in Sprague-Dawley rats with the 5-month streptozotocin (STZ) diabetes. The PGHS-1 abundance in platelets was evaluated with flow cytometry and Western blotting, while its activity monitored using a high resolution respirometry and the peroxidase fluorescent assay. The production of prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) in platelets were assayed immunoenzymatically. Circulating platelets from diabetic were characterised by increased size, elevated 'priming' and altered reactivity, compared to non-diabetic animals. Both Western blot analysis and flow cytometry revealed significantly elevated expressions of platelet PGHS-1 in STZ-diabetic rats (p < 0.05). We also observed significantly elevated platelet PGHS-1-related arachidonic acid metabolism in diabetic vs. non-diabetic animals, with the use of polarographic (p < 0.05) and total activity assay (p < 0.001). Such increases were accompanied by the elevated production of PGE2 (p < 0.001) and TXB2 (p < 0.05) in diabetic animals. The increased PGHS-1-dependent oxygen consumption and the total activity of PGHS-1 in diabetic animals remained very significant (p < 0.001) also upon adjusting for blood platelet PGHS-1 abundance. Therefore, our results further contribute to the explanation of the increased metabolism of arachidonic acid observed in diabetes.

Topics: Animals; Arachidonic Acid; Biomarkers; Blood Platelets; Cyclooxygenase 1; Diabetes Mellitus, Experimental; Dinoprostone; Disease Models, Animal; Enzyme Activation; Gene Expression; Male; Platelet Activation; Platelet Aggregation; Prostaglandin-Endoperoxide Synthases; Rats; RNA, Messenger; Thromboxane B2

This study aimed to investigate the endothelial function in a canine model of burn injury combined with seawater immersion. The model of burn injury was established. The dogs were randomly divided into four groups including dogs with burn injury (B group), or burn injury combined with seawater immersion (BI group), or only immersion in seawater (I group), or control animals with no injury or immersion (C group). The circulating endothelial cell (CEC) count and coagulation-fibrinolysis parameters were measured. The CEC count in B group increased at 4 h, 7 h, and 10 h after injury and then reduced, whereas it continuously increased to a greater extent in BI group (P < 0.05). The von Willebrand factor (vWF) activity, plasminogen activator inhibitor (PAI-1), and the ratio of thromboxane B2 (TXB2) to 6-keto-prostaglandin F1α (6-K-PGF1α ) in BI group had a marked increase after injury, and the tissue-type plasminogen activator (tPA) in the BI group decreased. Microscope observations revealed thrombus formation in lungs of the animals in BI group, but not in C, I, or B groups. Burn injury causes endothelial dysfunction, and seawater immersion lastingly aggravates this injury, leading to a higher risk of developing thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Blood Coagulation Disorders; Burns; Disease Models, Animal; Dogs; Endothelial Cells; Humans; Immersion; Lung; Plasminogen Activator Inhibitor 1; Seawater; Thromboxane B2; Tissue Plasminogen Activator; von Willebrand Factor

Prostaglandin E2 (PGE2), one of the terminal products in the cyclooxygenase pathway, plays an important role in various inflammatory responses. To determine whether selective inhibition of PGE2 may relieve these inflammatory symptoms, we synthesized a selective PGE2 synthesis inhibitor, compound A [1-(6-fluoro-5,7-dimethyl-1,3-benzothiazol-2-yl)-N-[(1S,2R)-2-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide], then investigated the effects on pyrexia, arthritis and inflammatory pain in guinea pigs. In LPS-stimulated guinea pig macrophages, compound A selectively inhibited inducible PGE2 biosynthesis in a dose-dependent manner whereas enhanced the formation of thromboxane B2 (TXB2). Compound A suppressed yeast-evoked PGE2 production selectively and enhanced the production of TXB2 and 6-keto PGF1αin vivo. In addition, compound A relieved yeast-induced pyrexia and also suppressed paw swelling in an adjuvant-induced arthritis model. The effect on gastrointestinal (GI) ulcer formation was also evaluated and compound A showed a lower GI adverse effect than indomethacin. However, compound A failed to relieve yeast-induced thermal hyperalgesia. These results suggest that selective inhibition of PGE2 synthesis may have anti-pyretic and anti-inflammatory properties without GI side effect, but lack the analgesic efficacy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Benzothiazoles; Depression, Chemical; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fever; Guinea Pigs; Imidazoles; Indomethacin; Inflammation; Macrophages; Pain; Peptic Ulcer; Phenanthrenes; Piperidines; Stimulation, Chemical; Thromboxane B2

Myocardial infarction (MI) is one of the leading causes of death worldwide. Oxidative stress and inflammation play vital role in the development of MI. The Indian basil or Tulsi (Ocimum sanctum Linn.), owing to its antioxidant potential, is used in the traditional system of Indian medicine to treat various disorders. We evaluated methanolic extract of O. sanctum (Tulsi) leaves on inflammation in isoproterenol (ISP) induced MI in rats. ISP-induced MI increased the levels of cardiac markers, phospholipases and phospholipid content. However, the same were reduced on pre-treatment with methanolic extract of O. sanctum leaves. The activities of 5-lipoxygenase and cycloxygenase-2 and levels of leukotriene B4 and thromboxane B2 were also elevated in ISP-treated rats, which were significantly decreased (P < 0.001) in extract pre-treated rats. The enhanced mRNA expressions of nuclear factor kappa-B, 5-lipoxygenase activating protein and receptor for leukotriene B4 on MI induction, were considerably reduced (P < 0.001) on extract pre-treatment. Histopathological analysis also confirmed the findings. The results also revealed the high phenolic content of methanolic extract of O. sanctum leaves. The study demonstrated that methanolic extract of Tulsi leaves can decrease inflammation in the cardiac tissue of ISP-induced MI in rats and its effect may be through downregulation of oxidative stress and arachidonic acid pathway. This cardioprotective effect may be due to the high phenolic content of methanolic extract of O. sanctum leaves.

Topics: Animals; Antioxidants; Disease Models, Animal; Inflammation; Isoproterenol; Leukotriene B4; Male; Medicine, Traditional; Methanol; Myocardial Infarction; NF-kappa B; Ocimum; Oxidative Stress; Phenols; Phospholipids; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thromboxane B2

Ocimum basilicum L. (OBL) is a plant used in traditional Uyghur medicine for the treatment and prevention of cardiovascular disease. In previous studies we had found an antihypertensive and antithrombotic effect suggestive of an effect on prostaglandins, which we attempt to document here.. 6-keto-PGF1α, the metabolite of prostacyclin, and PGE2 were measured in the supernatant of human umbilical vein endothelial cells (HUVEC) and basal or LPS-stimulated mouse coeliac macrophage cultures exposed to OBL ethanol (OBL-E) extracts and petroleum ether, chloroform, ethylacetate and butanol (PE, C, EA, B) fractions. In addition, 6-keto-PGF1α and thromboxane B2 (TXB2) were measured in a rat model of thromboangiitis obliterans exposed or not to OBL.. Short-term exposure to OBL-E dose-dependently increased 6-keto-PGF1α from HUVEC, and long-term (24h) exposure decreased it. OBL-C and OBL-B increased 6-keto-PGF1α, whereas the other fractions tended to decrease it after 24h exposure. The extract and all fractions decreased basal and stimulated PGE2 production, but only OBL-EA and OBL-B reduced PGE2 in stimulated cultures to concentrations below the unstimulated values (P<0.05). In vivo OBL increased 6-keto-PGF1α and decreased TXB2.. OBL and its extracts increased 6-keto-PGF1α and reduced PGE2 and TXB2 production in a dose and time-related manner. This could indicate simultaneous inhibition of COX-2 and stimulation of endothelial COX-1. The butanol fraction seemed most promising in this respect.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Dose-Response Relationship, Drug; Human Umbilical Vein Endothelial Cells; Humans; Macrophages; Male; Medicine, Traditional; Mice; Ocimum basilicum; Plant Extracts; Prostaglandins; Rats; Rats, Sprague-Dawley; Thromboangiitis Obliterans; Thrombosis; Thromboxane B2; Time Factors

To observe the effects of Rubiae Radix et Rhizoma (RRR) and carbonized Rubiae Radix et Rhizoma (CRRR) on the acute blood stasis rat model, and reveal their differences in efficacy.. The acute blood stasis model was induced by subcutaneously injecting adrenaline hydrochloride and soaking in ice water. Yunnan Baiyao was used as the positive control drug, and administered for consecutively seven days. This model was adopted to observe the effect of high, middle and low dose RRR and CRRR groups on hemorheology, thrombin activity, and blood platelet system.. RRR could significantly reduce the wholeblood viscosity and plasma viscosity of blood stasis rats under different shear rates, and showed certain two-way regulating function in hemostasis. It also showed certain effect on ADP-induced platelet aggregation rate, but which was lower than CRRR. CRRR achieved the main hemostatic mechanism by stimulating intrinsic and extrinsic blood coagulation and fibrinogen, and could significantly enhance the platelet aggregation rate of rats in the acute blood stasis model (P <0. 01).. RRR had the effect of removing blood stasis and hemostasis, while CRRR mainly has the hemostatic effect. This further demonstrates the traditional processing theory of "promoting blood circulation with crude herbs and stopping bleeding with processed herbs".

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Coagulation; Carbon; Chemistry, Pharmaceutical; Disease Models, Animal; Drugs, Chinese Herbal; Female; Hemodynamics; Male; Medicine, Chinese Traditional; Rats; Rats, Sprague-Dawley; Rubia; Thromboxane B2

To evaluate the renoprotection effects of non-steroidal anti-inflammatory drugs (NSAIDs) in renal ischemia-reperfusion injury (IRI) and the cyclooxygenase (COX)-1/2 blockade association by indomethacin (IMT) in the mice model.. After the left renal pedicle of mice was clamped, IMT was administrated by intraperitoneal injection with four doses: 1, 3, 5, and 7 mg/kg. Blood and kidney samples were collected 24 h after IRI. The renal functions were assayed by the cytokines and serum creatinine (SCr) using enzyme-linked immunosorbent assay (ELISA) kits. Kidney samples were analyzed by hematoxylin and eosin (H&E) and immunohistochemistry stainings.. The mice administered with 5 mg/kg IMT had a marked reduction in SCr and significantly less tubular damage. The tumor necrosis factor α (TNF-α) activity in renal homogenates and interleukin 6 (IL-6) activity in serum had a marked reduction at doses of 5 and 7 mg/kg IMT. The administration of 3 and 5 mg/kg IMT had a marked reduction in the ratio of thromboxane B2 to 6-keto-prostaglandin F1α. COX-1 and COX-2 stainings were weaker in 5 mg/kg IMT groups than that in the other groups.. There was a dose response in the IMT function of renal IRI in mice, and IMT had a protective effect in a certain dose range. The effect of IMT on mice IRI was related to COX-1/2 blockades.

Topics: Acute Kidney Injury; Animals; Anti-Inflammatory Agents, Non-Steroidal; Creatinine; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Cytokines; Dinoprost; Disease Models, Animal; Immunohistochemistry; Indomethacin; Interleukin-6; Kidney; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Reperfusion Injury; Thromboxane B2; Tumor Necrosis Factor-alpha

The Wistar-Furth (WF) rat strain is usually used in models of full major histocompatibility complex-mismatched kidney transplantation. Because these rats have been demonstrated to be resistant to several models of chronic kidney disease, the aim of the present study was to investigate their potential resistance to renal ischaemia-reperfusion (I/R) injury compared with another strain, namely Wistar-Hanover (WH) rats. Anaesthetized male WH and WF rats were submitted to I/R by occlusion of the left renal artery and contralateral nephrectomy. Urine, blood and tissue samples were collected at different time points after I/R to evaluate renal function, inflammation and tubular injury, along with determination of nitric oxide synthase (NOS) expression and thromboxane A2 (TxA2 ) production. Post-ischaemic renal function was better preserved in WF than WH rats, as evidenced by reduced levels of creatininaemia, urinary neutrophil gelatinase-associated lipocalin excretion and proteinuria. In addition, WF rats had less intrarenal inflammation than WH rats after I/R injury. These observations were associated with maintenance of neuronal NOS expression, along with lower induction of inducible NOS expression in WF versus WH rats. Moreover, WF rats excreted a significantly lower amount of TxB2 . The results indicate that WF rats are more resistant to an I/R injury than WH rats in terms of renal function and inflammation. These observations are associated with differential regulation of intrarenal NOS expression, as well as a reduction in thromboxane production, which could contribute to a better outcome for the postischaemic kidney in WF rats.

Topics: Acute Disease; Animals; Dinoprostone; Disease Models, Animal; Kidney; Kidney Function Tests; Male; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Rats, Inbred WF; Real-Time Polymerase Chain Reaction; Reperfusion Injury; Reverse Transcriptase Polymerase Chain Reaction; Thromboxane A2; Thromboxane B2

Danshensu, a type of dihydroxyphenyl lactic acid, is one of the most abundant active phenolic acids in the dried root of Salvia miltiorrhizae (Lamiaceae)--widely used traditional Chinese medicine. The effects of danshensu on platelet aggregation and thrombus formation in rats were examined using various methods. It was found that danshensu significantly reduced thrombus weight in 2 experimental thrombosis models; dose-dependent inhibition of adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation occurred in normal and blood stasis-induced rats; Danshensu also significantly mitigated blood viscosity, plasma viscosity and hematocrit levels. Moreover, danshensu significantly inhibited venous thrombosis-induced expression of cyclooxygenases-2 (COX-2) rather than cyclooxygenases-1(COX-1) in the venous walls, down regulated thromboxane B2 (TXB2) and up regulated 6-keto prostaglandin F1α (6-keto-PGF1α), normalizing the TXB2/6-keto-PGF1α ratio. In addition, danshensu did not induce gastric lesions and even had protective effects on aspirin-induced ulcer formation at doses as high as 60 mg/kg. These findings suggest that the antithrombotic and antiplatelet aggregation effects of danshensu are attributed to its highly selective inhibition of COX-2 and ability to normalize the thromboxane A2(TXA2)/prostacyclin(PGI2) balance. These findings suggest that danshensu have great prospects in antithrombotic and antiplatelet therapy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Lactates; Platelet Aggregation; Rats; Thromboxane A2; Thromboxane B2; Venous Thrombosis

Epidemiological studies have shown the prevention of cardiovascular diseases through the regular consumption of vegetables. Eruca sativa Mill., commonly known as rocket, is a leafy vegetable that has anti-inflammatory activity. However, its antiplatelet and antithrombotic activities have not been described.. Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL), was evaluated on human platelets: (i) P-selectin expression by flow cytometry; (ii) platelet aggregation induced by ADP, collagen and arachidonic acid; (iii) IL-1β, TGF-β1, CCL5 and thromboxane B2 release; and (iv) activation of NF-κB and PKA by western blot. Furthermore, (v) antithrombotic activity (200 mg/kg) and (vi) bleeding time in murine models were evaluated.. Eruca sativa Mill. aqueous extract (0.1 to 1 mg/mL) inhibited P-selectin expression and platelet aggregation induced by ADP. The release of platelet inflammatory mediators (IL-1β, TGF-β1, CCL5 and thromboxane B2) induced by ADP was inhibited by Eruca sativa Mill. aqueous extract. Furthermore, Eruca sativa Mill. aqueous extract inhibited NF-κB activation. Finally, in murine models, Eruca sativa Mill. aqueous extract showed significant antithrombotic activity and a slight effect on bleeding time.. Eruca sativa Mill. presents antiplatelet and antithrombotic activity.

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Brassicaceae; Chemokine CCL5; Disease Models, Animal; Fibrinolytic Agents; Humans; Interleukin-1beta; Mice; Mice, Inbred C57BL; NF-kappa B; P-Selectin; Plant Extracts; Platelet Aggregation; Platelet Aggregation Inhibitors; Thrombosis; Thromboxane B2; Transforming Growth Factor beta1

Bronchial hyperresponsiveness is a hallmark of asthma and many factors modulate bronchoconstriction episodes. A potential correlation of formaldehyde (FA) inhalation and asthma has been observed; however, the exact role of FA remains controversial. We investigated the effects of FA inhalation on Ovalbumin (OVA) sensitisation using a parameter of respiratory mechanics. The involvement of nitric oxide (NO) and cyclooxygenase-derived products were also evaluated. The rats were submitted, or not, to FA inhalation (1%, 90 min/day, 3 days) and were OVA-sensitised and challenged 14 days later. Our data showed that previous FA exposure in allergic rats reduced bronchial responsiveness, respiratory resistance (Rrs) and elastance (Ers) to methacholine. FA exposure in allergic rats also increased the iNOS gene expression and reduced COX-1. L-NAME treatment exacerbated the bronchial hyporesponsiveness and did not modify the Ers and Rrs, while Indomethacin partially reversed all of the parameters studied. The L-NAME and Indomethacin treatments reduced leukotriene B₄ levels while they increased thromboxane B₂ and prostaglandin E₂. In conclusion, FA exposure prior to OVA sensitisation reduces the respiratory mechanics and the interaction of NO and PGE₂ may be representing a compensatory mechanism in order to protect the lung from bronchoconstriction effects.

Topics: Administration, Inhalation; Airway Resistance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Bronchial Hyperreactivity; Bronchoconstrictor Agents; Cyclooxygenase 1; Dinoprostone; Disease Models, Animal; Eicosanoids; Formaldehyde; Gene Expression Regulation, Enzymologic; Leukotriene B4; Male; Membrane Proteins; Nitric Oxide; Nitric Oxide Synthase Type II; Rats; Rats, Wistar; Respiratory Insufficiency; Respiratory Mucosa; Thromboxane B2

High-mobility-group box protein 1 (HMGB1), as a late mediator of inflammation, plays a key role in inflammatory responses by inducing and extending the production of proinflammatory cytokines. The effect of HGMB1 in the inflammatory disease thromboangiitis obliterans (TAO) is unknown. We aimed to investigate the role of HMGB1 in sodium laurate-induced TAO in rats.. Male Wistar rats were randomly divided into five groups (n=8 each) for treatment: normal, sham-operated, TAO model, and low-dose (15 mg/kg) or high-dose (30 mg/kg) recombinant A box (rA box) infection (administered intraperitoneally once daily for 15 days). The TAO model was induced by sodium laurate and graded by gross appearance on day 15 after femoral artery injection. Histologic changes were measured by histopathology in rat femoral arteries. Plasma levels of HMGB1, thromboxane B2, 6-keto-prostaglandin F1-α, and blood cell counts and blood coagulation levels were measured. Expression of HMGB1, receptor for advanced glycation end-products (RAGE), interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was assessed by immunohistochemistry and immunofluorescence, Western blot analysis, and quantitative reverse-transcription polymerase chain reaction.. The typical signs and symptoms of TAO were observed on day 15 after sodium laurate injection. The expression of HMGB1, RAGE, interleukin-6, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 was markedly increased in rat femoral arteries. Plasma levels of HMGB1 and thromboxane B2 were elevated, but the level of 6-keto-prostaglandin F1-α was decreased. Blood was in a hypercoagulable state, and prothrombin, thrombin, and activated partial thromboplastin times were all significantly shortened, whereas fibrinogen level was increased in TAO rats compared with sham-operated rats. These effects were terminated by the HMGB1 antagonist rA box.. HMGB1 is involved in the inflammatory state in a model of TAO induced by sodium laurate in rats, probably via its receptor RAGE. As the antagonist of HMGB1, rA box can attenuate the development of TAO, which may be a potential therapeutic target for the treatment of TAO.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Binding, Competitive; Blood Cell Count; Blood Coagulation; Blood Coagulation Tests; Blotting, Western; Disease Models, Animal; Femoral Artery; Fluorescent Antibody Technique; HMGB1 Protein; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1; Interleukin-6; Lauric Acids; Male; Peptide Fragments; Rats; Rats, Wistar; Receptor for Advanced Glycation End Products; Receptors, Immunologic; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Thromboangiitis Obliterans; Thromboxane B2; Vascular Cell Adhesion Molecule-1

We have previously shown nutritional intervention with fish oil (n-3 PUFA) to reduce numerous complications associated with the metabolic syndrome (MetS) in the JCR:LA-corpulent (cp) rat. In the present study, we sought to explore the potential role of fish oil to prevent glomerulosclerosis in JCR:LA-cp rats via renal eicosanoid metabolism and lipidomic analysis. Male lean and MetS JCR:LA-cp rats were fed a lipid-balanced diet supplemented with fish oil (5 or 10 % of total fat). After 16 weeks of feeding, albuminuria was significantly reduced in MetS rats supplemented with 5 or 10 % fish oil ( - 53 and - 70 %, respectively, compared with the untreated MetS rats). The 5 % fish oil diet resulted in markedly lower glomerulosclerosis ( - 43 %) in MetS rats and to a lesser extent in those supplemented with 10 % fish oil. Interestingly, untreated MetS rats had higher levels of 11- and 12-hydroxyeicosatetraenoic acids (HETE) v. lean rats. Dietary fish oil reduced these levels, as well as other (5-, 9- and 15-) HETE. Whilst genotype did not alter prostanoid levels, fish oil reduced endogenous renal levels of 6-keto PGF1α (PGI2 metabolite), thromboxane B2 (TxB2), PGF2α and PGD2 by approximately 60 % in rats fed 10 % fish oil, and TxB2 ( - 50 %) and PGF2α ( - 41 %) in rats fed 5 % fish oil. In conclusion, dietary fish oil prevented glomerular damage in MetS rats and mitigated the elevation in renal HETE levels. These results suggest a potential role for dietary fish oil to improve dysfunctional renal eicosanoid metabolism associated with kidney damage during conditions of the MetS.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Dietary Fats; Dietary Supplements; Dinoprost; Disease Models, Animal; Fish Oils; Genotype; Hydroxyeicosatetraenoic Acids; Kidney Diseases; Kidney Glomerulus; Male; Metabolic Syndrome; Prostaglandin D2; Prostaglandins; Rats; Rats, Inbred Strains; Thromboxane B2

Previous studies have demonstrated that statin can reduce the risk of acute coronary syndrome. In order to explore the mechanism, we observed the effects of pravastatin on plaque stability in atherosclerotic rabbits. Sixteen male rabbits were fed with a high fat diet following their damaged abdominal aortic endothelium by using catheter. Eight of them were administered with pravastatin (10 mg·kg(-1)·d(-1)) for 4 weeks. Then the rabbit atherosclerotic plaque rupture and thrombosis were triggered by injection of viper venom and histamine. Compared with model group, the thrombus area on aorta in pravastatin-treated group was reduced. Fibre cap on plaque was more thick and integrant, and inflammatory cell infiltration was also decreased. Serum total cholesterol, triglyceride, low density lipoprotein-cholesterol and contents of cholesterol in abdominal aorta were decreased. 6-Keto-prostaglandin F(1α) (6-keto-PGF(1α)) level and ratio of 6-keto-PGF(1α)/thromboxane B(2) (TXB(2)) in aorta were significantly increased. These results suggested that pravastatin could increase plaque stability and inhibit thrombosis through both lipid-dependent and lipid-independent way.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anticholesteremic Agents; Aorta; Aorta, Abdominal; Atherosclerosis; Cholesterol; Cholesterol, LDL; Diet, High-Fat; Disease Models, Animal; Histamine; Hyperlipidemias; Male; Plaque, Atherosclerotic; Pravastatin; Rabbits; Thrombosis; Thromboxane B2; Triglycerides; Viper Venoms

Sphingosine-1-phosphate (S1P), a potent bioactive lipid, is emerging as a central mediator in inflammation and immune responses. We have previously implicated S1P and its synthetic enzyme sphingosine kinase (SK) in inflammatory and autoimmune disorders, including inflammatory bowel disease and rheumatoid arthritis. Generation of S1P requires phosphorylation of sphingosine by SK, of which there are two isoforms. Numerous studies have implicated SK1 in immune cell trafficking, inflammation and autoimmune disorders. In this study, we set out to determine the role of SK and S1P in lupus nephritis (LN). To this end, we examined S1P and dihydro-S1P (dh-S1P) levels in serum and kidney tissues from a mouse model of LN. Interestingly dh-S1P was significantly elevated in serum and kidney tissue from LN mice, which is more readily phosphorylated by SK2. Therefore, we employed the use of the specific SK2 inhibitor, ABC294640 in our murine model of LN. Treatment with ABC294640 did not improve vascular or interstitial pathology associated with LN. However, mice treated with the SK2 inhibitor did demonstrate decreases in glomerular pathology and accumulation of B and T cells in the spleen these were not statistically different from lpr mice treated with vehicle. LN mice treated with ABC294640 did not have improved urine thromboxane levels or urine proteinuria measurements. Both S1P and dh-S1P levels in circulation were significantly reduced with ABC294640 treatment; however, dh-S1P was actually elevated in kidneys from LN mice treated with ABC294640. Together these data demonstrate a role for SKs in LN; however, they suggest that inhibition of SK1 or perhaps both SK isoforms would better prevent elevations in S1P and dh-S1P and potentially better protect against LN.

Topics: Adamantane; Albumins; Animals; Cell Separation; Disease Models, Animal; Enzyme Inhibitors; Flow Cytometry; Gene Expression Regulation, Enzymologic; Inflammation; Isoenzymes; Kidney Glomerulus; Lupus Nephritis; Mice; Phosphotransferases (Alcohol Group Acceptor); Pyridines; Sphingolipids; Spleen; Thromboxane B2

Post-surgical pericardial adhesions pose an increased risk of complications during redo sternotomies. Adhesive tissue formation is a normal response to tissue injury and involves complex patho-physiological processes including the actions of prostaglandins to cause plasma leakage and fibrin formation. The purpose of this study was to assess the ability of two non-steroidal anti-inflammatory agents (Indomethacin and Rofecoxib) and a barrier (Coseal, a polyethylene glycol) to limit adhesion formation following cardiac surgery in a pig model.. Forty-four piglets were allocated equally to four treatment groups: Group 1: Control, Group 2: intramuscular Indomethacin, Group 3: oral Rofecoxib and Group 4: Coseal sprayed on the heart. A full median sternotomy was performed on each animal and the heart exposed. Adhesions were induced by rubbing tissues with gauze, applying sutures and leaving blood in the pericardial sac before chest closure. Plasma inflammatory markers including prostaglandin E(2) and thromboxane B(2) were measured preoperatively and on Days 2, 5 and 10 after surgery. Eight animals from each group were slaughtered after 12 weeks and 3 after 25 weeks. Adhesions were assessed macroscopically and microscopically.. Compared to the Control group, the extent of adhesions was significantly less in all other groups whilst adhesion density was least in the Indomethacin and Coseal groups. Indomethacin and less so Rofecoxib, inhibited the synthesis of prostaglandin E(2) and thromboxane B(2) but there were no significant changes in other inflammatory markers.. We conclude that systemic Indomethacin, and locally applied Coseal are suitable methods to markedly reduce pericardial and retrosternal adhesions.

Topics: Animals; Biological Availability; Biomarkers; Cyclooxygenase 2 Inhibitors; Dinoprostone; Disease Models, Animal; Drug Monitoring; Indomethacin; Inflammation; Lactones; Pericardium; Perioperative Period; Polyethylene Glycols; Postoperative Complications; Sternotomy; Sulfones; Surface-Active Agents; Swine; Thromboxane B2; Tissue Adhesions; Treatment Outcome

Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPARα activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl(4)-cirrhotic rats.. Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25mg/kg/day, n=10) or its vehicle (n=12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (α-SMA) protein expression, cyclo-oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB(2) production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers.. CCl(4) cirrhotic rats treated with fenofibrate had a significantly lower PP (-29%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX-1 expression and TXB(2) production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed.. PPARα activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis.

Topics: Animals; Blood Pressure; Carbon Tetrachloride; Cyclooxygenase 1; Disease Models, Animal; Endothelium, Vascular; Fibrosis; Hypertension, Portal; Liver; Liver Cirrhosis; Male; PPAR alpha; Rats; Rats, Wistar; Thromboxane B2

Interleukin-18 (IL-18) is an important proinflammatory cytokine. However, little is known about the roles of IL-18 in the process of venous thrombosis. This study aimed to investigate the roles of IL-18 during deep vein thrombosis (DVT).. Fifty rats were randomly divided into 0 (control group), 12, 24, 36 and 48 h groups (10 rats in each group) by observation time. The inferior vena cava (IVC) was ligated to establish the DVT model. Serum samples were extracted to determine the levels of IL-18, tumor necrosis factor-alpha (TNF-α), thromboxane B2 (TXB2) and 6-keto-prostaglandin Fl alpha (6-keto-PG Flα) by enzyme-linked immunosorbent assay (ELISA). The weight and length of IVC was also measured.. The DVT model was successfully established by ligating IVC. The injury of vein endothelium was observed in the model groups. IL-18, TNF-α, TXB2, TXB2/6-keto-PG Flα levels and thrombus weight were significantly increased in the model groups as compared with the control group, and peaked at 24 h after IVC ligation. 6-keto-PG F1α slightly decreased in the model groups comparing with the control group. IL-18 was positively correlated with TNF-α, TXB2, TXB2/6-keto-PG Flα ratio and thrombus weight. However, IL-18 was negatively correlated with 6-keto-PG Flα. There was a positive correlation between TXB2/6-keto-PG Flα ratio and thrombus weight.. Serum IL-18 level increased in the process of DVT, which might impair venous endothelial cells and result in venous thrombosis. IL-18 might be a new potential therapeutic target of DVT prevention.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Inflammation Mediators; Interleukin-18; Ligation; Male; Rats; Rats, Sprague-Dawley; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha; Up-Regulation; Vena Cava, Inferior; Venous Thrombosis

Steatosis accentuates the severity of hepatic ischemia-reperfusion injury (IRI). 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors ("statins") protect the heart and brain against post-ischemic injury, without necessarily lowering serum cholesterol. We tested whether 10-day or 1-day atorvastatin administration protects livers with fatty change or non-alcoholic steatohepatitis (NASH) against IRI.. Mice with dietary or genetic simple steatosis (SS) or NASH were subjected to 60 min of partial hepatic ischemia/24-h reperfusion, with/without atorvastatin administered with food (5 mg/kg body weight) for 10 days, or injected intravenously (5 mg/kg) 24 h before ischemia. Liver injury, Toll-like receptor-4 (TLR4), cytokines/chemokines, endothelial nitric oxide synthase (eNOS), activation and thromboxane B2 production were determined.. Atorvastatin conferred 70-90% hepatic protection against IRI in obese animals with SS or NASH, in which IRI was accentuated twofold to fivefold. IRI markedly upregulated TLR4 and activated nuclear factor-κB (NF-κB); atorvastatin abrogated these effects, as well as activating eNOS. Atorvastatin dampened the post-ischemic induction of thromboxane B2, macrophage inflammatory protein-1a, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin (IL)-12 p40, γ-interferon, IL-6, and adhesion molecules (vascular cell adhesion molecule-1, E-selectin, vascular endothelial-cadherin), and reduced macrophage and neutrophil recruitment. There was no reduction in serum cholesterol that could explain these effects, and hepatic cholesterol was normal in these mice. A single 24-h injection of atorvastatin conferred equivalent hepatoprotection.. Statins exert major hepatoprotection against IRI in lean, fatty, and NASH livers that is not due to cholesterol removal. Rather, statins downregulate TLR4 to prevent NF-κB activation, with resultant suppression of adhesion molecules, chemokines/cytokines, and thromboxane B2 production. Short-term statin treatment is an effective, readily-available preventive agent against hepatic IRI, irrespective of obesity and fatty liver disease.

Topics: Administration, Oral; Animals; Atorvastatin; Cell Adhesion Molecules; Cytokines; Cytoprotection; Disease Models, Animal; Down-Regulation; Drug Administration Schedule; Enzyme Activation; Fatty Liver; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Injections, Intravenous; Liver; Male; Mice; Mice, Obese; NF-kappa B; Nitric Oxide Synthase Type III; Non-alcoholic Fatty Liver Disease; Obesity; Pyrroles; Reperfusion Injury; RNA, Messenger; Thromboxane B2; Time Factors; Toll-Like Receptor 4

Prasugrel, through its active metabolite, reduces atherothrombosis and its clinical manifestations by inhibiting platelet activation and aggregation. Platelets also contribute to inflammation through interaction with different classes of leukocytes. We investigated whether the inhibitory effect of prasugrel on platelets also counteract inflammatory responses. The effect of prasugrel active metabolite, R-138727, was investigated on platelet P-selectin expression, platelet adhesion to polymorphonuclear leukocytes (PMN) and monocytes (MN) and Mac-1 expression in PMN and MN, in vitro, in human cells. The ex vivo effect of prasugrel administration on P-selectin, thromboxane (TXB)2 formation, platelet-PMN conjugates and Mac-1 expression in PMN triggered by PAR-4 agonist peptide was examined in whole blood from healthy mice as well as from mice in which an acute inflammatory reaction was induced by treatment with endotoxin. The effect of prasugrel on inflammatory markers in endotoxin-treated animals was also tested in vivo. R-138727 inhibited agonist-stimulated expression of platelet P-selectin, platelet-PMN and platelet-MN adhesion and platelet-dependent Mac-1 expression in leukocytes. Addition of aspirin did not modify the inhibitory effect elicited by R-138727. Treatment of mice with prasugrel resulted in a profound inhibition of platelet P-selectin expression, TXB2 production, platelet-PMN adhesion and Mac-1 expression in PMN induced by ex vivo stimulation with PAR-4 agonist peptide of whole blood from healthy or endotoxin-treated mice. Measurement of markers revealed that prasugrel reduced TXB2 and tumour necrosis factor-α synthesis and increased nitric oxide metabolites in endotoxin-treated mice in vivo. In conclusion, prasugrel reduces platelet interactions with PMN and MN. Through these effects prasugrel may curb platelet-mediated inflammatory responses.

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Biomarkers; Blood Platelets; Disease Models, Animal; Down-Regulation; Humans; Inflammation Mediators; Leukocytes; Macrophage-1 Antigen; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Piperazines; Platelet Adhesiveness; Platelet Aggregation Inhibitors; Platelet Function Tests; Prasugrel Hydrochloride; Purinergic P2Y Receptor Antagonists; Selenoprotein P; Shock, Septic; Thiophenes; Thromboxane B2; Tumor Necrosis Factor-alpha

Hypoxic pulmonary vasoconstriction (HPV) is a well known phenomenon to temporarily offset a ventilation-perfusion mismatch. Sustained HPV may lead to pulmonary hypertension. In this protocol, we studied the relationships between the HPV response and inducible cyclooxygenase II (COX II) activation after hypoxia-reoxygenation (H-R) challenge in an isolated perfused lung model.. An in situ isolated perfused rat lung model underwent inaction of hypoxia by ventilation with 5% CO(2)-95% N(2) for 10 minutes instead of 5% CO(2)-95% air; they were then reoxygenated with 5% CO(2)-95% air. We measured pulmonary arterial pressure (PAP) changes before, during, and after H-R challenge. We also estimated changes in blood concentrations of hydroxyl radicals, nitric oxide (NO) and thromboxane B(2) (TxB(2)) before and after H-R as well as mRNA expressions of COX II in lung tissue thereafter. A COX II inhibitor, celecoxib (10 mg/kg), was administered between 2 consecutive challenges.. Hypoxia induced pulmonary vasoconstriction by increasing PAP (4.1 ± 0.8 mm Hg). Consecutive hypoxic challenges did not show tachyphylaxis (P > .05). H-R of lung tissues induced significant increases in blood concentrations of hydroxyl radicals (48.5 ± 7.6 vs 75.8 ± 11.5 mmol/L; P < .01), NO (54.3 ± 12.3 vs 77.7 ± 15.7 pmol; P < .05), and TxB(2) (42.3 ± 6.9 vs 58.7 ± 8.6 pg/mL; P < .05). Lung tissue H-R also significantly increased COX II mRNA expression compared with sham tissues (1 ± 0 vs 4.0 ± 2.8; P < .001). The COX II inhibitor celecoxib significantly attenuated HPV responses (P < .05) and attenuated the elevated blood concentrations of TxB(2) (P < .05), hydroxyl radicals (P < .01), nitric oxide (P < .05), and COX II mRNA expression (P < .05) after H-R challenge.. Lung tissue H-R induced significant increases blood concentrations of inflammatory mediators and tissue mRNA expression of COX related to elevation of HPV responses. COX II inhibitor celecoxib attenuated the HPV responses by reducing TxB(2) release.

Topics: Animals; Biomarkers; Blood Pressure; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Disease Models, Animal; Hydroxyl Radical; Hypoxia; Inflammation Mediators; Nitric Oxide; Oxidative Stress; Perfusion; Pulmonary Artery; Pyrazoles; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sulfonamides; Thromboxane B2; Time Factors; Vasoconstriction

To screen the main component of Dahuangzhechong pill's anti-arterial thrombosis with the orthogonal design and refine Dahuangzhechong pills.. In accordance with the orthogonal design table (L(16)2(15)), divided herbs into 16 groups and made the appropriate liquid. The liquid was gave to SD rats by intragastric administration,the model group, normal control group received the same volume of physiological saline. Isolated rats' carotid artery after intragastric administration a week,modeled according to ferric chloride inducement the carotid artery thrombosis method, then collected blood, detected content of platelet, thromboxane B2 (TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha), sheared and measured dry weight of the modeling artery, then placed arteries in 10% formalin fixation, observed morphological changes in vascular tissue by HE staining.. Pathological examination revealed: each experimental group had thrombosis, softening, dissolution, absorption, and intimal injury, but the severity of thrombosis were diferent. Orthogonal analysis showed: 1, influence on dry weight of thrombus: rhubarb, ground beetle, leeches, peach seed, dry paint, except dry paint P<0.05, the others P<0.01.2, influence on plasma 6- keto-PGF1alpha level: peach seed, dry paint, ground beetle, gadfly, grubs, leeches, rhubarb, except rhubarb P<0.05, the others P<0.01.3, influence on plasma TXB2: ground beetle, peach seed, dried paint, rhubarb, leeches, except leech P<0.05, the others P<0.01.4, influence on platelet count: peach seed, dry paint, rhubarb, ground beetle, gadfly, leeches, except gadfly, leeches P<0.05, the others P<0.01.. Anti-artery thrombosis of Dahuangzhechong Pill is most closely related with rhubarb, ground beetle, leeches, peach seed, dry paint and gadfly.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Carotid Artery Thrombosis; Carotid Artery, Common; Disease Models, Animal; Drug Combinations; Drugs, Chinese Herbal; Female; Fibrinolytic Agents; Platelet Aggregation; Random Allocation; Rats; Rats, Sprague-Dawley; Rheum; Thrombolytic Therapy; Thromboxane B2

To investigate the mechanism of gastric mucosal demage induced by water immersion restraint stress (WRS) and its prevention by growth hormone releasing peptide-6 (GHRP-6).. Male Wistar rats were subjected to conscious or unconscious (anesthetized) WRS, simple restraint (SR), free swimming (FS), non-water fluid immersion, immersion without water contact, or rats were placed in a cage surrounded by sand. To explore the sensitivity structures that influence the stress reaction besides skin stimuli, a group the rats had their eyes occluded. Cervical bilateral trunk vagotomy or atropine injection was performed in some rats to assess the parasympathetic role in mucosal damage. Gastric mucosal lesions, acid output and heart rate variability were measured. Plasma renin, endothelin-1 and thromboxane B2 and gastric heat shock protein 70 were also assayed. GHRP-6 was injected [intraperitoneal (IP) or intracerebroventricular (ICV)] 2 h before the onset of stress to observe its potential prevention of the mucosal lesion.. WRS for 6 h induced serious gastric mucosal lesion [lesion area, WRS 81.8 ± 6.4 mm² vs normal control 0.0 ± 0.0 mm², P < 0.01], decreased the heart rate, and increased the heart rate variability and gastric acid secretion, suggesting an increase in vagal nerve-carrying stimuli. The mucosal injury was inversely correlated with water temperature (lesion area, WRS at 35 °C 56.4 ± 5.2 mm² vs WRS at 23 °C 81.8 ± 6.4 mm², P < 0.01) and was consciousness-dependent. The injury could not be prevented by eye occlusion, but could be prevented by avoiding contact of the rat body with the water by dressing it in an impermeable plastic suit. When water was replaced by vegetable oil or liquid paraffin, there were gastric lesions in the same grade of water immersion. When rat were placed in a cage surrounded by sand, there were no gastric lesions. All these data point to a remarkable importance of cutenuous information transmitted to the high neural center that by vagal nerves reaching the gastric mucosa. FS alone also induced serious gastric injury, but SR could not induce gastric injury. Bilateral vagotomy or atropine prevented the WRS-induced mucosal lesion, indicating that increased outflow from the vagal center is a decisive factor in WRS-induced gastric injury. The mucosal lesions were prevented by prior injection of GHRP-6 via IP did, but not via ICV, suggesting that the protection is peripheral, although a sudden injection is not equivalent to a physiological release and uptake, which eventually may affect the vagal center.. From the central nervous system, vagal nerves carry the cutaneous stimuli brought about by the immersion restraint, an experimental model for inducing acute gastric erosions. GHRP-6 prevents the occurrence of these lesions.

Topics: Animals; Anti-Ulcer Agents; Biomarkers; Disease Models, Animal; Endothelin-1; Gastric Acid; Gastric Mucosa; Heart Rate; HSP70 Heat-Shock Proteins; Immersion; Injections, Intraperitoneal; Injections, Intraventricular; Male; Oligopeptides; Parasympatholytics; Photic Stimulation; Rats; Rats, Wistar; Renin; Restraint, Physical; Skin; Stomach Ulcer; Stress, Psychological; Thromboxane B2; Time Factors; Touch; Vagotomy; Vagus Nerve; Water

Several murine models are susceptible to atherosclerosis, such as low density-lipoprotein receptor-deficient (LDLR-/-) and apolipoprotein E-deficient (apoE-/-) mice, and are used for studying pathophysiological mechanisms. Atherosclerotic lesions in the aortic valve and thoracic/abdominal aorta are commonly associated with hyperlipidemia. We recently demonstrated the development of large atherosclerotic plaques in Helicobacter pylori-infected heterozygous LDLR+/- apoE+/- mice.. To measure novel biomarkers related to atherosclerosis, blood coagulation, and oxidative stress in order to investigate their possible pathogenic roles in atherosclerosis-prone mice.. Mice were fed with a normal chow diet or high-fat diet and sacrificed at different age intervals to measure aortic plaque size. Plasma cholesterol was enzymatically measured. Enzyme-linked immunosorbent assay was used to measure oxidized LDL (oxLDL)/beta-2-glycoprotein I (beta2GPI) complexes, immunoglobulin M (IgM) antibodies against native LDL, oxLDL, or oxLDL/beta2GPI, and urine 11-dehydro-thromboxane B2 (11-dhTxB2) or 8-hydroxy-deoxyguanosine.. There was a parallel increase in plaque size, plasma cholesterol, and urinary 11-dhTxB2 in atherosclerosis-prone mice. In contrast to atherosclerosis-prone strains, an elevation of urinary 11-dhTxB2 with no significant plaque generation was observed in LDLR+/- 1 apoE+/- mice. The atherogenic autoantigen oxLDL/beta2GPI complex was detected only in LDLRI mice. These levels seem to depend on plaque size. IgM antibodies against oxLDL in apoE-/- mice were found, accompanied by atherosclerotic progression.. Progression of atherosclerotic lesions was associated not only with hypercholesterolemia but also with platelet activation and natural autoimmune-mediated regulatory mechanism(s) in murine models.

Topics: Animals; Apolipoproteins E; Atherosclerosis; beta 2-Glycoprotein I; Biomarkers; Disease Models, Animal; Immunity, Innate; Immunoglobulin M; Lipoproteins, LDL; Male; Mice; Oxidative Stress; Platelet Activation; Receptors, LDL; Thromboxane B2

To explore the effects and mechanism of electroacupuncture combined with medium frequency therapy on lumbar nerve root compression.. Seventy-two Sprague-Dawley (SD) rats were randomly divided into a normal group, a sham operation group, a model group, an electroacupuncture group (EA group), a medium frequency group(MF group) and an electroacupuncture combined with medium frequency group (EA + MF group), twelve rats in each group. Models were established by surgery except the normal group and the sham operation group. Rats in the normal group, the sham operation group and the model group were not treated. In the EA group, the rats were treated by electroacupuncture at "Jiaji" (EX-B 2) and "Huantiao" (GB 30) etc., and by medium frequency at the "Jiaji" (EX-B 2) and "Huantiao"(GB 30) in the MF group. Rats in the EA + MF group were treated by both electroacupuncture and medium frequency. All treatments were started on the fifth day of established model, once a day for fourteen days. Rats' lower limb functions were observed before and after treatment, thromboxane B 2 (TXB 2) and prostacyclin F1alpha (PGF1alpha) in blood plasma were tested after treatment, and pathological changes in the local compressed nerve root were observed by light microscope.. After treatment, the scores of rats' lower limb neurologic function in three therapy groups were significantly lower than before (all P < 0.01). Compared with the model group, TXB 2 in the EA group and the EA + MF group after treatment were decreased significantly (both P < 0.01), and PGF1alpha in the EA + MF group was increased significantly (P < 0.01), and TXB 2/PGF1alpha level were all regulated favorably in three therapy groups (all P < 0.01), and the pathological scores in the EA group and the EA + MF group were improved significantly (both P < 0.01).. n Electroacupuncture combined with medium frequency has anti-inflammatory and analgesic effects in model rats with lumbar nerve root compression, and its mechanism may be related with the regulation of homeostasis M between TXB 2 and PGF1alpha so as to improve microcirculation.

Topics: Acupuncture Analgesia; Animals; Disease Models, Animal; Electric Stimulation; Electroacupuncture; Epoprostenol; Female; Humans; Lumbar Vertebrae; Male; Radiculopathy; Random Allocation; Rats; Rats, Sprague-Dawley; Thromboxane B2

To expedite the investigation of new devices for inhibiting restenosis, we aimed to develop a modified model of arterial angioplasty and stenting in rats that showed greater face validity than the traditional rat model.. Carotid arteries from Sprague-Dawley rats fed a normal or an atherogenic diet containing a low dose of cholate underwent balloon pre-dilation followed by placement of a bare metal stent. Vessel patency was followed for 28d using ultrasound. Stented vessels were then harvested and were subjected to histologic analysis. Plasma lipid profiles and biomarkers of endothelial dysfunction, inflammation and thrombosis were assessed.. There was significant interaction between stenting injury and the atherogenic diet, leading to higher levels of markers for inflammation, platelet activation, and endothelial dysfunction, as well as neointimal hyperplasia, compared with stented rats on normal chow. There was a significant correlation between plasma IL-6 and TXB(2) in stented rats, a relationship which may have contributed to exaggerated vessel remodeling with increased platelet sensitivity. Compared to normal chow, the atherogenic diet also increased fibrin and proteoglycan deposition near stent struts.. Arterial stenting, in combination with the atherogenic diet, led to exacerbated endothelial dysfunction, inflammation, platelet activation, and vascular remodeling compared with stented rats on normal chow. By reproducing key features of clinical restenosis that are lacking in other rat models, this modified rat model may serve as a valuable screening tool to rapidly evaluate new coatings and devices before moving candidates into expensive, more time-consuming rabbit or porcine models.

Topics: Angioplasty, Balloon; Animals; Arginine; Biomarkers; Carotid Arteries; Carotid Artery Injuries; Carotid Stenosis; Choline Deficiency; Diet, Atherogenic; Disease Models, Animal; Endothelial Cells; Female; Hyperplasia; Inflammation Mediators; Interleukin-6; Lipids; Male; Platelet Activation; Rats; Rats, Sprague-Dawley; Recurrence; Reproducibility of Results; Stents; Thromboxane B2; Time Factors; Ultrasonography, Doppler, Color

To observe the effect of electroacupuncture (EA) on plasma thromboxane B2(TXB2) and 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) levels in dysmenorrhea rats in order to investigate its mechanism underlying relief of primary dysmenorrhea and specificity of acupoint efficacy.. Female SD rats with diestrus were randomly divided into saline control (control), model, EA Sanyinjiao (SP 6), EA Xuehai (SP 10), EA Xuanzhong (GB 39) and EA non-acupoint (NAP) groups, with 10 rats in each. Dysmenorrhea model was established by subcutaneous injection of Estradiol Benzoate (0.5 mg/rat on the 1st and 10th day, and 0.2 mg/rat from the 2nd to the 9th day) and intraperitoneal injection of Oxytocin (0.2 mL/rat, 1 h after last injection of Estradiol Benzoate on the 10th day). EA was applied to bilateral SP 6, SP 10, GB 39, and non-acupoint (the mid-point between the Gallbladder and Stomach meridian at the GB 39 level) for 20 min. The latency and score of writhing were recorded for 20 min. Plasma TXB2 and 6-keto-PGF1alpha contents were detected by radioimmunoassay.. Compared with the control group, the latency of writhing in the model group was shortened considerably (P < 0.01), and the writhing score was increased significantly (P < 0.01). In comparison with the model group, the writhing latency was increased significantly only in the EA-SP 6 group (P < 0.05), and the writhing scores in the EA-SP 6, EA-SP 10, EA-GB 39 and EA-NAP groups were reduced remarkably (P < 0.01). Plasma TXB2 content and the ratio of TXB2/6-keto-PGF1alpha. were significantly higher in the model group than in the control group (P < 0.01). Compared to the model group, plasma TXB2 levels and the ratios of TXB2/6-keto-PGF1alpha. in the EA-SP 6, EA-SP 10, EA-GB 39 and EA-NAP groups were downregulated markedly (P < 0.05, P < 0.01), while plasma 6-keto-PGF1alpha was upregulated strikingly only in the EA-SP 6 group (P < 0.05). No significant differences were found among the EA-SP 6, EA-SP 10, EA-GB 39 and EA-NAP groups in the writhing latency and writhing score, plasma TXB2 and 6-keto-PGF1alpha, levels (P > 0.05).. EA can relieve pain reaction in dysmenorrhea rats, which may be closely associated with its effects in downregulating plasma TXB2, upregulating plasma 6-keto-PGF1alpha, content, and balancing plasma TXB2/6-keto-PGF1alpha. The effect of EA of SP 6 is relatively better.

Topics: 6-Ketoprostaglandin F1 alpha; Acupuncture Analgesia; Acupuncture Points; Animals; Disease Models, Animal; Dysmenorrhea; Electroacupuncture; Female; Humans; Rats; Rats, Sprague-Dawley; Thromboxane B2

In order to study circadian rhythms and decompression sickness (DCS), we determined: 1) the baseline circadian time structure in noncompressed rats of potential response variables to compression/decompression (C/D), and 2) whether rats subjected to C/D display a circadian time-dependent difference in inflammatory response intensity and biological tolerance. Subgroups of male rats, standardized to a 12 h light/12 h dark schedule, were evaluated every 4 h over 24 h after they were either compressed to 683 kPa (group E) or remained at sea level (group C). During 60 min recovery, evaluation included gross DCS symptoms and pulmonary edema in all E rats, and cell counts, nitric oxide, protein, thromboxane B(2,) and leukotriene E(4) levels in survivors. Chi-square, ANOVA, and 24 h cosinor analyses were used to test for time-of-day effects. C/D exposures near the end of dark/activity or during light/resting were generally better tolerated, with lowest signs of DCS symptoms and lowest responses by most of the variables monitored. More deaths were observed in the first half of the dark/activity span. Of the 16 subsets of inflammatory-associated variables, overall increases were observed in 13 and decreases in 2. Significant or borderline significant circadian time effects were found in 14 variables in group C, 12 variables in group E, and 13 variables in response (E%C). Thus, nearly all baseline indices of DCS demonstrated circadian time-dependencies in the sea-level exposed control rats (group C), and nearly all were modified by the circadian time of C/D. Such time-of-day effects of DCS are potentially relevant to the operational concerns of occupations involving decompression exposures and the investigation of prevention and treatment intervention strategies of DCS.

Topics: Animals; Bronchoalveolar Lavage Fluid; Circadian Rhythm; Decompression Sickness; Disease Models, Animal; Inflammation Mediators; Leukocyte Count; Leukotriene E4; Male; Nitric Oxide; Photoperiod; Proteins; Pulmonary Edema; Rats; Rats, Sprague-Dawley; Thromboxane B2

Portal-systemic collateral vascular resistance and vasoconstrictor responsiveness are crucial in portal hypertension and variceal bleeding control. Statins enhance vasodilators production, but their influence on collaterals is unknown. This study aimed to survey the effect of simvastatin on collaterals.. Partially portal vein-ligated rats received oral simvastatin (20 mg/kg/day) or distilled water from -2 to +7 day of ligation. After hemodynamic measurements on the eighth postoperative day, baseline perfusion pressure (i.e. an index of collateral vascular resistance) and arginine vasopressin (AVP, 0.1 nM-0.1 microM) responsiveness were evaluated with an in situ perfusion model for collateral vascular beds. RT-PCR of endothelial NO synthase (eNOS), inducible NOS (iNOS), cyclooxygenase-1 (COX-1), COX-2, thromboxane A(2) synthase (TXA(2)-S) and prostacyclin synthase genes was performed in parallel groups for splenorenal shunt (SRS), the most prominent intra-abdominal collateral vessel. To determine the acute effects of simvastatin, collateral AVP response was assessed with vehicle or simvastatin. SRS RT-PCR of eNOS, iNOS, COX-1, COX-2 and TXA(2)-S, and measurements of perfusate nitrite/nitrate, 6-keto-PGF1(alpha) and TXB(2) levels were performed in parallel groups without AVP.. Acute simvastatin administration enhanced SRS eNOS expression and elevated perfusate nitrite/nitrate and 6-keto-PGF1(alpha) concentrations. Chronic simvastatin treatment reduced baseline collateral vascular resistance and portal pressure and enhanced SRS eNOS, COX-2 and TXA(2)-S mRNA expression. Neither acute nor chronic simvastatin administration influenced collateral AVP responsiveness.. Simvastatin reduces portal-systemic collateral vascular resistance and portal pressure in portal hypertensive rats. This may be related to the enhanced portal-systemic collateral vascular NO and prostacyclin activities.

Topics: Animals; Arginine Vasopressin; Collateral Circulation; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression Regulation, Enzymologic; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension, Portal; Male; Membrane Proteins; Nitrates; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitrites; Portal Pressure; Portal System; Rats; Rats, Sprague-Dawley; RNA, Messenger; Simvastatin; Thromboxane B2; Thromboxane-A Synthase; Time Factors; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents

This study was to evaluate the protective effects of Danshensu on liver injury induced by omethoate in Sprague Dawley rats. The acute omethoate poisoning model was established by administrating subcutaneously with omethoate at a single dose of 60 mg/kg. Danshensu treatment markedly inhibited the increases of aspartate aminotransferase, alanine aminotransferase, cyclooxygenase-2, tumor necrosis factor-alpha, thromboxane B(2), and thromboxane B(2)/6-keto-PGF1alpha ratio induced by omethoate. The histopathological examination further confirmed that administration with Denshensu ameliorated liver injury. The results demonstrated that Danshensu possesses protective action on hepatic injury induced by omethoate and the pharmacological mechanism was related to the anti-inflammatory effect and circulation improvement of Danshensu, at least in part.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Chemoprevention; Cyclooxygenase 2; Dimethoate; Disease Models, Animal; Drugs, Chinese Herbal; Injections, Subcutaneous; Lactates; Liver; Male; Rats; Rats, Sprague-Dawley; Thromboxane B2; Tumor Necrosis Factor-alpha

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

Freund's complete adjuvant (FCA) is an animal model of inflammatory pain commonly used in the screening of COX-inhibitors. However, there is little understanding of how behavioural measures of the anti-inflammatory effect in the FCA model correlate to differences in mechanism of action and whether such endpoints equally reflect drug activity in humans. In the current investigation we evaluate the time course of the analgesic effect for different endpoints after treatment with drugs with varying degrees of selectivity for COX-1 and COX-2. We also assess prostaglandin (PGE(2)) and thromboxane (TXB(2)) inhibition to establish the correlation between behavioural measures and the degree of selectivity for COX-1 and COX-2.. Sprague-Dawley rats were treated with FCA by intra-plantar injection. On post-inoculation day (PID) 7, rats received a single oral dose of naproxen, diclofenac, ketorolac or rofecoxib. Drug treatment continued until PID 21. A control group received placebo only. Behavioural endpoints for inflammatory pain and blood samples for biomarkers were obtained at various time points before and after dosing to characterise the time course of drug effect and disease progression.. COX-inhibitors showed no effect on the dynamic plantar test. In contrast, full analgesia was observed after drug administration for weight bearing capacity (WBC) and paw pressure (PP), with varying duration of the effect for each of the endpoints. No tolerance to drug effect was observed up to 14 days of chronic treatment. Rofecoxib showed an increase in baseline pain threshold values after chronic treatment, which may be related to its pharmacokinetic characteristics.. Changes in paw pressure threshold seem to best reflect the anti-hyperalgesic properties of COX-inhibitors with enough sensitivity to enable estimation of the dose-exposure-response curve.

Topics: Animals; Behavior, Animal; Biomarkers; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Endpoint Determination; Freund's Adjuvant; Inflammation; Inflammation Mediators; Male; Membrane Proteins; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Sensitivity and Specificity; Thromboxane B2; Time Factors

Acute lung injury (ALI) remains an important cause of mortality in intensive care units. Inflammation is controlled by cytokines and eicosanoids derived from the n-6 fatty acid (FA) arachidonic acid (AA). The n-3 FA eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and mediators derived from EPA and DHA possess reduced inflammatory potency.. To determine whether the ability of fat-1 mice to endogenously convert n-6 to n-3 FA, and thus generate an increased ratio of n-3 to n-6 FA, impacts experimental ALI.. We investigated ALI induced by intratracheal instillation of endotoxin in fat-1 and wild-type (WT) mice, assessing leukocyte numbers, protein concentration, and prostaglandin and cytokine levels in bronchoalveolar lavage fluid, as well as free FA in plasma, and lung ventilator compliance. Body temperature and motor activity of mice--markers of sickness behavior--were also recorded.. In ALI, fat-1 mice exhibited significantly reduced leukocyte invasion, protein leakage, and macrophage inflammatory protein-2 and thromboxane B(2) levels in lavage fluid compared with WT mice. Free AA levels were increased in the plasma of WT mice in response to endotoxin, whereas EPA and DHA were increased in the fat-1 group. Ventilator compliance was significantly improved in fat-1 mice. Body temperature and motor activity were decreased in ALI. fat-1 Mice recovered body temperature and motor activity faster.. fat-1 Mice exhibited reduced features of ALI and sickness behavior. Increasing the availability of n-3 FA may thus be beneficial in critically ill patients with ALI.

Topics: Acute Lung Injury; Animals; Arachidonic Acid; Behavior, Animal; Body Temperature; Bronchoalveolar Lavage Fluid; Caenorhabditis elegans Proteins; Chemokine CXCL2; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fat Emulsions, Intravenous; Fatty Acid Desaturases; Fish Oils; Leukocyte Count; Leukocytes; Lung; Mice; Mice, Transgenic; Motor Activity; NF-kappa B; Respiration, Artificial; Thromboxane B2; Tumor Necrosis Factor-alpha

Compound ZLJ-6 [(Z)-1-methyl-1,5-dihydro-2-amino-5-[4-(mesyl)benzylidene]-4H-imi-dazole-4-one mesilate] is a potent inhibitor of cyclooxygenase (IC(50)=0.73 and 0.31 microM, for cyclooxygenase-1 and cyclooxygenase-2 respectively) in human whole blood. It also inhibited the production of thromboxane B(2) and prostaglandin E(2) in calcium ionophore A23187-induced human (IC(50)=0.50 microM) and rat whole blood (IC(50)=0.93 microM), and rat peritoneal leukocytes (IC(50)=2.27 microM). ZLJ-6 suppressed the activity of 5-lipoxygenase in the rat basophilic leukemia (RBL-1) cell lysate (IC(50)=0.32 microM) and in intact cells (IC(50)=1.06 microM) and reduced the generation of leukotriene B(4) (LTB(4)) in A23187-stimulated human (IC(50)=1.61 microM) or rat whole blood (IC(50)=0.99 microM), and rat peritoneal leukocytes (IC(50)=2.59 microM). In vivo, ZLJ-6, administered orally, demonstrated potent anti-inflammatory activity in the carrageenin-induced paw oedema model in rats and showed analgesic activity in the acetic acid-induced abdominal construction model in mice. No gastrointestinal ulcers were found with the anti-inflammatory dose (30 mg/kg) in normal rats. These results indicated that ZLJ-6 potently inhibited 5-lipoxygenase and cyclooxygenase, and blocked the production of LTB(4), TXB(2) and PGE(2). Thus ZLJ-6 is an ideal substitute for classical non-steroidal anti-inflammatory therapy.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Edema; Female; Humans; Imidazoles; Inhibitory Concentration 50; Leukocytes; Leukotriene B4; Lipoxygenase Inhibitors; Male; Rats; Rats, Sprague-Dawley; Sulfones; Thromboxane B2

Selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) increase the incidence of cardiovascular and cerebrovascular events. Complete disruption of the murine gene encoding COX-2 (Ptgs2) leads to renal developmental problems, as well as female reproductive anomalies and patent ductus arteriosus of variable penetrance in newborns, thus rendering this genetic approach difficult to compare with coxib administration. Here, we created hypomorphic Ptgs2 (COX-2(Neo/Neo)) mice in which COX-2 expression is suppressed to an extent similar to that achieved with coxibs, but not eliminated, in an attempt to circumvent these difficulties. In LPS-challenged macrophages and cytokine-stimulated endothelial cells obtained from COX-2(Neo/Neo) mice, COX-2 expression was reduced 70-90%, and these mice developed a mild renal phenotype compared with COX-2 mice possessing an active site mutation (COX-2(Y385F/Y385F)), with minimal signs of renal dysfunction as measured by FITC-inulin clearance and blood urea nitrogen. These COX-2 knockdown mice displayed an increased propensity for thrombogenesis compared with their wild-type (COX-2(+/+)) littermates observed by intravital microscopy in cremaster muscle arterioles upon ferric chloride challenge. Measurement of urinary prostanoid metabolites indicated that COX-2(Neo/Neo) mice produced 50% less prostacyclin but similar levels of PGE(2) and thromboxane compared with COX-2(+/+) mice in the absence of any blood pressure and ex vivo platelet aggregation abnormalities. COX-2(Neo/Neo) mice, therefore, provide a genetic surrogate of coxib therapy with disrupted prostacyclin biosynthesis that predisposes to induced arterial thrombosis.

Topics: Animals; Blood Pressure; Blood Urea Nitrogen; Cardiovascular System; Cells, Cultured; Chlorides; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Dinoprostone; Disease Models, Animal; Endothelial Cells; Epoprostenol; Ferric Compounds; Glomerular Filtration Rate; Heart Rate; Kidney; Macrophages, Peritoneal; Membrane Proteins; Mice; Mice, Knockout; Microscopy, Video; Thrombosis; Thromboxane B2; Time Factors

Increasing evidence in human chronic kidney disease and in animal models indicates the potential utility of dietary soy protein in the treatment of this disorder. A model in which a beneficial soy protein effect has been consistently demonstrated is the Han:SPRD-cy rat model of polycystic kidney disease. Therefore, since dietary soy protein alters renal hemodynamics and prostanoid production, the effects of dietary soy protein on renal prostanoids and related rate-limiting enzymes were examined. Normal and diseased weanling rats were given diets containing casein or soy protein for 7 wk. At 10 wk of age, renal levels of thromboxane B(2) (TXB(2), stable metabolite of TXA(2)), prostaglandin E(2) (PGE(2)) and 6-keto PGF(1alpha) (stable metabolite of PGI(2)) and activities of cyclooxygenase 1 (COX1) and COX2 were elevated in diseased compared to normal kidneys. Soy protein feeding resulted in 49% lower in vitro steady-state levels of TXB(2), and 76% less 6-keto PGF(1alpha) produced by COX1 activity in diseased kidneys, while not altering these parameters in normal kidneys. It also resulted in 47% less TXB(2) and 36% lower 6-keto PGF(1alpha) produced by COX2 activity in diseased kidneys. The relative effect of soy protein feeding on COX2 activity was in the order of TXB(2) > 6-keto PGF(1alpha) > PGE(2). Diseased kidneys had elevated protein and mRNA levels of cytosolic phospholipase A(2) (cPLA(2)) and COX1 and lower levels of COX2. Dietary soy protein attenuated the protein levels of cPLA(2) in diseased kidneys, and reduced COX2 mRNA expression in both normal and diseased kidneys. Dietary soy protein therefore reduced the levels of specific renal prostanoids, cPLA(2) and COX enzymes in this model of polycystic kidney disease, a model in which soy protein has been demonstrated to reduce disease progression.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Disease Progression; Kidney; Male; Phospholipases A2; Polycystic Kidney Diseases; Prostaglandins; Rats; Rats, Mutant Strains; RNA, Messenger; Soybean Proteins; Thromboxane B2

Inflammatory responses exacerbate ischemia-reperfusion (IR) injury of spinal cord, although understanding of mediators is incomplete. The major inducible 70kDa heat shock protein (hsp70) is induced by ischemia and extracellular hsp70 (e-hsp70) can modulate inflammatory responses, but there is no published information regarding e-hsp70 levels in the cerebrospinal fluid (CSF) or serum as part of any neurological disease state save trauma. The present work addresses this deficiency by examining e-hsp70 in serum and CSF of dogs in an experimental model of spinal cord IR injury. IR injury of spinal cord caused hind limb paraplegia within 2-3 h that was correlated to lumbosacral poliomalacia with T cell infiltrates at 3 d post-ischemia. In this context, we showed a 5.2-fold elevation of e-hsp70 in CSF that was induced by ischemia and was sustained for the following 3 d observation interval. Plasma e-hsp70 levels were unaffected by IR injury, indicating e-hsp70 release from within the central nervous system. A putative source of this e-hsp70 was ependymal cells in the ischemic penumbra, based upon elevated i-hsp70 levels detected within these cells. Results warrant further investigation of e-hsp70's potential to modulate spinal cord IR injury.

Topics: Animals; Disease Models, Animal; Dogs; Gene Expression; Gene Expression Regulation; Granulocyte Colony-Stimulating Factor; HSP70 Heat-Shock Proteins; Interleukin-3; Lipid Peroxides; Motor Neurons; Recombinant Fusion Proteins; Recombinant Proteins; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Thromboxane B2; Time Factors

Actions of the lipid mediator thromboxane (Tx) A2 acting through the TP receptor contribute to the pathogenesis of cardiovascular disease. To further explore the role of TxA2 in hypertension, we examined the consequences of deficiency of the TP receptor on the course of hypertension associated with endothelial dysfunction and salt sensitivity. To this end, the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to TP-deficient (Tp-/-) and wild-type (Tp+/+) control mice in drinking water for 21 wk along with a high-salt (HS; 6% NaCl) diet. Administration of L-NAME increased urinary excretion of TxB2 to a similar extent in both Tp+/+ and Tp-/- animals. L-NAME also caused significant and sustained elevations in blood pressure that reached a maximum between weeks 3 and 6. However, the severity of hypertension was attenuated in the Tp-/- mice throughout the study period (P<0.001). At the end of the study, the wild-type mice developed significant cardiac hypertrophy (23.6+/-2% increase in heart-to-body weight ratio). The severity of cardiac hypertrophy was attenuated in the TP-deficient group (11.1+/-2.6%; P<0.05). In contrast, kidney hypertrophy was exaggerated in the Tp-/- mice compared with controls (37.1+/-5.4 vs. 12.3+/-2.3%; P<0.01). Moreover, the severity of glomerulosclerosis, tubule vacuolization, and interstitial chronic inflammation was also enhanced in the Tp-/- group (P<0.01). Thus, in L-NAME hypertension, TP receptors contribute to elevated blood pressure and cardiac hypertrophy. In this model, TP receptors also provided unexpected protection against kidney injury.

Topics: Albuminuria; Animals; Blood Pressure; Cardiomegaly; Disease Models, Animal; Drinking; Eating; Enzyme Inhibitors; Hypertension, Renal; Isoprostanes; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; NG-Nitroarginine Methyl Ester; Nitric Oxide; Receptors, Thromboxane A2, Prostaglandin H2; Renin-Angiotensin System; Sodium, Dietary; Thromboxane B2

Acute lung injury (ALI) and its most severe form, the acute respiratory distress syndrome (ARDS) are frequent complications in critically ill patients and are responsible for significant morbidity and mortality. So far, experimental evidence supports the role of oxidants and oxidative injury in the pathogenesis of ALI/ARDS. In this study, the antioxidant effects of conventional N-acetylcysteine (NAC) and liposomally entrapped N-acetylcysteine (L-NAC) were evaluated in experimental animals challenged with lipopolysaccharide (LPS). Rats were pretreated with empty liposomes, NAC, or L-NAC (25mg/kg body weight, iv); 4h later were challenged with LPS (E. coli, LPS 0111:B4) and sacrificed 20h later. Challenge of saline (SAL)-pretreated animals with LPS resulted in lung injury as evidenced by increases in wet lung weight (edema), increases in lipid peroxidation (marker of oxidative stress), decreases of lung angiotensin-converting enzyme (ACE) (injury marker for pulmonary endothelial cells) and increases in the pro-inflammatory eicosanoids, thromboxane B(2) and leukotriene B(4). The LPS challenge also increased pulmonary myeloperoxidase activity and chloramine concentrations indicative of neutrophil infiltration and activation of the inflammatory response. Pretreatment of animals with L-NAC resulted in significant increases in the levels of non-protein thiols and NAC levels in lung homogenates (p<0.05) and bronchoalveolar lavage fluids (p<0.001), respectively. L-NAC was significantly (p<0.05) more effective than NAC or empty liposomes in attenuating the LPS-induced lung injuries as indicated by the aforementioned injury markers. Our results suggested that the delivery of NAC as a liposomal formulation improved its prophylactic effectiveness against LPS-induced lung injuries.

Topics: Acetylcysteine; Acute Lung Injury; Animals; Antioxidants; Bronchoalveolar Lavage Fluid; Chemistry, Pharmaceutical; Chloramines; Disease Models, Animal; Drug Compounding; Injections, Intravenous; Leukotriene B4; Lipid Peroxidation; Lipopolysaccharides; Liposomes; Lung; Male; Organ Size; Peptidyl-Dipeptidase A; Peroxidase; Rats; Rats, Sprague-Dawley; Sulfhydryl Compounds; Thromboxane B2; Tumor Necrosis Factor-alpha

This study evaluated the bronchodilating activity of the beta(2)-agonist carmoterol and the muscarinic M(3)-antagonist tiotropium, given intratracheally alone or in combination in anaesthetized artificially ventilated normal and actively sensitized guinea-pigs. Carmoterol (0.3-100pmol) and tiotropium (10-1000pmol) were superfused (0.01ml/min) for 5min before challenges with acetylcholine (20mug/kg i.v.), histamine (10mug/kg i.v.) or ovalbumin (5mg/kg i.v.). Both compounds given alone were markedly active against all the challenges. Tiotropium resulted more effective towards cholinergic challenge and carmoterol was very potent against histamine and ovalbumin-induced reaction, being effective already at 1pmol. In the presence of tiotropium, the bronchodilating activity of carmoterol was significantly augmented. The ED(50) value of carmoterol on the acetylcholine challenge was reduced by about 10 and 28 times (0.1 and 0.3pmol of tiotropium), that on the histamine one by 4.5 and 13 times (1 and 3pmol of tiotropium) and that on the ovalbumin-induced one by 8 and 25 times (10 and 30pmol of tiotropium). A positive interaction was also evident when other parameters were evaluated. The histamine-induced release of thromboxane B(2) was markedly reduced (56%, P<0.001) by combining completely ineffective doses of the two drugs (0.3 and 3pmol for carmoterol and tiotropium, respectively). In ovalbumin-challenged animals the time to death, amounting in control animals to 7.2+/-0.9min, was dose-dependently prolonged up to achieve complete protection from death with combination of 1 and 30pmol of carmoterol and tiotropium, respectively. The favorable interaction between carmoterol and tiotropium can represent a good option in the control of bronchopulmonary diseases marked by an increase of airway resistances.

Topics: Acetylcholine; Adrenergic beta-2 Receptor Agonists; Airway Obstruction; Airway Resistance; Amphetamines; Animals; Bronchoconstriction; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guinea Pigs; Histamine; Hydroxyquinolines; Injections, Intraperitoneal; Injections, Intravenous; Injections, Subcutaneous; Male; Ovalbumin; Quinolones; Scopolamine Derivatives; Survival Analysis; Thromboxane B2; Tiotropium Bromide; Treatment Outcome

Licofelone, a dual anti-inflammatory drug that inhibits 5-lipoxygenase (LOX) and cyclooxygenase (COX) enzymes, may have a better cardiovascular profile that cycloxygenase-2 inhibitors due to cycloxygenase-1 blockade-mediated antithrombotic effect and a better gastrointestinal tolerability. We examined the anti-inflammatory effect of licofelone on atherosclerotic lesions as well as in isolated neutrophils from whole blood of rabbits compared with a selective inhibitor of COX-2, rofecoxib. We also assessed the antithrombotic effect of licofelone in rabbit platelet-rich plasma. For this purpose, 30 rabbits underwent injury of femoral arteries, and they were randomized to receive 10 mg/kg/day licofelone or 5 mg/kg/day rofecoxib or no treatment during 4 weeks with atherogenic diet in all cases. Ten healthy rabbits were used as controls. Neutrophils and platelets were isolated from peripheral blood of rabbits for ex vivo studies. Licofelone reduced intima/media ratio in injured arteries, the macrophages infiltration in the neointimal area, monocyte chemoattractant protein-1 (MCP-1) gene expression, and the activation of nuclear factor-kappaB in rabbit atheroma. Moreover, licofelone inhibited COX-2 and 5-LOX protein expression in vascular lesions. Rofecoxib only diminished COX-2 protein expression and MCP-1 gene expression in vascular atheroma. Prostaglandin E(2) in rabbit plasma was attenuated by both drugs. Licofelone almost abolished 5-LOX activity by inhibiting leukotriene B4 generation in rabbit neutrophils and prevented platelet thromboxane B2 production from whole blood. Licofelone reduces neointimal formation and inflammation in an atherosclerotic rabbit model more markedly than rofecoxib. This effect, together with the antiplatelet activity of licofelone, suggests that this drug may have a favorable cardiovascular profile.

Topics: Acetates; Animals; Atherosclerosis; Chemokine CCL2; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Leukotriene B4; Lipids; Lipoxygenase Inhibitors; Macrophages; Male; NF-kappa B; Pyrroles; Rabbits; RNA, Messenger; Thromboxane B2; Tunica Intima

Neuroinflammation, caused by a 6-day intracerebroventricular infusion of lipopolysaccharide (LPS) in rats, is associated with the up-regulation of brain arachidonic acid (AA) metabolism markers. Because chronic LiCl down-regulates markers of brain AA metabolism, we hypothesized that it would attenuate increments of these markers in LPS-infused rats. Incorporation coefficients k* of AA from plasma into brain, and other brain AA metabolic markers, were measured in rats that had been fed a LiCl or control diet for 6 weeks, and subjected in the last 6 days on the diet to intracerebroventricular infusion of artificial CSF or of LPS. In rats on the control diet, LPS compared with CSF infusion increased k* significantly in 28 regions, whereas the LiCl diet prevented k* increments in 18 of these regions. LiCl in CSF infused rats increased k* in 14 regions, largely belonging to auditory and visual systems. Brain cytoplasmic phospholipase A(2) activity, and prostaglandin E(2) and thromboxane B(2) concentrations, were increased significantly by LPS infusion in rats fed the control but not the LiCl diet. Chronic LiCl administration attenuates LPS-induced up-regulation of a number of brain AA metabolism markers. To the extent that this up-regulation has neuropathological consequences, lithium might be considered for treating human brain diseases accompanied by neuroinflammation.

Topics: Animals; Anti-Inflammatory Agents; Antimanic Agents; Arachidonic Acid; Biomarkers; Brain; Dinoprostone; Disease Models, Animal; Down-Regulation; Drug Administration Schedule; Encephalitis; Lipopolysaccharides; Lithium Chloride; Male; Phospholipases A; Rats; Rats, Inbred F344; Thromboxane B2; Treatment Outcome; Up-Regulation

Target levels of ex vivo inhibition of platelet aggregation (IPA) induced by adenosine diphosphate (ADP) that produce clinically relevant effects of clopidogrel, a P2Y12 antagonist, are unclear. We examined standard and modified IPA and P2Y12 receptor occupancy as predictors of antithrombotic (% thrombus weight reduction) and bleeding time (BT, fold-increase over control) effects of clopidogrel in rabbit models of carotid artery thrombosis and cuticle bleeding, respectively. Standard and modified IPA with 20 microM ADP were measured in the absence and presence of partial P2Y1 blockade, respectively. Clopidogrel maximally produced standard IPA of 57% +/- 5%, antithrombotic effect of 85% +/- 1%, BT increase of 6.0 +/- 0.4-fold and P2Y12 receptor occupancy of 87% +/- 5%. Surprisingly, a clopidogrel dose that produced a low standard IPA of 17% +/- 4% and P2Y12 receptor occupancy of 39% +/- 5% achieved a significant antithrombotic activity of 55% +/- 2% with a moderate increase in BT of 2.0 +/- 0.1-fold. This underestimation of clopidogrel efficacy by standard IPA was improved by measuring either modified IPA or P2Y12 receptor occupancy. These results suggest that in clopidogrel-treated rabbits, low standard IPA is associated with significant antithrombotic effects. Moreover, modified IPA and P2Y12 receptor occupancy appear to better predict the magnitude of clopidogrel's efficacy compared with standard IPA, which may be a better predictor of BT.

Topics: Adenosine Diphosphate; Analysis of Variance; Animals; Aspirin; Biomarkers; Bleeding Time; Blood Platelets; Carotid Artery Thrombosis; Carotid Artery, Common; Clopidogrel; Disease Models, Animal; Dose-Response Relationship, Drug; Hemostasis; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Predictive Value of Tests; Protein Binding; Rabbits; Receptors, Purinergic P2; Regional Blood Flow; Thromboxane B2; Ticlopidine

To investigate the changes in plasma endothelin-1 (ET-1) , von Willebrand factor (vWF), serum 6-keto-prostaglandin(1alpha) (PGF(1alpha)) , thromboxane B2 (TXB2), platelet aggregation rate maximum (PAGm) and pancreatic blood flow after reproduction of severe acute pancreatitis (SAP) in rat, and the effect of recombinant staphylokinase (r-Sak) on SAP.. Eighty-one SD rats were divided randomly into the sham-operated group (n=27), the SAP model group (n=27), and the r-Sak treatment group (n=27). SAP was produced by administration of 5% sodium taurocholate into the pancreatic duct. The abdomen of rats was opened at 6, 12 and 18 hours after reproduction of SAP for determining the pancreatic blood flow. Blood was obtained at 6, 12 and 18 hours after reproduction of SAP for determining the concentration of plasma vWF with enzyme-labeled immunosorbent assay (ELISA). The concentration of plasma ET-1 and serum 6-keto-PGF(1alpha), and TXB2 were detected by radioimmunoassay. The PAGm induced by collagen and eicosanoids was assessed.. Pancreatic blood flow in the SAP group appeared to have a decreasing trend at 6,12 and 18 hours after operation and were significantly decreased at all time points after reproduction of the model, compared with those of the sham-operated group (all P<0.05). The PAGm, content of plasma ET-1, vWF, and TXB2 were significantly increased at all time points after reproduction of the model, while 6-keto-PGF(1alpha) was significantly decreased, compared with those of the sham-operated group (all P < 0.05). Compared with SAP model group, PAGm, the content of plasma ET-1, vWF, and serum TXB2 in the r-Sak group were decreased at all time points, however, the content of serum 6-keto-PGF(1alpha) was increased (all P<0.05).. The r-Sak can improve pancreatic microcirculation and enhance pancreatic blood flow in rats with SAP, and may be beneficial in the treatment of SAP.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Endothelin-1; Ischemia; Metalloendopeptidases; Pancreas; Pancreatitis; Platelet Aggregation; Random Allocation; Rats; Rats, Sprague-Dawley; Regional Blood Flow; Thromboxane B2; von Willebrand Factor

To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo.. Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1alpha, TXB2, PGE2 and LTB4 were also performed.. The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1alpha was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged.. These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2 pathway more than the COX 1, predominant for aspirin at higher doses.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Platelets; Cyclooxygenase Inhibitors; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Hypertension, Portal; Lasers; Leukotriene B4; Male; Nitrobenzenes; Platelet Activation; Pyrazoles; Rats; Rats, Wistar; Sulfonamides; Thrombosis; Thromboxane B2

COX-1-dependent eicosanoid formation accelerates atherogenesis, and low-dose aspirin reduces early atherosclerosis. However, the role of aspirin in modulating progression of vascular atherosclerotic lesions once established is less investigated. We wished to determine the effect of low-dose aspirin on vascular inflammation, plaque composition, and progression of established atherosclerosis. Low-density lipoprotein receptor-deficient mice (LDLR(-/-)) were fed a high-fat diet for 3 months. At this time, one group of mice underwent baseline analysis. Two additional groups, while continuing the high-fat diet, were randomized to receive placebo or aspirin for additional 3 months. At the end of the study, LDLR(-/-) mice that had received aspirin had suppressed biosynthesis of thromboxane B2, the major products of COX-1 activity, reduced monocyte chemoattractant protein-1, and soluble intercellular adhesion molecule-1 levels compared with controls. Compared with baseline, the placebo group had significant progression of atherosclerosis. In contrast, aspirin treated mice showed a significant reduction in progression of atherosclerosis, and a significant decrease in foam cell content. These results suggest that in murine atherosclerosis, low-dose aspirin retards progression of established and advanced vascular atherosclerotic lesions by suppressing the formation of bioactive lipids and vascular inflammation.

Topics: Animals; Aorta, Thoracic; Aspirin; Atherosclerosis; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Immunohistochemistry; Male; Mice; Receptors, LDL; Thromboxane B2; Treatment Outcome

Hemostatic disturbances are common in asphyxiated newborns after resuscitation. We compared platelet function in hypoxic newborn piglets reoxygenated with 21% or 100% oxygen. Piglets (1-3 d, 1.5-2.1 kg) were anesthetized and acutely instrumented for hemodynamic monitoring. After stabilization, normocapnic hypoxia was induced with an inspired oxygen concentration of 10-15% for 2 h. Piglets were then resuscitated for 1 h with 21% or 100% oxygen, followed by 3 h with 21% oxygen. Platelet counts and collagen (2, 5, and 10 microg/mL)-stimulated whole blood aggregation were studied before hypoxia and at 4 h of post-hypoxia/reoxygenation. Platelet function was studied using transmission electron microscopy and by measuring plasma thromboxane B2 (TxB2) and matrix metalloproteinase (MMP)-2 and -9 levels. Control piglets were sham-operated without hypoxia/reoxygenation. The hypoxemic (PaO2 33 mm Hg) piglets developed hypotension with metabolic acidosis (pH 7.02-7.05). Upon reoxygenation, piglets recovered and blood gases gradually normalized. At 4 h reoxygenation, platelet aggregation ex vivo was impaired as evidenced by a rightward-downward shifting of the concentration-response curves. Electron microscopy showed features of platelet activation. Plasma MMP-9 but not MMP-2 activity significantly increased. Resuscitation with 100% but not 21% oxygen increased plasma TxB2 levels. Platelet counts decreased after hypoxia/reoxygenation but were not different between groups during the experiment. Resuscitation of hypoxic newborn piglets caused platelet activation with significant deterioration of platelet aggregation ex vivo and increased plasma MMP-9 levels. High oxygen concentrations may aggravate the activation of prostaglandin-thromboxane mechanistic pathway.

Topics: Animals; Animals, Newborn; Asphyxia Neonatorum; Blood Platelets; Disease Models, Animal; Humans; In Vitro Techniques; Infant, Newborn; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microscopy, Electron; Oxygen; Platelet Activation; Platelet Aggregation; Platelet Count; Resuscitation; Sus scrofa; Thromboxane B2

Jia Wei Cang Er Zi San, a traditional Chinese herbal formula, has been used to treat allergic rhinitis (AR) for several centuries. However, its effect on experimental animal models and its therapeutic mechanism remain unclear.. To study the effect of Shu-Bi-Lin, a modified Jia Wei Cang Er Zi San, on an animal model of AR.. Shu-Bi-Lin was administered to the guinea pig model of AR. Meanwhile, an antihistamine-treated group for the treatment control, an ovalbumin-sensitized and untreated group for the positive control, and a sham-sensitized, sham-challenged group for the sham control were studied in parallel. Symptomatic and some pathophysiologic variables were evaluated.. Sneezing and nasal scratching after challenges were significantly ameliorated in the Shu-Bi-Lin-treated group compared with the ovalbumin-sensitized and untreated group, but rhinorrhea volume was not reduced. Shu-Bi-Lin significantly suppressed the production of IgG1 in the passive cutaneous anaphylaxis test. The thromboxane B2 level in nasal lavage fluid was significantly deceased in the Shu-Bi-Lin-treated group; however, the reduction in histamine and peptide leukotriene levels did not reach statistical significance. In addition, eosinophil infiltration and endothelial nitric oxide synthase immunoreactivity in the nasal tissues were reduced in the Shu-Bi-Lin-treated group.. Shu-Bi-Lin could alleviate the nasal symptoms of AR, and its mechanism might be related to its inhibitory effect on type I anaphylaxis reactions and eosinophil infiltration in the nasal tissues, as well as the inhibition of some mediators related to AR.

Topics: Animals; Anti-Allergic Agents; Disease Models, Animal; Drugs, Chinese Herbal; Eosinophils; Guinea Pigs; Histamine; Histamine H1 Antagonists, Non-Sedating; Immunoglobulin E; Immunoglobulin G; Leukotrienes; Loratadine; Nasal Lavage Fluid; Nasal Mucosa; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Ovalbumin; Rhinitis; Sneezing; Thromboxane B2

1. This manuscript presents the preclinical profile of lumiracoxib, a novel cyclooxygenase-2 (COX-2) selective inhibitor. 2. Lumiracoxib inhibited purified COX-1 and COX-2 with K(i) values of 3 and 0.06 microM, respectively. In cellular assays, lumiracoxib had an IC(50) of 0.14 microM in COX-2-expressing dermal fibroblasts, but caused no inhibition of COX-1 at concentrations up to 30 microM (HEK 293 cells transfected with human COX-1). 3. In a human whole blood assay, IC(50) values for lumiracoxib were 0.13 microM for COX-2 and 67 microM for COX-1 (COX-1/COX-2 selectivity ratio 515). 4. Lumiracoxib was rapidly absorbed following oral administration in rats with peak plasma levels being reached between 0.5 and 1 h. 5. Ex vivo, lumiracoxib inhibited COX-1-derived thromboxane B(2) (TxB(2)) generation with an ID(50) of 33 mg kg(-1), whereas COX-2-derived production of prostaglandin E(2) (PGE(2)) in the lipopolysaccharide-stimulated rat air pouch was inhibited with an ID(50) value of 0.24 mg kg(-1). 6. Efficacy of lumiracoxib in rat models of hyperalgesia, oedema, pyresis and arthritis was dose-dependent and similar to diclofenac. However, consistent with its low COX-1 inhibitory activity, lumiracoxib at a dose of 100 mg kg(-1) orally caused no ulcers and was significantly less ulcerogenic than diclofenac (P<0.05). 7. Lumiracoxib is a highly selective COX-2 inhibitor with anti-inflammatory, analgesic and antipyretic activities comparable with diclofenac, the reference NSAID, but with much improved gastrointestinal safety.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Biological Availability; Blood Platelets; Cell Line; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diclofenac; Dinoprostone; Disease Models, Animal; Drug Evaluation, Preclinical; Edema; Female; Fever; Fibroblasts; Humans; Hyperalgesia; Male; Membrane Proteins; Organic Chemicals; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Rats, Wistar; Skin; 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

Preventing anaphylactic reactions as a result of natural rubber latex (NRL) proteins is an important concern in anaesthesia. The clinical relevance of a bacterial/viral filter (Pall BB25) in preventing sensitization to NRL by inhalation was tested in guinea pigs.. Guinea pigs (n=8-10 in each group) were exposed to aerosolized NRL-contaminated cornstarch powder or to NRL in saline for 1 h every day for 2 weeks. The experiments were repeated with a Pall BB25 filter placed over the aerosol system. Control groups were exposed to non-contaminated cornstarch or to saline alone. Three weeks after the last exposure, specific bronchial challenge was performed and thromboxane (Tx) B2 levels in bronchoalveolar lavage fluid were measured.. After bronchial challenge, the animals exposed to NRL or NRL-contaminated cornstarch with the BB25 filter in place showed a level of bronchoconstriction (i.e. the variation of pulmonary insufflation pressure) not different from controls. Conversely, those exposed to NRL or NRL-contaminated cornstarch without the filter showed a higher level of bronchoconstriction (respectively, P<0.02 and P<0.001) than control. Elevated TxB2 levels were found in the lungs of the guinea pigs, which inhaled NRL or NRL-contaminated cornstarch in the absence of a filter. Animals treated with the filter showed comparable TxB2 levels with those of control.. The Pall BB25 filter efficiently protected the guinea pigs from sensitization to NRL. This filter can be used as a complementary measure for avoidance of NRL contact during surgical procedures particularly if the mechanical ventilator apparatus contain NRL devices.

Topics: Anesthesia, Inhalation; Animals; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstriction; Disease Models, Animal; Guinea Pigs; Latex; Latex Hypersensitivity; Male; Micropore Filters; Ovalbumin; Starch; Thromboxane B2

We previously reported that thromboxane (TX)A2 synthesis and receptor blockade prevented recombinant human erythropoietin (rhEPO)-induced hypertension in chronic renal failure rats. The present study was designed to investigate the effect of a cyclooxygenase inhibitor, acetylsalicylic acid (ASA), on blood pressure, renal function, and the concentration of eicosanoïds and endothelin-1 (ET-1) in vascular and renal tissues of rhEPO-treated or rhEPO-untreated uremic rats. Renal failure was induced by a 2-stage 5/6 renal mass ablation. Rats were divided into 4 groups: vehicle, rhEPO (100 U/kg, s.c., 3 times per week), ASA (100 mg x kg(-1) x day(-1), and rhEPO + ASA; all animals were administered drugs for 3 weeks. The TXA2- and prostacyclin (PGI2)-stable metabolites (TXB2 and 6-keto-PGF1alpha, respectively), as well as ET-1, were measured in renal cortex and either the thoracic aorta or mesenteric arterial bed. The uremic rats developed anemia, uremia, and hypertension. They also exhibited a significant increase in vascular and renal TXB2 (p < 0.01) and 6-keto-PGF1alpha (p < 0.01) concentrations. rhEPO therapy corrected the anemia but aggravated hypertension (p < 0.05). TXB2 and ET-1 tissue levels further increased (p < 0.05) whereas 6-keto-PGF1alpha was unchanged in rhEPO-treated rats compared with uremic rats receiving the vehicle. ASA therapy did not prevent the increase in systolic blood pressure nor the progression of renal disease in rhEPO-treated or rhEPO-untreated uremic rats, but suppressed both TXB2 and 6-keto-PGF1alpha tissue concentrations (p < 0.05). ASA had no effect on vascular and renal ET-1 levels. Cyclooxygenase inhibition had no effect on rhEPO-induced hypertension owing, in part, to simultaneous inhibition of both TXA2 and its vasodilatory counterpart PGI2 synthesis, whereas the vascular ET-1 overproduction was maintained. These results stress the importance of preserving PGI2 production when treating rhEPO-induced hypertension under uremic conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta, Thoracic; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Endothelin-1; Epoprostenol; Erythropoietin; Humans; Hypertension; Kidney Cortex; Kidney Function Tests; Male; Mesenteric Arteries; Rats; Rats, Wistar; Recombinant Proteins; Thromboxane B2; Uremia

Platelet activation and subsequent aggregation play a key role in the pathogenesis of ischemic brain damage. Recent studies revealed that enhanced platelet activation is also observed after ischemia, suggesting that secondary thrombus formation might participate in the development of cerebral infarction. The binding of platelet glycoprotein GPIIb/IIIa (integrin alpha(IIb)beta3) to fibrinogen is the final common pathway in platelet aggregation. Therefore, GPIIb/IIIa antagonists might be useful in acute ischemic stroke as well as in the secondary prevention of ischemic stroke. In the present study, we evaluated the effect of three compounds, FK419 ((S)-2-acetylamino-3-[(R)-[1-[3-(piperidin-4-yl) propionyl] piperidin-3-ylcarbonyl] amino] propionic acid trihydrate), a novel nonpeptide GPIIb/IIIa antagonist, ozagrel, a selective thromboxane A(2) synthase inhibitor, and argatroban, a thrombin inhibitor, on middle cerebral artery (MCA) patency and ischemic brain damage using photochemically induced MCA thrombosis model in guinea pigs. FK419, ozagrel, or argatroban was administered 5 min after the termination of photoirradiation. FK419 dose-dependently improved MCA patency by decreasing the total occlusion time, time to continuous reperfusion, and the number of cyclic flow reductions, at doses that inhibited ADP-induced platelet aggregation ex vivo. In contrast, ozagrel only improved total occlusion time, and argatroban showed no improvement in MCA patency. FK419 also reduced ischemic brain damage in a dose-dependent fashion, whereas ozagrel and argatroban did not. Finally, FK419 ameliorated neurological deficits, whereas ozagrel and argatroban did not. These results indicate that FK419, a GPIIb/IIIa antagonist, ameliorates ischemic brain damage by improving MCA patency after occlusion and that FK419 is a promising candidate for the treatment of acute ischemic stroke.

Topics: Animals; Antithrombins; Arginine; Blood Coagulation; Blood Platelets; Brain Ischemia; Disease Models, Animal; Guinea Pigs; Infarction, Middle Cerebral Artery; Male; Methacrylates; Pipecolic Acids; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Reperfusion Injury; Sulfonamides; Thromboxane B2

Vein graft failure within the first month after bypass surgery is largely because of thrombosis. However, systemic study of thrombus formation in vein grafts is still lacking, and few effective techniques are available to prevent this event. Herein, we analyzed the kinetics of thrombosis and tested the effectiveness of locally applied aspirin on prevention of the disease in a mouse model. En face analysis of vein grafts revealed that 67+/-12% and 54+/-17% of the surface areas were covered by microthrombi at 1 and 3 days, respectively. Thrombus generation was also identified by labeling of platelets and fibrin, which occurred in 35 grafts examined at 1 and 3 days and 1, 2, 4, and 8 weeks. In a fifth of grafts, the thrombus occluded the vessel lumen by > or =1/4. Furthermore, a significant loss of endothelial cells was evidenced by beta-gal staining for vein grafts in transgenic mice expressing LacZ gene controlled by TIE2-endothelial specific gene promoter. Following thrombosis, neointimal lesions were significantly increased by 4-fold 2 weeks after the operation. When vein grafts were treated locally with aspirin in pluronic gel-127, the thrombus area was significantly reduced (P<0.005) at 1, 4, and 8 weeks. Interestingly, neointimal lesions were markedly reduced in the local, but not oral, aspirin-treated group at 4 and 8 weeks by 50% to 70% (P<0.005). The mechanism of reduced lesions by locally applied aspirin involved the protection of vein graft endothelium. Thus, we provide strong evidence that thrombus formation occurs before the development of neointimal lesions in vein grafts and that local aspirin treatment successfully reduces vein graft arteriosclerosis through endothelial protection, resulting in reduction of thrombosis.

Topics: Animals; Arteriosclerosis; Aspirin; Blood Vessel Prosthesis Implantation; Carotid Arteries; Disease Models, Animal; Endothelium, Vascular; Fibrinolytic Agents; Graft Occlusion, Vascular; Hyperplasia; Mice; Mice, Knockout; Mice, Transgenic; Platelet Aggregation Inhibitors; Postoperative Complications; Receptor, TIE-2; Thrombosis; Thromboxane B2; Tunica Intima; Venae Cavae

The effect of oxidative stress on coronary microvascular disease is unknown. We investigated whether chronic administration of ascorbic acid (ASC) or glutathione (GSH) prevents microvascular dysfunction and remodeling induced by upstream repeated coronary artery endothelial injury.. Balloon endothelial injury was repeated at the left anterior descending coronary artery (LAD), just distal to an implanted flow meter, every 2 weeks for 6 weeks in pigs. Changes in LAD blood flow induced by acetylcholine (ACh) and 5-hydroxytryptamine were assessed before each endothelial injury and at 8 weeks after the first endothelial injury in pigs without treatment (endothelial injury group, n = 12) and in pigs treated with oral ASC (3 g/day) (ASC group, n = 12) and ASC (3 g/day) plus GSH (1 g/day) (ASC + GSH group, n = 12).. In the endothelial injury group, reduced blood flow in response to ACh was augmented from a decrease of 18 +/- 17% to a decrease of 100% (that is, zero flow, 8 weeks, P < 0.01), accompanied by an increase of ascorbyl free radicals (AFRs) in coronary sinus blood. In contrast, in the ASC + GSH group, blood flow response to ACh was altered to a decrease of 45 +/- 17% (8 weeks, P < 0.01 compared with the endothelial injury group), coronary sinus blood AFRs did not change (8 weeks, 21.4 +/- 12.5 signal intensities, P < 0.01 compared with the endothelial injury group) and the rate of platelet aggregation induced by adenosine diphosphate was small (8 weeks, 56 +/- 17%, P < 0.01 compared with the endothelial injury group).. Chronic administration of antioxidants suppressed microvascular hypercontraction, suggesting that it may be a promising therapeutic strategy for treating coronary microvessel disorders, including microvascular angina.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Antioxidants; Ascorbic Acid; Biomarkers; Blood Pressure; Coronary Circulation; Coronary Vasospasm; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Free Radical Scavengers; Free Radicals; Glutathione; Heart Rate; Models, Cardiovascular; Oxidative Stress; Pericardium; Platelet Aggregation; Swine; Thromboxane B2; Time Factors

Silsosangami is a dried decoctum of a mixture of seven Korean herbal medicine, which is consisted of seven herbs (indicated as concentrations) of Typhae Pollen, Pteropi Faeces, Paeoniae Radicis rubra, Cnidii Rhizoma, Persicae Semen, Carthami Flos and Curcumae Tuber. In the present study, the effects of Silsosangami water extract (SSG) on hemolysis in human blood were studied. Using an in vitro system, only Curcumae Tuber, Persicae Semen and Paeoniae Radicis rubra had the strongest effects on hemolysis; Typhae Pollen and Pteropi Faeces had the slight effects; and Cnidii Rhizoma and Carthami Flos had no effect. On the other hand, the SSG inhibited neutrophil functions, including degranulation, superoxide generation, and leukotriene B4 production, without any effect on 5-lipoxygenase activity. This SSG reduced nitric oxide (NO) and prostaglanin E2 (PGE2) production in mouse peritoneal macrophages stimulated with lipopolysaccharide, without the influence on the activity of inducible NO synthase (iNOS), cyclooxygenase COX-2 and COX-1 being observed. SSG significantly reduced mouse paw oedema induced by carrageenan. Western blot analysis showed that SSG reduced the expression of iNOS and COX-2. These results suggested that SSG might be used as a novel antithrombotic therapeutic agents in post-myocardial infarction and also, indicated that SSG exerts anti-inflammatory effects related to the inhibition of neutrophil functions and of NO and PGE2 production, which could be due to a decreased expression of iNOS and COX-2.

Topics: Animals; Anti-Inflammatory Agents; Carrageenan; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Edema; Erythrocytes; Gene Expression; Hemolysis; Herbal Medicine; Humans; Korea; Leukotriene B4; Macrophages, Peritoneal; Medicine, East Asian Traditional; Membrane Proteins; Mice; Neutrophils; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pancreatic Elastase; Phytotherapy; Plant Extracts; Prostaglandin-Endoperoxide Synthases; Thromboxane B2

Our objective was to test the effect of inhibition of thromboxane synthase versus inhibition of cyclooxygenase (COX)-1/2 on pulmonary gas exchange and heart function during simulated pulmonary embolism (PE) in the rat. PE was induced in rats via intrajugular injection of polystyrene microspheres (25 micro m). Rats were randomized to one of three posttreatments: 1) placebo (saline), 2) thromboxane synthase inhibition (furegrelate sodium), or 3) COX-1/2 inhibition (ketorolac tromethamine). Control rats received no PE. Compared with controls, placebo rats had increased thromboxane B(2) (TxB(2)) in bronchoalveolar lavage fluid and increased urinary dinor TxB(2). Furegrelate and ketorolac treatments reduced TxB(2) and dinor TxB(2) to control levels or lower. Both treatments significantly decreased the alveolar dead space fraction, but neither treatment altered arterial oxygenation compared with placebo. Ketorolac increased in vivo mean arterial pressure and ex vivo left ventricular pressure (LVP) and right ventricular pressure (RVP). Furegrelate improved RVP but not LVP. Experimental PE increased lung and systemic production of TxB(2). Inhibition at the COX-1/2 enzyme was equally as effective as inhibition of thromboxane synthase at reducing alveolar dead space and improving heart function after PE.

Topics: Angiography; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Disease Models, Animal; Extravascular Lung Water; Hypotension; Isoenzymes; Ketorolac; Membrane Proteins; Microspheres; Pleural Effusion; Polystyrenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Pulmonary Circulation; Pulmonary Embolism; Rats; Rats, Sprague-Dawley; Respiratory Dead Space; Survival Rate; Thromboxane B2; Thromboxane-A Synthase

D-003 is a mixture of higher primary aliphatic saturated acids purified from sugarcane wax, with antiplatelet and antithrombotic effects experimentally demonstrated. Octacosanoic acid is the main component of D-003, followed by triacontanoic, dotriacontanoic, and tetracontanoic acids, while other acids are minor components. This work investigates the effects of combination therapy D-003+aspirin (ASA) on arachidonic acid (AA)-induced sudden death in mice and bleeding time in rats. In addition, the effects of D-003 on serum levels of two metabolites of AA: thromboxane A(2) and prostacyclin, assessed through the measurement of their stable metabolites: thromboxane B(2) (TxB(2)) and 6 keto PgF1alpha by radioimmunoassay kits, were also investigated. Combination therapy of D-003 (50mg/kg) and ASA (3mg/kg) significantly increased bleeding time in rats in a synergistic manner compared with D-003 or ASA alone. Moreover, the combined treatment of D-003 (200mg/kg) and ASA (5mg/kg) in mice protected against AA-induced sudden death (83% survivors) in a synergistic manner which was compared with each treatment alone (33% survivors). These results indicate that antiplatelet effects of D-003 are not mediated by a cyclooxygenase inhibition. D-003 and ASA monotherapies reduced serum TxB(2) levels, whereas D-003, but not ASA, significantly increased 6 keto PgF1alpha levels.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Aspirin; Death, Sudden; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Fatty Acids; Mice; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Thrombosis; Thromboxane B2

The synthetic chalcone derivative 1-(2,4-dichlorophenyl)-3-(3-(6,7-dimethoxy-2-chloroquinolinyl))-2-propen-1-one (ClDQ) was evaluated for its anti-inflammatory, analgesic and immunomodulatory efficacy in-vitro and in-vivo. ClDQ concentration-dependently inhibited the production of nitric oxide (NO) (IC50 4.3 microM) and prostaglandin E(2) (PGE(2)) (IC50 1.8 microM) in RAW 264.7 macrophages stimulated with lipopolysaccharide. Human mononuclear cell proliferation was significantly inhibited by 10 microM ClDQ. Oral administration of ClDQ (10-30 mg kg(-1)) in the 24-h zymosan-stimulated mouse air-pouch model produced a dose-dependent reduction of cell migration as well as NO and PGE(2) levels in exudates. ClDQ (20 mg kg(-1), p.o.) inhibited ear swelling and leucocyte infiltration in the delayed-type hypersensitivity response to 2,4-dinitrofluorobenzene in mice. In the rat adjuvant-arthritis model, this compound reduced joint inflammation as well as PGE(2) and cytokine levels. In addition, ClDQ displayed analgesic effects in the phenylbenzoquinone-induced abdominal constriction model in mice and in the late phase of the nociceptive response to formalin. Our findings indicated the potential interest of ClDQ in the modulation of some immune and inflammatory conditions.

Topics: Abdominal Injuries; Administration, Oral; Animals; Arthritis, Experimental; Blood Platelets; Cell Line; Cyclooxygenase 1; Cyclooxygenase 2; Dinitrofluorobenzene; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Formaldehyde; Group II Phospholipases A2; Group IV Phospholipases A2; Humans; Inflammation; Lipopolysaccharides; Lymphocyte Activation; Macrophages; Mice; Microsomes; Nitrites; Pain; Pain Measurement; Phospholipases A; Pyridazines; Rats; Rats, Inbred Lew; Thromboxane B2; Zymosan

To investigate the effect of selective cyclooxygenase-2 (COX-2) inhibitor on alcohol-induced liver injury in rats.. 58 male Wistar rats were randomly divided into three groups: control group treated with dextrose and corn oil, model group with ethanol and corn oil, treatment group with corn oil and ethanol plus a selective COX-2 inhibitor celecoxib. All treatments were injected into stomach through intragastric tubes. Liver samples were analyzed for histopathology with light microscope (LM) and transmission electron microscope (TEM), and the expression of COX-2 with western blotting. Levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum, levels of 6-Keto-prostaglandin F1 alpha (6-k-PGF1a) and thromboxane B2 (TXB2) in liver, and activity of glutathione s-transferase (GST) both in liver tissue and in plasma were measured.. LM and TEM indicated hepatocytes were injured obviously in the model group and slightly in the treatment group. The levels of AST and ALT in serum, TXB2 in liver and the activity of GST in plasma increased significantly in the model group (t> or =2.294, P<0.05), but the activity of GST in liver decreased significantly (t=8.856, P<0.01) compared with those in the control group. To compare with the model group, the levels of AST and TXB2 decreased significantly (t=4.305, P<0.01; t=2.799, P<0.01), meanwhile the activity of GST increased significantly (t=10.134, P<0.01) in the treatment group. COX-2 expression in liver by western blotting increased significantly in the model group, compared with the control group (t=4.067, P<0.01) and the treatment group (t=2.251, P<0.05). Exceptionally, the level of 6-k-PGF1a decreased significantly (t=2.284, P<0.05) in the model group.. COX-2 has involved in the alcohol-induced liver injury, and its inhibitor can diminish alcohol-induced liver injury in rats through decreasing TXB2 level

Topics: Animals; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Ethanol; Isoenzymes; Liver Diseases, Alcoholic; Male; Prostaglandin-Endoperoxide Synthases; Protective Agents; Rats; Rats, Wistar; Thromboxane B2

To observe the correlation between serum level of TXB2, 6-Keto-PGF1alpha and liver metastasis.. The metastatic model was made by injection of W256 carcinosarcoma. Rats were randomly divided into two groups: rats with blood stasis group and control group. Rats in control group were given normal saline via abdominal cavity once a day. Rats in blood stasis group were injected adrenalin in the fourteenth day. Tumor size and liver metastasis were observed. Serum TXB2 and 6-Keto-PGF1alpha were tested by radioimmunoassay.. Tumor size in rats with blood stasis was significantly smaller than that of the control group (P<0.01). Occurrence of liver metastasis in rats with blood stasis was significantly lower than that of the control group (P<0.01). The values of 6-Keto-PGF1alpha, TXB2, and TXB2/6-Keto-PGF1alpha were higher in the group with blood stasis.. In the status of blood stasis, W256 carcinosarcoma grows slowly, and liver metastasis increases insignificantly, with the elevations of 6-Keto-PGF1alpha, TXB2 and TXB2/6-Keto-PGF1alpha.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carcinosarcoma; Cell Line, Tumor; Disease Models, Animal; Liver Neoplasms, Experimental; Male; Medicine, Chinese Traditional; Rats; Rats, Wistar; Thromboxane B2

To study the modifying effect and mechanism of Tangshenning Recipe on micro-albuminuria in rats with early diabetic nephropathy (DN).. Male Wistar rats were randomly divided into the normal group (n=8) and model group (n=24). Intraperitoneal injecting of streptozotocin (STZ) plus complete Freund's adjuvant (CFA) was applied once a week for 3 times to induce the DN rats model. Three weeks later, the model group rats were randomly divided into pathologic group (n=8), monopril group (n=8) and Tangshenning Recipe group(n=8) according to the 24 h U-Alb. Each group's renal hemodynamics index and SOD, GSH, MDA in renal tissue were determined by radioimmunoassay (RIA) and colorimetric method respectively.. The levels of plasmatic TXB(2), the ratio of TXB(2) and 6-keto-PGF1alpha, and the CGRP in pathologic group were significantly higher than those in normal group. The levels of plasmatic ET decreased obviously, SOD decreased and MDA increased significantly in the rats' renal tissue of pathologic group. The levels of plasmatic TXB(2), the ratio of TXB(2) and 6-keto-PGF1alpha decreased significantly in both Tangshenning Recipe group and monopril group, and the therapeutic effect of Tangshenning Recipe group was better than that of monopril group. SOD was higher and MDA was lower in Tangshenning Recipe group than that in pathologic group.. The results indicates that Tangshenning Recipe can lower the micro-albuminuria in early DN rats, the mechanism of which probably lies in the modification of glycometabolism, the ratio of TXB(2) and 6-keto-PGF1alpha, the plasmatic CGRP and the renal lipid preoxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Albuminuria; Animals; Diabetic Nephropathies; Disease Models, Animal; Drugs, Chinese Herbal; Glutathione; Male; Malondialdehyde; Phytotherapy; Radioimmunoassay; Random Allocation; Rats; Rats, Wistar; Superoxide Dismutase; Thromboxane B2; Treatment Outcome

The authors recently demonstrated that methylene blue (MB), an inhibitor of the nitric oxide (NO) pathway, reduces the increments in pulmonary capillary pressure, lung lymph flow and protein clearance in endotoxaemic sheep. In the present study, the authors examined whether MB influences pulmonary haemodynamics and accumulation of extravascular lung water (EVLW) by mechanisms other than the NO pathway. Sixteen awake, chronically-instrumented sheep randomly received either an intravenous injection of MB 10 mg x kg(-1) or isotonic saline. Thirty minutes later, all sheep received an intravenous infusion of Escherichia coli endotoxin 1 microg x kg(-1) for 20 min and either an intravenous infusion of MB 2.5 mg x kg(-1) x h(-1) or isotonic saline for 6 h. MB markedly attenuated the endotoxin-induced pulmonary hypertension and right ventricular failure, and reduced the accumulation of EVLW. Moreover, MB reduced the increments in plasma thromboxane B2 and 6-keto-prostaglandin F1alpha, and abolished the febrile response. However, MB had no effect on the changes in circulating neutrophils, serum hyaluronan, and total haemolytic activity of the alternative complement pathway. The authors conclude that in sheep, methylene blue attenuates the endotoxin-induced pulmonary hypertension and oedema, at least in part, by inhibiting the cyclo-oxygenase products of arachidonic acid. This is a novel effect of methylene blue in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Disease Models, Animal; Endotoxins; Extravascular Lung Water; Female; Lung; Male; Methylene Blue; Probability; Prostaglandin-Endoperoxide Synthases; Pulmonary Circulation; Pulmonary Edema; Random Allocation; Reference Values; Sensitivity and Specificity; Sheep; Thromboxane B2

Wistar rats were fed Se-deficient (0.038 mg/kg diet) and adequate (0.326 mg/kg diet) diets for 13 weeks. The blood Se content, blood and vascular wall glutathione peroxidase (GPx) activity, serum high-density lipoprotein cholesterol (HDL-C) level and plasma prostacyclin (PGI(2)) concentration were decreased significantly, and the blood lipid peroxide (LPO) concentration, serum low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) level and plasma thromboxane A(2) (TXA(2)), content were increased significantly in Se-deficient rats compared with Se-adequate group, respectively. Furthermore the Se-deficient and adequate rats were given 5 mg/kg of cholestane-3 beta, 5 alpha, 6 beta -triol (3-triol) or vehicle only. Twenty four hours after treatment, the plasma PGI(2) level was decreased in Se-adequate rats infused 3-triol (+3 triol), meanwhile, the level in Se- deficient +3-triol group was much lower than that in Se-adequate +3-triol group. Compared with Se-adequate group, plasma TXA(2) content in Se-adequate +3-triol group had no significantly difference, but in Se- deficient rats infused 3-triol, plasma TXA(2) content was much higher than that in Se-adequate +3-triol group. The plasma ET concentration in Se-deficient group decreased slightly, but the concentration in Se-adequate +3-triol group increased significantly with respect to Se-deficient group. Although plasma ET concentration in Se-deficient group +3-triol did not increase, it was significantly lower than that in Se-adequate +3-triol group. The luminal surfaces of aorta thoracica of experimental rats were examined by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Observed by SEM, the luminal surface of aorta of Se-deficient rats showed few crater-like defects due to the disruption of endothelial cell. Se-adequate +3-triol group showed some crater-like defects on the their aorta luminal surface, but the luminal surface of Se-deficient +3-triol group exhibited numerous crater-like defects and appeared sponge-like as well as platelets adhering followed by thrombus formation in focal area of extensive endothelial damage. TEM studies also showed that the endothelium of aorta of Se deficient +3-triol group had more frequent lesion where endothelial cell plasma were swelling with profuse intracellular edema and some vacuoles were seen in cytoplasm. In severely injured areas, endothelial integrity was completely destroyed and smooth muscle cells were proliferat

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Cholestanols; Cholesterol, HDL; Cholesterol, LDL; Cytoprotection; Disease Models, Animal; Endothelins; Endothelium, Vascular; Glutathione Peroxidase; Hypolipidemic Agents; Lipid Peroxides; Lipoproteins, LDL; Male; Microscopy, Electron; Microscopy, Electron, Scanning; Muscle, Smooth, Vascular; Rats; Rats, Wistar; Selenium; Thromboxane B2; Triglycerides

Serum collected from unilaterally clipped and unclipped rats before and after treatment with water, garlic or cilazapril and subsequent to measuring blood pressure was assayed for thromboxane-B2 and prostaglandin-E2. The unclipped rats' thromboxane-B2 and prostaglandin-E2 levels were about 23 ng/ml and 2 ng/ml, respectively, and blood pressure was 126+/-3 mmHg. These values were not affected by either water or garlic administration. The clipped rats' thromboxane-B2 and prostaglandin-E2 concentrations were close to 34 ng/ml and 4 ng/ml, respectively, and declined only in response to garlic (by 15 ng/ml and 3 ng/ml) and cilazapril (by 12 ng/ml and 1.5 ng/ml). The blood pressure of these rats was 196+/-7 mmHg and again was reduced only by garlic to 169+/-14 mmHg and cilazapril to 137+/-5 mmHg. The no-treatment and water-treatment readings were significantly higher in the clipped rats. The data suggest that prostanoid system activity in the 2-kidney 1-clip rat is enhanced and mostly toward maintaining the hypertension. Furthermore, the blood pressure lowering effects of garlic and cilazapril might have been induced partially by a greater reduction in the synthesis of vasoconstrictor prostanoids.

Topics: Animals; Cilazapril; Dinoprostone; Disease Models, Animal; Down-Regulation; Garlic; Hypertension, Renovascular; Male; Phytotherapy; Plants, Medicinal; Rats; Rats, Sprague-Dawley; Thromboxane B2; Time Factors; Water

Liver grafts from non-heart-beating donors inevitably suffer from warm ischemic injury. In these grafts, large quantities of inflammatory cytokines and arachidonic acid metabolites are induced, further aggravating injury. Cyclooxygenase (COX) is an intracellular enzyme that converts arachidonic acid into prostaglandin (PG)G2 and PGH2. COX has two isoforms: constitutive COX-1 and inducible COX-2. The aim of this study was to evaluate the effects of COX-2 inhibition by FK3311 (FK) on warm ischemic injury in a canine total hepatic vascular exclusion (THVE) model.. Sixteen mongrel adult dogs were studied. The portal triad of the hilum and the inferior vena cava above and below the liver was clamped for 1 hour. Splanchnic decompression was achieved by active splenofemorojugular bypass. The animals were divided into two groups. FK (1 mg/kg) was administered in the FK group (n = 8), and saline was administered in the control group (n = 8). Hepatic venous blood was collected to measure serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase (LDH), and hyaluronic acid levels. Serum thromboxane (Tx)B2 and 6-keto-PGF1alpha levels were also measured. Hepatic tissue blood flow was estimated simultaneously. Liver specimens were harvested for histologic study and polymorphonuclear neutrophils were counted.. Alanine aminotransferase, aspartate aminotransferase, and hyaluronic acid 2 and 6 hours after reperfusion and LDH 30 minutes and 2 and 6 hours after reperfusion were significantly (p < 0.05) lower in the FK group than in the control group. Hepatic tissue blood flow remained significantly (p < 0.05) higher in the FK group than in the control group 1, 2, and 6 hours after reperfusion. Histologic tissue damage was mild and polymorphonuclear neutrophil infiltration was significantly lower (p < 0.05) in the FK group than in the control group 1 and 6 hours after reperfusion. Thirty minutes after reperfusion, TxB2 was significantly reduced (p < 0.05) in the FK group, and 6-keto-PGF1alpha was not significantly lower.. FK protected against hepatic warm ischemia-reperfusion injury by marked inhibition of TxA2.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Analysis of Variance; Anilides; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Disease Models, Animal; Dogs; Enzyme Inhibitors; Hyaluronic Acid; Isoenzymes; L-Lactate Dehydrogenase; Leukocyte Count; Liver; Liver Circulation; Neutrophils; Prostaglandin-Endoperoxide Synthases; Random Allocation; Reperfusion Injury; Thromboxane B2

The effect of a receptor binding protein for tumor necrosis factor (TNFrbp) on cell infiltration, bronchial hyperreactivity, and release of inflammatory mediators were studied following antigen challenge in sensitized rats. A 3-fold increase in total cell number, mainly neutrophils and eosinophils, was noted in bronchoalveolar lavage (BAL) fluid 8 hours after antigen challenge. Antigen challenge also induced a significant hyperreactivity of the lower bronchus to carbachol and serotonin, but did not affect the reactivity of the trachea and upper bronchus. This increased responsiveness of the lower bronchus was transient, being detected 8 hours but not 24 hours after antigen challenge. Thromboxane B2 (TxB2), prostaglandin E2 (PGF2), and nitric oxide (NO) levels increased in the BAL fluid of sensitized rats 8 hours after antigen challenge by 197%, 172%, and 173%, respectively. TNFrbp treatment reduced by 83% the antigen-induced cell infiltration, with neutrophils being the cells most affected. The bronchial hyperreactivity induced by antigen challenge was also significantly inhibited by TNFrbp, whereas TxB2, PGE2, and NO levels in the BAL fluid were not affected. In our animal model, the cell infiltration and bronchial hyperreactivity appear to be mediated to some extent by TNF, but not by prostanoids nor NO.

Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Bronchopneumonia; Carbachol; Carrier Proteins; Cell Count; Cell Movement; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Eosinophils; In Vitro Techniques; Muscle Contraction; Muscle, Smooth; Neutrophils; Nitric Oxide; Rats; Rats, Wistar; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Serotonin; Thromboxane B2; Tumor Necrosis Factor Decoy Receptors

Sepsis is a major cause of adult respiratory distress syndrome. In this study, we evaluated the effect of FR167653, which is a potent suppressant of tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 production, on lipopolysaccharide (LPS)-induced lung injury and lethality in rats, and we examined the involvement of p38 mitogen-activated protein (MAP) kinase in the action of FR167653.. Prospective, randomized study.. Animal research facility in a university.. Male Sprague-Dawley rats weighing 200-270 g.. All the animals were assigned to one of the following four groups: control group, FR-only group, LPS-only group, and LPS/FR group. Animals in the LPS-only and LPS/FR groups received 6 mg/kg of LPS intravenously. The animals in the FR-only and LPS/FR groups also received an infusion of FR167653 at 0.2 mg x kg(-1) x hr(-1), commencing 30 mins before the LPS (or vehicle) injection and continuing for 5.5 hrs.. LPS significantly induced the accumulation of pulmonary neutrophils and lung edema, both of which were significantly attenuated by treatment with FR167653. FR167653 also significantly decreased the LPS-induced lethality. Histologically, tissue damage was milder in the LPS/FR group than in the LPS-only group. Serum concentrations of TNF-alpha and IL-1beta and plasma concentrations of thromboxane B2 were all suppressed in the LPS/FR group compared with the LPS-only group. Western blot analysis revealed that FR167653 inhibited the phosphorylation of p38 MAP kinase in lung tissues.. FR167653 administration decreased serum TNF-alpha and IL-1beta concentrations, which was associated with decreased lung injury and lethality. The mechanism responsible for the decreased TNF-alpha and IL-1 may be related to the inhibitory effect of FR167653 on p38 MAP kinase activation.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli; Escherichia coli Infections; Immunosuppressive Agents; Interleukin-1; Lipopolysaccharides; Lung; Male; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Prospective Studies; Pyrazoles; Pyridines; Random Allocation; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Survival Analysis; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha

Pravastatin is useful in restoring endothelium-dependent relaxation in hypercholesterolemic animals. A single intravenous bolus injection of N(omega)-nitro-L-arginine methyl ester (L-NAME), a non-specific inhibitor of NO synthase, causes myocardial necrosis and reduces coronary flow in rats. Since rats do not develop hypercholesterolemia and atherosclerosis, we have tested the hypothesis that pravastatin protects the heart from myocardial lesions induced by L-NAME in the absence of alterations in cholesterol levels and plaque formation. Male Wistar rats fed standard chow were divided into four groups: CONTROL (n=14) - rats that received tap water alone for 18 days; L-NAME (n=14) -- rats that received L-NAME (15 mg/kg, i.v.) on the 14th day of the study; PRAVASTATIN (n=11) -- rats that received pravastatin (6 mg/kg/day) in their drinking water for 18 days; PRAVASTATIN+L-NAME (n=12) -- rats that received pravastatin (6 mg/kg/day) and L-NAME (15 mg/kg, i.v.) as indicated in the preceding groups. At the end of 18 days, the rats were sacrificed and the hearts removed for stereological analysis by light microscopy. Plasma nitrate/nitrite and thromboxane B(2) concentrations were determined immediately before and after L-NAME administration. Pravastatin prevented the ischemic lesions induced by the acute inhibition of NO biosynthesis (the area of myocardial lesions in the L-NAME group was greater than in the Pravastatin+L-NAME group: 101.6 microm(2) vs. 1.2 microm(2), respectively; P<0.0001) and markedly increased the plasma nitrate/nitrate concentrations, even before L-NAME administration. There were no significant changes in the plasma thromboxane B(2) concentrations.

Topics: Analysis of Variance; Animals; Anticholesteremic Agents; Cardiomyopathies; Disease Models, Animal; Endothelium, Vascular; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Necrosis; NG-Nitroarginine Methyl Ester; Nitrates; Nitric Oxide Synthase; Nitrites; Pravastatin; Rats; Rats, Wistar; Thromboxane B2

Approaches to the treatment of lupus nephritis include immunosuppressants associated with anti-inflammatory drugs, mainly steroids, which, however, cause major side effects. Mycophenolate mofetil (MMF) has been described as being less toxic than conventional immunosuppressants, and it was effective in preventing progressive nephritis in lupus mice. Our study evaluated the therapeutic effect of MMF in NZB/W F1 hybrid mice with established disease. We also examined the combination of MMF with a selective cyclooxygenase-2 (COX-2) inhibitor, DFU, based on previous findings of excessive renal production of COX-2-derived thromboxane A2 (TXA2) in lupus nephritis.. Four groups of NZB/W mice (N = 30 each group), starting at five months of age, were given daily by gavage the following: vehicle, MMF 60 mg/kg, DFU 3 mg/kg, or MMF + DFU. Fifteen mice for each group were used for the survival studies, and the remaining mice were sacrificed at nine months.. MMF or DFU alone partially delayed the onset of proteinuria compared with vehicle. Combined therapy was significantly (P < 0.05) more effective than single drugs. Animal survival was partially ameliorated by MMF and significantly improved by the drug combination in comparison with the vehicle (P = 0.005) and DFU alone (P < 0.03). At nine months, serum blood urea nitrogen (BUN) levels were lower in all of the treated groups than in the vehicle group. Renal damage was also limited, but to a greater extent in mice given the combined therapy. In untreated mice, renal COX-2 mRNA expression was up-regulated, and generation of TXB(2), the stable breakdown product of TXA(2), increased. DFU prevented the abnormal renal TXB(2) production, confirming the COX-2 origin of this eicosanoid, whereas renal 6-keto-PGF(1 alpha) and prostaglandin E(2) (PGE(2)) were not affected substantially.. These results offer a strong case for exploring the possibility that in humans MMF combined with COX-2 inhibitors has a role in the treatment options for lupus nephritis. This combined drug therapy may be at least as effective as steroids but without the obvious nephrotoxicity of the latter.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antibodies, Antinuclear; Blood Urea Nitrogen; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Drug Therapy, Combination; Female; Furans; Gene Expression Regulation, Enzymologic; Immunosuppressive Agents; Isoenzymes; Kidney; Lupus Nephritis; Lymphocyte Count; Lymphocyte Subsets; Membrane Proteins; Mice; Mice, Inbred NZB; Mycophenolic Acid; Prostaglandin-Endoperoxide Synthases; Proteinuria; Spleen; Survival Rate; Thromboxane B2

Lipid peroxidation and platelet activation are thought to be important contributors to the pathogenesis of atherosclerosis. The relevance of their interaction in vivo, however, is unknown.. LDL receptor-deficient (LDLR(-/-)) mice on a high-fat diet developed extensive atherosclerosis and had increased urinary levels of 8,12-iso-isoprostane (iP) F(2alpha)-VI and 2,3-dinor-thromboxane (Tx) B(2), markers of in vivo lipid peroxidation and platelet activation, respectively. Vitamin E supplementation suppressed 8,12-iso-iPF(2alpha)-VI biosynthesis and reduced atherosclerosis (65%) without having a significant effect on lipid levels or TxB(2) biosynthesis. Addition of the platelet inhibitor indomethacin to vitamin E simultaneously suppressed 8,12-iso-iPF(2alpha)-VI and TxB(2), significantly reduced soluble intercellular adhesion molecule-1 and monocyte chemoattractant protein-1, and remarkably, further reduced atherosclerosis (80%).. These results indicate that in vivo lipid peroxidation and platelet activation coexist in murine atherosclerosis and that lipid peroxidation does not contribute to platelet activation and reflects the oxidant component of the inflammatory response. Our findings suggest that oxidant stress and platelet activation represent 2 distinct therapeutic targets in atherogenesis. We propose that a combination of antioxidants and platelet inhibitors might be rationally evaluated in the prevention of progression of human atherosclerosis.

Topics: Animals; Antioxidants; Aorta; Arteriosclerosis; Cyclooxygenase Inhibitors; Diet, Atherogenic; Dietary Supplements; Dinoprost; Disease Models, Animal; Disease Progression; Female; Immunohistochemistry; Indomethacin; Lipid Peroxidation; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Platelet Activation; Receptors, LDL; Thromboxane A2; Thromboxane B2; Vitamin E

This work studied the effects of hydrocortisone treatment in experimental acute pancreatitis on cytokines, phospholipase A2, and breakdown products of arachidonic acid and survival. Edematous and necrotizing pancreatitis were induced in Wistar rats by cerulein hyperstimulation and retrograde intraductal infusion of sodium taurocholate, respectively. Hydrocortisone (10 mg/kg) was administered intravenously 10 minutes after induction of acute pancreatitis. Serum was assayed for phospholipase A2; interleukin (IL) 1beta, IL-6, IL-10, thromboxane B2; Prostaglandin E2; and leukotriene B4 at five different time points. A significant release of inflammatory mediators was seen only in the severe model. Hydrocortisone powerfully suppressed arachidonic acid breakdown products and only mildly attenuated the systemic increase of phospholipase A2 and pro- and antiinflammatory cytokines. The mortality rate after 72 hr in the severe model was 86%. Hydrocortisone treatment reduced mortality to 13% (P = 0.001; Fisher's exact test). Hydrocortisone seems to be effective in the treatment of the early systemic inflammatory response syndrome associated with severe acute pancreatitis.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Cytokines; Dinoprostone; Disease Models, Animal; Female; Hydrocortisone; Leukotriene B4; Pancreatitis; Rats; Rats, Wistar; Systemic Inflammatory Response Syndrome; 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

Renal vascular resistance in deoxycorticosterone acetate (DOCA) salt-treated uninephrectomized rats is increased by high dietary chloride. Because DOCA salt-hypertensive rats exhibit an increased urinary excretion of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), the increased TXB2 excretion by DOCA salt-treated rats could relate to elevated dietary chloride, increased blood pressure, and/or the presence of intact renal tubules. We hypothesized that high NaCl intake, resulting in an elevated tubular chloride excretion, stimulates TXA2 production. A result of that production could be renal vasoconstriction. Baseline blood pressures were measured for 10 days, and then the rats were treated with DOCA (30 mg/kg) and fed (1) normal NaCl, (2) normal sodium with high chloride, or (3) high sodium chloride (NaCl) for 4.5 weeks. Next, the rats were uninephrectomized (1K) or unihydronephrectomized (1KHK) to yield one kidney without an intact tubular system and therefore no macula densa. Two and a half weeks later, urinary excretion of TXB2 was determined. DOCA-high NaCl-fed 1KHK or 1K rats had significant increases in systemic blood pressure to 172 +/- 12 and 190 +/- 5 mm Hg, respectively, compared with no significant increase in blood pressure among the other groups. Urinary TXB2 excretion was increased to 29 +/- 4 pg per 24 hours per gram of body weight in all DOCA-treated 1KHK and 1K animals regardless of diet compared with DOCA-treated animals with two intact kidneys (13 +/- 2 pg per 24 hours per gram of body weight). DOCA treatment in rats with one functional kidney results in the excretion of high levels of urinary TXB2 unrelated to dietary chloride load, blood pressure, or intact renal tubules.

Topics: Animals; Blood Pressure; Chlorides; Desoxycorticosterone; Disease Models, Animal; Hydronephrosis; Hypertension; Ligation; Male; Nephrectomy; Rats; Rats, Sprague-Dawley; Renal Circulation; Sodium; Sodium Chloride, Dietary; Thromboxane B2; Ureteral Obstruction

Having developed a non-insulin-dependent diabetes mellitus (NIDDM) syndrome model in the rabbit using Wirsung duct ligation, it appeared interesting to use it to study the relationship between glycemia and the plasma levels of TXA(2)and PGI(2), and of some other biochemical parameters such as cholesterol, triglycerides, alkaline phosphatase and transaminases. A comparative study was carried out in the sham-operated rabbits (controls, C) and those having their pancreatic duct ligatured (NIDDM, D) at 15, 30, 40, 50 and 60 days post-ligation. On the 40th days, whereas in the controls, glycemia was 1.17 +/- 0.04 g.l(-1), it reached a maximum of 4.62 +/- 0.76 g.l(-1)(25.40 mM) in the NIDDMs. No significant modification was observed either in cholesterolemia or in triglyceridemia in either group. The GOT and GPT were highly increased, from 11.50 +/- 4.00 IU. l(-1)and 27.00 +/- 1.50 IU.l(-1)(C) to 37.50 +/- 5.64 IU.l(-1)(P<0. 001) and 58.50 +/- 7.50 IU.l(-1)(D) (P<0.001) in the NIDDM group, suggesting that hyperglycemia occurred simultaneously with the degeneration of the pancreatic tissue. In parallel, in D rabbits, the plasma levels of TXB(2)and 6 keto PGF(1alpha)were augmented to 68.22 +/- 6.20 pg.ml(-1)versus 22.49 +/- 5.74 pg.ml(-1)(C) (P<0.001), and 127.11 +/- 14.39 pg.ml(-1)versus 48.65 +/- 4.51 pg.ml(-1)(C) (P<0. 001) respectively. Statistical studies showed a significant correlation (P<0.05 and <0.02) between glycemia and the biosynthesis of eicosanoids under study. Moreover, 25 mM was found to be the threshold level of glucose excess essential to increase the TXA(2)and PGI(2)biosynthesis significantly. This supports the results obtained by other authors studying the action of glucose on phospholipase activity and consequent eicosanoid production.

Topics: 6-Ketoprostaglandin F1 alpha; Alkaline Phosphatase; Animals; Blood Glucose; Blood Proteins; Cholesterol; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Epoprostenol; Hyperglycemia; Ligation; Pancreatic Ducts; Platelet Aggregation Inhibitors; Rabbits; Thromboxane A2; Thromboxane B2; Time Factors; Transaminases

Magnesium (Mg) has been shown to reduce platelet aggregation both in vitro and ex vivo, and this antiplatelet effect may be advantageous in the prevention of arterial thrombosis. Previous animal studies have shown an antithrombotic effect of Mg also in vivo, but mainly with higher Mg concentrations ( approximately 3.0-4.0 mM). The objectives of the present study were to evaluate the antithrombotic effect of (1) intravenous Mg at a lower and clinically more relevant concentration and (2) topically applied Mg. The study comprised 30 male rats, randomly assigned into 3 groups: (1) placebo group, (2) intravenous Mg group, and (3) topical Mg group. A thrombogenic lesion was established by making a standardised arteriotomy in the right femoral artery. The vessel was transilluminated and thrombus formation was visualised dynamically by in vivo microscopy and recorded on videotapes. Thrombus area was measured after ended experiment by computer-assisted image analysis. Intravenously administered Mg, elevating the S-Mg level to 2.2 mmol/L, significantly reduced the mean thrombus area (p<0.05) compared to the control group. Topically applied Mg significantly decreased the maximum thrombus area, without any increase in S-Mg level (p<0.05). The Mg-treated groups showed no increase in bleeding complications. A transient fall in blood pressure was seen in the systemic Mg group, but blood pressures were not significantly different between any of the groups at the end of the experiment. In conclusion, topically as well as intravenously infused Mg reduce arterial thrombus formation in this in vivo rat model without compromising haemostasis.

Topics: Administration, Topical; Animals; Arterial Occlusive Diseases; Blood Pressure; Disease Models, Animal; Hemorrhage; Infusions, Intravenous; Magnesium; Male; Rats; Rats, Wistar; Thrombosis; Thromboxane B2

Microvascular thrombosis plays a significant role in the pathophysiology of ischaemic reperfusion injury. A fish oil-supplemented diet containing n-3 polyunsaturated fatty acids (PUFA) reduces thromboxane A(2) (TxA(2)) synthesis and, thus, vasoconstriction and platelet aggregation. The aim of this study was to elucidate whether n-3 PUFA in a porcine model of ischaemia and reperfusion injury 1) inhibit accumulation of platelets and fibrinogen in ischaemia-reperfusion injured tissue, 2) prolong the bleeding time, and 3) inhibit TxA(2) synthesis. Nine pigs were fed a standard diet supplemented with 7 g n-3 PUFA/day for 3 weeks. Nine pigs on the standard diet served as controls. Unilateral myocutaneous flaps were exposed to ischaemia for a period of 6 hours. Contralateral flaps were nonischaemic. Tissue contents of radioactive-labelled platelets and fibrinogen were measured after 4 hours of reperfusion. Platelet count, serum TxB(2), and the cutaneous bleeding time were measured before and after 3 weeks of diet. In the fish oil group, the accumulation of platelets was significantly reduced in all the myocutaneous flaps, except in the ischaemic skin part, when compared to control animals. Fibrinogen was significantly reduced in nonischaemic flaps, but not in ischaemic flaps. After the feeding period, the level of TxB(2) was significantly lowered in the fish oil group (p<0.01). No difference in the bleeding time was observed. Thus, dietary supplementation with n-3 PUFA inhibits the formation of microvasculatory thrombosis in this model.

Topics: Animals; Bleeding Time; Dietary Fats, Unsaturated; Disease Models, Animal; Fatty Acids, Omega-3; Fibrinogen; Fish Oils; Microcirculation; Platelet Count; Reperfusion Injury; Swine; Thrombosis; Thromboxane B2

The possibility of NQ12 (2-chloro-3-[4-(ethylcarboxy)-phenyl]-amino-1,4-naphthoquinone) as a novel antithrombotic agent and its mode of action were investigated. The effects of NQ12 on platelet aggregation in human platelet-rich plasma in vitro, in rats ex vivo, and on murine pulmonary thrombosis in vivo, as well as the mode of antithrombotic action were examined. NQ12 potently inhibited ADP-, collagen-, epinephrine-, and calcium ionophore-induced human platelet aggregations in vitro concentration-dependently. NQ12 significantly inhibited rat platelet aggregation in an ex vivo study. NQ12 prevented murine pulmonary thrombosis in a dose-dependent manner. However, NQ12 did not affect coagulation parameters such as activated partial thromboplastin time, prothrombin time, and thrombin time. NQ12 inhibited fibrinogen binding to the platelet surface GPIIb/IIIa receptor, but failed to inhibit binding to the purified GPIIb/IIIa receptor. Thromboxane B(2) formation caused by thrombin or collagen was inhibited significantly by NQ12. The phosphoinositide breakdown induced by thrombin or collagen was inhibited concentration-dependently by NQ12. These results suggest that NQ12 may be a promising antithrombotic agent, and its antithrombotic activity may be due to antiplatelet aggregation activity, which may result from the inhibition of phosphoinositide breakdown and thromboxane A(2) formation.

Topics: Animals; Blood Coagulation; Blood Platelets; Disease Models, Animal; Fibrinolytic Agents; Inositol Phosphates; Male; Mice; Mice, Inbred ICR; Naphthalenes; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pulmonary Embolism; Rats; Rats, Sprague-Dawley; Thromboxane B2

Epidemiological and animal studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce colon cancer risk. NSAIDs nonselectively inhibit both the constitutive cyclooxygenase (COX) 1 associated with side effects and the desired therapeutic target COX-2, which is induced in inflammation and neoplasia. We used the adenomatous polyposis coli (Apc) mutant Min mouse model to determine whether the selective COX-2 inhibitor celecoxib is effective for adenoma prevention and/or regression, and whether it might be safer than the nonselective NSAID previously shown to be most effective in this model, piroxicam. Min mice (n = 120) were randomized to treatment with celecoxib (0, 150, 500, or 1500 ppm celecoxib mixed in the diet) or piroxicam. To distinguish prevention from regression effects, groups were treated either "early" (before adenomas develop) or "late" (after most adenomas are established). Celecoxib caused dramatic reductions in both the multiplicity and size of tumors in a dose-dependent manner (P < 0.01). Early treatment with 1500 ppm of celecoxib was effective for prevention, decreasing tumor multiplicity to 29% and tumor size to only 17% of controls (P < 0.01). Late treatment demonstrated regression effects, reducing tumor multiplicity and size by about half. In contrast to the significant toxicity of piroxicam, which caused ulcers complicated by perforation and bleeding, celecoxib caused no gastrointestinal side effects and did not inhibit platelet thromboxane B2 at plasma drug levels similar to those obtained in early clinical trials in humans. These results provide the first evidence that selective inhibitors of COX-2 are safe and effective for the prevention and regression of adenomas in a mouse model of adenomatous polyposis and strongly support ongoing clinical trials in humans with the same syndrome. The broader population of patients with common sporadic adenomas that have somatic mutations of the same gene (APC) may also benefit from this treatment approach.

Topics: Adenomatous Polyposis Coli; Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents; Celecoxib; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Disease Models, Animal; Female; Isoenzymes; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Substrate Specificity; Sulfonamides; Thromboxane B2

Thromboxane A(2) is a potent vasoconstrictor and platelet agonist; prostacyclin is a potent platelet inhibitor and vasodilator. Altered biosynthesis of these eicosanoids is a feature of human hypercholesterolemia and atherosclerosis. This study examined whether in 2 murine models of atherosclerosis their levels are increased and correlated with the evolution of the disease. Urinary 2,3-dinor thromboxane B(2) and 2,3-dinor-6-keto prostaglandin F(1 alpha), metabolites of thromboxane and prostacyclin, respectively, were assayed in apoliprotein E (apoE)-deficient mice on chow and low-density lipoprotein receptor (LDLR)-deficient mice on chow and a Western-type diet. Atherosclerosis lesion area was measured by en face method. Both eicosanoids increased in apoE-deficient mice on chow and in LDLR-deficient mice on a high-fat diet, but not in LDLR-deficient mice on chow by the end of the study. Aspirin suppressed ex vivo platelet aggregation, serum thromboxane B(2), and 2,3-dinor thromboxane B(2), and significantly reduced the excretion of 2,3-dinor-6-keto prostaglandin F(1 alpha) in these animals. This study demonstrates that thromboxane as well as prostacyclin biosynthesis is increased in 2 murine models of atherogenesis and is secondary to increased in vivo platelet activation. Assessment of their generation in these models may afford the basis for future studies on the functional role of these eicosanoids in the evolution and progression of atherosclerosis. (Blood. 2000;96:3823-3826)

Topics: Age Factors; Animals; Aorta; Arteriosclerosis; Aspirin; Diet, Atherogenic; Disease Models, Animal; Eicosanoids; Epoprostenol; Female; Hominidae; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Platelet Aggregation; Platelet Aggregation Inhibitors; Prostaglandins F; Receptors, LDL; Thromboxane A2; Thromboxane B2

Olive oil is the main source of dietary fatty acids in the Mediterranean region. The objective of this study was to evaluate the effect of dietary supplementation with virgin olive oil in an experimental model with rabbits fed an atherogenic diet (saturated fat 48% of total fat). Four different groups of 10 animals each were studied: (1) normolipemic diet (NLD), (2) atherogenic diet or saturated fatty acid-enriched diet (SFAED), (3) NLD with 15% olive oil (NLD+OLIV), and (4) SFAED with 15% virgin olive oil (SFAED+OLIV). The animals were fed the experimental diets for 6 weeks, after which we determined serum lipid profile (total cholesterol, HDL-cholesterol, and triglycerides), platelet aggregation, platelet thromboxane B(2), aortic prostacyclin, and platelet and vascular lipid peroxidation. Scanning electron microscopic images of the vascular endothelium were studied, as were morphometric parameters in the arterial wall and thrombogenicity of the subendothelium (annular perfusion chamber). Animals fed the SFAED showed platelet hyperactivity and increased subendothelial thrombogenicity. Animals fed the SFAED+OLIV showed, compared with the SFAED group, an improved lipid profile with decreased platelet hyperactivity and subendothelial thrombogenicity and less severe morphological lesions of the endothelium and vascular wall. We conclude that supplementation of the SFAED with 15% olive oil reduced vascular thrombogenicity and platelet activation in rabbits. Although the percentage of olive oil in the diet was higher than the amount in the human diet, these results may be helpful in determining the effect of olive oil in the human thrombogenic system.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Arteriosclerosis; Cholesterol; Diet, Atherogenic; Disease Models, Animal; Drug Evaluation, Preclinical; Endothelium, Vascular; Fatty Acids; Fatty Acids, Unsaturated; Fibrinolytic Agents; Hyperlipidemias; Lipids; Male; Malondialdehyde; Microscopy, Electron, Scanning; Olive Oil; Plant Oils; Platelet Aggregation; Rabbits; Stress, Mechanical; Thrombosis; Thromboxane B2

Many researches show that traditional Indonesian diet is good for physical health. The present study examines the antioxidative, anti-inflammatory and antithrombotic potentials of aqueous extract of tempe (fermented soya-beans) and Curcuma domestica in an experimental photochemical thrombogenesis model using rat femoral artery. A total of 15 male Wistar rats weighing 250 g were used, and divided into three groups: control (group-1, n = 5), animals, treated orally with 0.25 ml aqueous extracts of 50 g tempe (fermented soybean cake) once daily for 7 consecutive days (group-2, n = 5) and animals treated orally with 0.25 ml aqueous extracts of 10 g roots of Curcuma domestica once daily for 5 consecutive days (group-3, n = 5). All animals were anesthetized, and Sn-pyrophosphate and Tc99m solutions were injected intravenously for in vivo red cell radioactive labeling. Femoral arterial occlusion was observed, using a gamma camera. Induction of femoral arterial thrombosis was effected following an endothelial injury by free radicals produced by green light-irradiated Rose Bengal (10 mg/kg). The results showed that in the control group arterial total flow occlusion was seen in 15 min of irradiation. The results of MDA absorbency was 0.3700 +/- 1.7 nmol/ml in control group-1, 0.0520 +/- 0.025 in group-2 (significant p < 0.05 in comparison to control group) and 0.2780 +/- 0.027 in group-3 (non-significant). Interleukin-1alpha plasma level was 14.44 +/- 2.3 in control group-1, 8.93 +/- 2.4 in group-2 (significant p < 0.05), and 6.21 +/- 2.5 in group-3 (significant p < 0.05). Plasma thromboxane B2 plasma level was 20.31 +/- 2.4 in control group-1, 14.32 +/- 2.2 in group-2 (significant p < 0.05), and 19.41 +/- 2.1 in group-3 (significant). This study suggests the potential antioxidative, anti-inflammatory and antithrombotic effect that the dietary aqueous extracts has in rat femoral artery.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Arterial Occlusive Diseases; Curcuma; Diet; Disease Models, Animal; Femoral Artery; Fibrinolytic Agents; Indonesia; Interleukin-1; Lipid Peroxidation; Male; Malondialdehyde; Photochemistry; Plant Extracts; Plant Proteins; Polysaccharides; Radionuclide Imaging; Rats; Rats, Wistar; Rose Bengal; Soy Foods; Thiobarbituric Acid Reactive Substances; Thromboxane B2

Responses to inhaled nitric oxide (iNO) in acute lung injury (ALI), as evidenced by improvements in oxygenation, are variable. We hypothesized that the effect of iNO may be related to the pre-iNO distribution of pulmonary blood flow (PBF). In the present study we evaluated the effect of iNO on PBF in normal healthy dogs and in a canine model of ALI induced by oleic acid (OA). In Group "OA only" (n = 5), ALI was induced by central venous injection of 0.08 ml/kg OA. In Group "E+OA" (n = 5), hypoxic pulmonary vasoconstriction after ALI was blocked with low-dose endotoxin (15 microg/kg of Escherichia coli endotoxin) administered 30 min before giving the same dose of OA. Measurements of regional PBF and lung water concentration (LWC) using positron emission tomography (PET) and H215O were performed before and after OA or placebo, and then again at concentrations of 10, 40, and 0 ppm iNO. One hundred twenty minutes after OA injury, PaO2/FIO2 fell significantly in Group OA only, from 567 +/- 32 to 437 +/- 67 mm Hg. In these animals, PBF redistributed from the dorsal edematous regions of the lungs to the nondependent zones, thus partially preserving normal ventilation/ perfusion relationships. As in the normal animals, in Group OA only, iNO did not significantly change either PBF or oxygenation. In Group E+OA, the administration of low-dose endotoxin eliminated perfusion redistribution from the dorsal edematous lung regions. As a result, PaO2/FIO2 fell from 558 +/- 70 to 119 +/- 53 mm Hg, a decrease that was significantly greater than that in Group OA only. In Group E+OA, administration of iNO restored perfusion redistribution to a similar level as in Group OA only, which was associated with a significant improvement in PaO2/FIO2, from 119 +/- 53 to 251 +/- 159 (10 ppm iNO), and 259 +/- 165 mm Hg (40 ppm iNO). We conclude that the effect of iNO on oxygenation after ALI depends on the pre-iNO perfusion pattern, which may help explain the variable response to iNO often observed in patients with acute respiratory distress syndrome.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Inhalation; Animals; Blood Gas Analysis; Bronchodilator Agents; Cardiac Output; Disease Models, Animal; Dogs; Lung; Nitric Oxide; Oleic Acid; Pulmonary Wedge Pressure; Regional Blood Flow; Respiratory Distress Syndrome; Thromboxane B2; Tomography, Emission-Computed

The aim of this study was to examine antigen-induced lung cell migration, eosinophil activation, and pulmonary reactivity of Wistar rats exposed to a new sensitization technique. The animals were sensitized with a single subcutaneous implant of a fragment of heat coagulated hen egg white and challenged 21 days later with an intratracheal injection of heat-aggregated ovalbumin (EWI). For comparison, another group of rats were sensitized by an intraperitoneal injection of ovalbumin in alum as adjuvant, with one booster on day 14 and challenge on day 21 post immunization (OVA/AL). Twenty-four hours after antigen challenge, the EWI group presented a higher number of eosinophils in the bronchoalveolar lavage (BAL) (4.85 +/- 1.43 x 10(6)) than the OVA/AL group (0.2 +/- 0.06 x 10(6)) or the control group, where the level of eosinophils were essentially undetectable. Levels of eosinophil peroxidase activity were increased in the cell-free BAL and homogenates of lung tissue in the EWI group (12.10 +/- 2.97 mg/mL and 36.14 +/- 7.21 ng/mg, respectively), but not in the OVA/AL group (4.83 +/- 1.4 ng/mL and 11.95 +/- 2.54 ng/mg, respectively), as compared with controls (5.16 +/- 1.65 ng/mL and 12.13 +/- 1.74 ng/mg, respectively). Thromboxane B2 levels were also increased in the BAL of EWI group (2.89 +/- 0.54 ng/mL) but not the OVA/AL group (1.13 +/- 0.23 ng/mL) as compared with controls (1.14 +/- 0.19 ng/mL). In contrast, the levels of prostaglandin E2 in the BAL were increased in both groups (456.4 +/- 11.8 pg/mL in the EWI group and 303.5 +/- 31.7 pg/mL in the OVA/AL group) as compared with controls (205.7 +/- 29.7 ng/mL). Moreover, only the EWI group developed increased pulmonary reactivity to serotonin (around two-fold), 24 hours after antigen challenge. The extent of lung eosinophil migration and activation and the pulmonary hyperreactivity induced by this novel sensitization procedure without adjuvants represents a significant improvement over existing experimental models of asthma.

Topics: Animals; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Dinoprostone; Disease Models, Animal; Eosinophil Peroxidase; Eosinophils; Immunization; Ovalbumin; Peroxidases; Pulmonary Eosinophilia; Rats; Rats, Wistar; Respiratory Function Tests; Respiratory Hypersensitivity; Serotonin; Thromboxane B2

The purpose of the present study was to examine the efficacy of U-74006F, a 21-aminosteroid, on lung dysfunction induced by endotoxaemia in awake sheep with lung lymph fistula and haemodynamic monitoring. We measured pulmonary haemodynamics, lung lymph balance, circulating leucocyte count, arterial blood gas tensions, and levels of thromboxane (Tx) B2 and 6-keto-prostaglandin (PG) F1 alpha in plasma and lung lymph. We performed two experiments. In experiment 1 (n = 6), we intravenously infused Escherichia coli lipopolysaccharide endotoxin (1 microgram/kg) over 30 min and observed the parameters over 5 h. In experiment 2 (n = 6), we pretreated sheep with an intravenous bolus of U-74006F (2 mg/kg) 30 min before the infusion of endotoxin in the same manner of experiment 1, and continuously infused U-74006F (0.5 mg/kg per h) over 5 h after the bolus during the experiment. The U-74006F significantly suppressed the early pulmonary hypertension, the late increase in pulmonary permeability and the elevations of TxB2 and 6-keto-PGF1 alpha levels in plasma and lung lymph during the early period following endotoxaemia, although the compound did not change the time course of leucocytopenia and hypoxaemia. These findings suggest that the administration of U-74006F attenuates the lung dysfunction induced by endotoxaemia in awake sheep.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antioxidants; Blood Gas Analysis; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli; Hemodynamics; Leukocyte Count; Lipopolysaccharides; Lymph; Pregnatrienes; Pulmonary Circulation; Respiratory Distress Syndrome; Sheep; Thromboxane B2; Wakefulness

The role of cysteinyl leukotrienes (cys-LTs) and thromboxane A(2) (TXA(2)) in guinea pig models of aspects of bronchial asthma was investigated. In a novel antigen (BSA)-induced asthmatic model using passively sensitized guinea pigs, pretreatment with varying doses of indomethacin controlled the ratio of followed lipid mediators, LTC(4)/D(4)/E(4) and TXB(2), in lungs of challenged guinea pigs. The predominant mediator in indomethacin-untreated asthma was TXA(2), and complete inhibition of cyclooxygenase by i.v. injection of 5-mg/kg indomethacin-induced cys-LTs mainly mediated asthmatic response. Furthermore, a 1-mg/kg indomethacin dose induced an asthmatic state where both cys-LTs and TXA(2) equally participated. Either LTD(4) or TXA(2) receptor antagonists given alone inhibited the asthmatic response in conditions where the corresponding mediator plays a predominant role. The combination of LTD(4) and TXA(2) receptor antagonists exhibited significant effects irrespective of the condition used. Under conditions where both mediators equally participate, a combination of both receptor antagonists showed additive inhibition. YM158, a newly synthesized and orally active dual antagonist for LTD(4) and TXA(2) receptors, showed the same antiasthmatic effect as a combinated LTD(4) receptor antagonist and a TXA(2) receptor antagonist mixture. Therefore, broad-acting compounds such as YM158 are expected to have antiasthmatic efficacies in a broader class of asthmatic patients than single-acting drugs.

Topics: Administration, Oral; Animals; Asthma; Chromones; Disease Models, Animal; Guinea Pigs; Immunization, Passive; Leukotriene Antagonists; Leukotrienes; Male; Membrane Proteins; Phenylacetates; Receptors, Leukotriene; Receptors, Thromboxane; Serum Albumin, Bovine; Sulfonamides; Tetrazoles; Thiazoles; Thromboxane A2; Thromboxane B2

To evaluate the hemodynamic effects of inhaled nitric oxide (NO) during a venous air infusion (VAI) in dogs. We also addressed the question of whether NO therapy changes thromboxane (Tx) A(2) release and nitrate/nitrite production during a VAI.. Prospective trial.. University laboratory.. Anesthetized mongrel dogs received a VAI (0.2 ml x kg(-1)x min(-1)) after the measurement of baseline hemodynamics. Control dogs (n = 8) received no further treatment. After 30 min of VAI, NO 3 ppm inhalation was initiated (n = 7) for 30 min, followed by 30 min without NO inhalation, and then a final 30 min of NO 40 ppm treatment. Hemodynamic variables were registered and arterial and mixed venous blood samples were drawn for gas analysis and for the determinations of serum TxB(2) (by enzyme-linked immunosorbent assay) and nitrate/nitrite (by high-performance liquid chromatography) levels.. The cardiac index increased 24 % and the pulmonary vascular resistance index decreased 30 % during both periods of NO inhalation. Arterial oxygen tension and arterial oxygen saturation were slightly lower after NO therapy. Nitrate/nitrite concentrations were unaltered in the control group and there were no differences between the arterial and mixed venous serum nitrate/nitrite levels. Nitrite concentrations remained below 1 microM in both groups of animals, but the nitrate concentration increased after inhalation of 40 ppm NO. Serum TxB(2) increased after 60 min of VAI in the control group, but there was no increase in NO-treated animals (all p < 0.05). Nitrate/nitrite concentrations were unaltered after VAI in dogs. NO therapy attenuated TxA(2) release and improved hemodynamics, but not blood oxygenation, in dogs with a VAI. There were no differences between the responses to 3 ppm and 40 ppm NO.

Topics: Administration, Inhalation; Animals; Disease Models, Animal; Dogs; Drug Evaluation, Preclinical; Embolism, Air; Female; Hemodynamics; Hypertension, Pulmonary; Male; Nitrates; Nitric Oxide; Nitrites; Prospective Studies; Thromboxane A2; Thromboxane B2; Vasodilator Agents; Veins

Thrombus formation in the carotid artery is one of the common causes of transient ischemic attacks and stroke. Platelet aggregation seems to be an essential component in these processes. The present study was conducted to determine the ability of cilostazol, a phosphodiesterase III inhibitor, to prevent formation of totally occlusive thrombus in a porcine carotid artery, in comparison with ticlopidine. Castrated male Yorkshire pigs were allocated to control (n=8), cilostazol (30 mg/kg, twice a day [b.i.d] for 2 days, n=8), and ticlopidine (50 mg/kg, b.i.d. for 3 days, n=7) groups. The endothelium of the right common carotid artery was injured with electrical stimulation (150 microA) without constriction and blood flow in this region was monitored by Doppler flow probe. Arterial blood was sampled during electrical stimulation for the measurement of platelet aggregation. Total occlusion rates within 240 minutes were 87.5% (7:8), 37.5% (3:8), and 85.7% (6:7) in the control, cilostazol, and ticlopidine groups, respectively. Compared with the control group, the time to total occlusion was significantly prolonged in the cilostazol group, but not in the ticlopidine group. Consistently, platelet aggregation was significantly inhibited only in the cilostazol group. Because ticlopidine increases blood flow in the intact carotid artery before injury to a greater extent than cilostazol, direct antiplatelet action is thought to be responsible for cilostazol's beneficial effect in preventing thrombotic occlusion. These results suggest that cilostazol may be useful for the inhibition of the thrombus formation in the carotid artery and for the prevention of cerebral ischemic events.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Carotid Arteries; Cilostazol; Cyclic Nucleotide Phosphodiesterases, Type 3; Disease Models, Animal; Electric Stimulation; Endothelium, Vascular; Hemodynamics; Male; Orchiectomy; Platelet Aggregation; Serotonin; Swine; Tetrazoles; Thrombosis; Thromboxane B2; Ticlopidine

BMS182874, an endothelin receptor antagonist, blocks the effects of exogenously administered endothelins in chronically instrumented awake sheep. A possible role for endothelin in endotoxin-induced pulmonary hypertension in sheep was investigated by studying animals given intravenous endotoxin with and without pretreatment with BMS182874. BMS182874 administration alone caused a reduction in pulmonary artery pressure (P[PA]) and systemic arterial pressure (P[SA]). Endotoxin alone caused an acute, nearly threefold increase in P(PA) which was followed, from 2-5 h after endotoxin, by a sustained but less severe increase in P(PA). These changes were accompanied by a threefold increase in lung lymph flow and dramatic increases in plasma and lung lymph thromboxane B2 concentrations. Pretreatment with BMS182874 significantly attenuated the early endotoxin-induced acute increase in P(PA) and completely blocked the late sustained pulmonary hypertension (p < 0.05), while having no affect on the increases in thromboxane levels. BMS182874 shifts the dose response curve for U46619, a prostaglandin H2 analogue, to the right. BMS182874, in addition to functioning as an endothelium receptor antagonist, appears to counteract the action of thromboxane at the receptor level. We theorize that BMS182874 attenuates the early endotoxin-induced pulmonary hypertension by counteracting the effects of thromboxane, since previous studies demonstrated that the early acute rise in P(PA) is caused by thromboxane. The late sustained pulmonary hypertension of endotoxemia, on the other hand, appears to be mediated by endothelin.

Topics: Animals; Antihypertensive Agents; Dansyl Compounds; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelin Receptor Antagonists; Endothelins; Endotoxemia; Female; Hypertension, Pulmonary; Lymph; Male; Premedication; Pulmonary Wedge Pressure; Sheep; Thromboxane B2

Dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were compared for their effects on arterial thrombus formation in vivo using a well validated rat model. Platelet aggregation (triggered by collagen or adenosine diphosphate in whole hirudinized blood), thromboxane formation (TxB2) and platelet phospholipid fatty acid composition were measured also. Animals fed diets containing hydrogenated coconut oil or sunflower seed oil served as pro- and anti-thrombotic controls, respectively. In a first study, rats were fed a mixture of EPA and DHA ethyl esters (MIX) in increasing amounts and results indicated that 4% of n-3 fatty acids had an optimum reducing effect on thrombosis tendency. Dietary administration of MIX further resulted in a dose-dependent promotion of disaggregation after collagen-induced aggregation, which significantly correlated with the reduction in platelet TxB2 formation. In a subsequent comparative study, both EPA and DHA ethyl esters affected thrombosis tendency, platelet aggregation and TxB2 formation to a similar extent. In addition, both polyenes increased the apparent thromboxane A2-sensitivity of platelets, which appeared negatively related to arterial thrombosis tendency. We conclude that EPA and DHA have similar reducing effects on arterial thrombogenesis in vivo in rats and have comparable effects on the selected platelet functions in vitro.

Topics: Animals; Aorta, Abdominal; Collagen; Dietary Fats, Unsaturated; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Wistar; Thrombosis; Thromboxane B2

To assess the role of renal thromboxane in a salt sensitive pressor response in hypertension, urinary excretion of thromboxane and its release from isolated glomeruli and renal papillae were examined in deoxycorticosterone acetate treated rats with normal (0.6%, n = 12) and high (4%, n = 12) salt diets for 8 weeks. Mean blood pressure, measured directly by an implanted aortic catheter, was higher in the high salt diet group than in the normal salt diet group (146 +/- 2 vs 119 +/- 2 mmHg, P<0.01). Urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1alpha in the high salt group were significantly higher than those in the normal salt diet group, but there was no difference in urinary excretion of prostaglandin E2 between the two groups. Release of thromboxane B2, 6-keto-prostaglandin F1alpha, and prostaglandin E2 from isolated glomeruli in the high salt diet group increased significantly by 104%, 55%, and 74%, respectively, compared with the normal salt diet group. Stepwise multiple linear regression analysis showed that significant contributory factors for mean blood pressure in deoxycorticosterone acetate treated rats were urinary excretion of sodium (F=14.187, P<0.01) and release of thromboxane B2 from isolated glomeruli (F=4.135, P<0.05). The unstandardized coefficient (R) calculated from the regression function using these two factors was 0.875 and R2 was 0.765. The manifest synthesis of thromboxane in renal glomeruli has an important role on salt sensitive pressor response in deoxycorticosterone acetate-salt hypertension of rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Creatinine; Desoxycorticosterone; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart Rate; Hypertension; Kidney Glomerulus; Kidney Medulla; Multivariate Analysis; Potassium; Prostaglandins; Rats; Rats, Sprague-Dawley; Regression Analysis; Sodium; Sodium Chloride, Dietary; Thromboxane B2; Thromboxanes

This investigation sought to determine how different components of the hemostatic system affect the development of venous thrombosis in rats displaying hyperlipidemia, either on a genetic basis or secondary to metabolic disorders. On employing an experimental model of collagen-triggered venous thrombosis, both spontaneously hyperlipidemic (Yoshida strain) and streptozotocin-induced diabetic rats generated about 2.3-fold greater thrombi than normolipidemic controls. This was associated with significant platelet activation, as revealed by increased levels of serum thromboxane B2 in diabetics (1.5-fold) as well as in Yoshida (8-fold) rats, in comparison with controls. In contrast, ex vivo total fibrinolytic activity, as measured by euglobulin lysis time, did not differ between normo- and hyperlipidemic or diabetic animals. Plasminogen activator inhibitor activity was lower in both Yoshida and diabetic rats than in controls. However, tissue-type plasminogen activator activity was differently affected by the genetic or the diabetes-related hyperlipidemia, showing significantly lower values in Yoshida (-26%), but significantly higher values in diabetic rats (+29%) than in normolipidemic controls. We conclude that platelet activation, rather than consistent modifications of the fibrinolytic system, is likely to influence the enhanced thrombus development associated with primary or secondary forms of hyperlipidemia.

Topics: Animals; Disease Models, Animal; Fibrinolysis; Hyperlipidemias; Male; Platelet Activation; Rats; Rats, Inbred BN; Rats, Inbred Strains; Rats, Sprague-Dawley; Thrombophlebitis; Thromboxane B2

Injections of mild irritants intradermally (carrageenan, zymosan and dextran) and intracaveally (carrageenan) in a tissue cage model of inflammation were used in studies of the pharmacodynamics and pharmacokinetics of tolfenamic acid administered intramuscularly in calves. Inhibition of serum thromboxane (TX)B2 and inflammatory exudate prostaglandin (PG)E2 were used as indicators of the magnitude and time course of blockade of cyclo-oxygenase isoforms COX-1 and COX-2, respectively. Single doses of 2, 4 and 8 mgkg-1 tolfenamic acid partially inhibited irritant-induced rises in skin temperature (non-dose dependently) and skin oedema (dose-dependently). These doses also markedly inhibited serum TXB2 synthesis and the duration of inhibition was dose-related. A dose of 2 mgkg-1 tolfenamic acid also attenuated skin temperature rise over carrageenan-injected tissue cages, and markedly inhibited exudate PGE2 synthesis, even though drug penetration into both exudate and tissue cage transudate was limited. Tolfenamic acid pharmacokinetics were characterized by a relatively short tmax (0.94-2.04 h), a high estimated Vdarea (1.79-3.20 Lkg-1), an estimated t1/2 beta of 8.01-13.50 h and Cl beta of 0.142-0.175 Lkg-1h-1. The actions of tolfenamic acid in inhibiting PGE2 synthesis and in attenuating two of the cardinal signs of inflammation (heat and swelling) suggest that a dosage of 2 mgkg-1 administered intramuscularly should be effective clinically as an anti-inflammatory agent.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cattle; Dinoprostone; Disease Models, Animal; Inflammation; Irritants; Male; ortho-Aminobenzoates; Skin Diseases; Skin Temperature; Thromboxane B2

To elucidate the role of thromboxane A2 (TxA2) and prostaglandin I2 (PGI2) in acute necrotizing pancreatitis (ANP) in rats and to determine the effect of the TxA2 synthesis inhibitor OKY-046 and the PGI2 analogue OP-2507, the levels of two prostanoids (TxB2, 6-keto PGF1alpha) and two types of phospholipase A2 (PLA2) activity (cytosolic and secretory) were measured in plasma and three tissues (pancreas, lung, and kidney) after injection of a mixed solution of 5% sodium taurocholate and 0.1% trypsin into the pancreatic duct to induce ANP. The survival rate 24 h after inducing ANP was 33.3% in the nontreated group, versus 83.3 and 58.3% in the groups treated with OKY-046 and OP-2507, respectively. Only the group treated with OKY-046 showed significant improvement compared with the nontreated group. The plasma, pancreatic, and pulmonary TxB2 levels decreased significantly in the group treated with OKY-046, and the histopathological changes were not as severe. The levels of pancreatic and pulmonary cytosolic PLA2 activities decreased, and plasma and pancreatic secretory PLA2 activities also decreased. In conclusion, the levels of both types of PLA2 activity and TxA2 production decreased, and the survival rate improved as a result in the group treated with OKY-046, but OP-2507 had no effect on ANP. TxA2 and two types of PLA2 activity play an important role in the process of aggravation of acute pancreatitis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Epoprostenol; Injections, Subcutaneous; Kidney; Lung; Male; Methacrylates; Pancreas; Pancreatitis, Acute Necrotizing; Phospholipases A; Phospholipases A2; Rats; Rats, Wistar; Survival Rate; Taurocholic Acid; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Time Factors

To examine the pathophysiologic role of vasoactive eicosanoids and endothelin-1 in granulocyte-mediated effects in the pulmonary vasculature.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. Thirty adult rabbits.. The experiments were performed on 30 isolated and ventilated rabbit lungs that were perfused with a cell- and plasma-free buffer solution.. The pulmonary arterial pressure and the lung weight gain were continuously registered. Intermittently perfused samples were taken to determine endothelin-1 and thromboxane A2 concentrations. Six experiments without intervention served as the sham group. The granulocytes in the pulmonary circulation were stimulated with N-formyl-L-leucin-methionyl-L-phenylalanine (FMLP; 10(-6) M; control, n = 6). To investigate whether activated granulocytes influence the pulmonary vasculature via endothelin-1, the endothelin-A receptor antagonist LU135252 (10(-6) M) was added to the perfusate before FMLP injection (n = 6). The potential involvement of thromboxane A2 in granulocyte-endothelial interaction was investigated by pretreatment with the cyclooxygenase inhibitor diclofenac (10 microg/mL; n = 6). Activation of granulocytes resulted in an acute increase in pulmonary arterial pressure (>9 mm Hg), which was followed by a second delayed pressure increase after 60 mins (>14 mm Hg) and was paralleled by a massive generation of thromboxane A2 (>250 pg/ mL). Fifteen minutes after FMLP-injection, endothelin-1 was detectable in the perfusate. Pretreatment with the selective endothelin-A antagonist LU135252 significantly (p< .01) reduced the initial pressure response after FMLP stimulation, while diclofenac significantly reduced (p < .05) the delayed pressure increase. Using diclofenac (10 microg/mL) in conjunction with LU135252 (10(-6) M; n = 6) before FMLP injection significantly reduced the early and the delayed pressure increase.. Activated granulocytes seem to enhance pulmonary vascular resistance via endothelin-1 and thromboxane A2. The endothelin-1 effects are probably mediated via endothelin-A receptors since the endothelin-A receptor antagonist LU135252 was able to suppress the early pressure reaction after FMLP injection, whereas the cyclooxygenase inhibitor diclofenac was able to reduce the second pressure increase.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Female; Granulocytes; In Vitro Techniques; Male; N-Formylmethionine Leucyl-Phenylalanine; Perfusion; Phenylpropionates; Prospective Studies; Pulmonary Artery; Pyrimidines; Rabbits; Random Allocation; Respiratory Distress Syndrome; Thromboxane A2; Thromboxane B2; Vascular Resistance

Multiple drugs have been used in experimental skin flap models to reduce the effects of reperfusion ischemia. The effects of antiproteases, however, have not been studied. A skin flap ischemia reperfusion model was developed in the rat to study the effects that aprotinin, a broad-spectrum antiserine protease, would have on skin flap viability. Thirty-two male rats underwent elevation of a ventral pedicled skin flap based on the superficial inferior epigastric artery. The flaps were subjected to 10 hr of warm ischemia by clamping the neurovascular pedicle followed by reperfusion. Aprotinin or saline (control) was administered systemically via the contralateral femoral vein either before or after the ischemic insult. Full-thickness skin biopsies were obtained at 1, 8, and 24 hr into reperfusion. Biopsies were evaluated for neutrophil concentration (using a myeloperoxidase [MPO] assay) and thromboxane B2 [TxB2] content. Flap survival was calculated at 1 week using standardized photography and computer-assisted digital imaging. Aprotinin given before an ischemic insult significantly improved flap survival compared to saline controls (52.3% alive vs. 29.6%, P = 0.0132, unpaired t-test). Aprotinin given after ischemia did not significantly influence flap survival (28.8% vs. 34.4% in saline controls, P = 0.708). MPO levels in the aprotinin preischemia treatment group were significantly less at 1 and 8 hr into reperfusion, indicating decreased neutrophil numbers. No statistical difference in TxB2 levels was noted in either group at any time after reperfusion. Aprotinin significantly improves skin flap survival when given prior to but not after an ischemic insult. Aprotinin appears to lower the concentration of neutrophils in skin flaps pretreated with the drug. Reperfused skin flap levels of thromboxane B2 are unaffected by the pre- or postischemic administration of aprotinin.

Topics: Analysis of Variance; Animals; Aprotinin; Disease Models, Animal; Drug Evaluation, Preclinical; Male; Neutrophils; Peroxidase; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Serine Proteinase Inhibitors; Skin; Surgical Flaps; Thromboxane B2; Time Factors; Tissue Survival

The cause of proteinuria in passive Heymann nephritis has been attributed to the activation of the C5b-9 membrane attack complex following the antibody binding on the glomerular epithelial cell. Previous studies have shown an association between release of prostaglandin thromboxane B2 (TxB2) and proteinuria. Whether this release is dependent on antibody binding per se, or on secondary actions subsequent to antibody binding has not been clarified. The present study was designed to address this issue. Antibody binding event was experimentally separated from the proteinuria by employing a rabbit antibody which produces equivalent glomerular binding equal to that produced by a sheep antibody but without causing proteinuria. Comparisons were made with animals injected with the sheep antibody which produces all the hallmarks of the disease, including proteinuria. Animals injected with the rabbit antibody showed glomerular immunofluorescent deposits which were identical to the deposits produced by the control sheep antibody. However, rabbit antibody failed to produce the typical electron-dense subepithelial deposits, complement binding and proteinuria. Comparison of prostaglandin profile in isolated glomeruli revealed that TxB2 was unchanged in rabbit antibody-injected glomeruli (compared with its nonimmune antibody control). On the other hand, glomeruli from sheep antibody-injected animals released 45% higher TxB2 compared with their respective nonimmune antibody control. These data suggest that the binding of antibody per se may not be a sufficient stimulus for TxB2 release. Subsequent events of subepithelial electron dense deposit formation, complement activation, and proteinuria are associated with TxB2 release.

Topics: Animals; Complement Membrane Attack Complex; Disease Models, Animal; Eicosanoids; Fluorescent Antibody Technique, Direct; Glomerulonephritis; Kidney Glomerulus; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Thromboxane B2

Two murine models of lupus were employed to challenge an hypothesized mechanism by which antiphospholipid antibodies (APLA) might promote thrombosis: altering prostacyclin (PGI2) and thromboxane (TX) production. PGI2 levels in mouse blood and the ex vivo release of PGI2 and TX from mouse kidney were measured. Since APLA have been reported to alter synthesis or activation of several molecules mediating fibrinolysis, murine plasma levels of the fibrin degradation product, D-dimer were also determined. Two murine strains, one prone to spontaneous "lupus-like" illness (MRL-lpr) and related strain (MRL-(+2)), were compared. The assays confirm that MRL-lpr mice have increased anticardiolipin antibody (ACA) and two-fold increased release of TX from renal tissues compared to MRL-(+2) mice. However, these mice have low levels of plasma D-dimer. NIH Swiss mice injected with IgG (containing APLA) from thrombosis-prone lupus patients had high blood ACA titers and D-dimer levels, but both ACA and D-dimer were low or non-detectable in Swiss mice injected with saline or normal IgG. Unlike mice with spontaneous lupus-like illness, healthy mice injected with APLA did not differ from controls with respect to plasma or tissue PGI2 or TX levels. The two murine models of lupus differ, because an altered PGI2-TX ratio is a finding in the chronic murine lupus strain MRL-lpr, but is not seen when APLA are injected into normal mice. It is unlikely that APLA alone has a direct effect on cellular production of eicosanoids in vivo.

Topics: Animals; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Calcimycin; Disease Models, Animal; Eicosanoids; Epoprostenol; Female; Fibrin Fibrinogen Degradation Products; Humans; Immunoglobulin G; Kidney; Lupus Erythematosus, Systemic; Male; Mice; Mice, Inbred Strains; Thrombin; Thromboxane B2

The manipulation of stress gene expression by heavy metals provides protection against the lethal effects of endotoxemia in murine models of septic shock. These findings suggest that the increased resistance to endotoxin in vivo after stress protein induction could be explained by an attenuation of hemodynamic alterations and an altered pattern of inflammatory mediator release. Therefore, we measured main hemodynamic variables such as systemic and pulmonary artery pressure, cardiac output, heart rate, central venous pressure, and pulmonary artery wedge pressure, as well as the time-course of thromboxane-B2, 6-keto-PGF1 alpha, and interleukin 6 formation with and without induction of the stress response in an established porcine model of recurrent endotoxemia (Circ Shock 35:237-244, 1991). Induction of the stress response was carried out by a pretreatment with Zn2+ (25 mg/kg zinc-bis-(DL-hydrogenaspartate) = 5 mg/kg Zn2+). Pretreatment with Zn2+ prior to lipopolysaccharide (LPS) infusion induced an increased heat shock protein 70 (HSP70) expression in the lungs, liver, and kidneys and significantly increased plasma levels of interleukin 6, 6-keto-PGF1 alpha, and thromboxane-B2, compared with untreated controls. After LPS infusion, however, pretreated animals showed significantly decreased peak plasma levels of all mediators compared with the untreated group. Hemodynamic data presented significantly decreased peak pulmonary artery pressure and pulmonary vascular resistance index values, significantly increased systemic artery pressure and systemic vascular resistance index values, and significantly altered hypodynamic/hyperdynamic cardiac output levels in the pretreated group. In conclusion, the data show that the induction of HSP70 by Zn2+ attenuates the liberation of inflammatory mediators, as well as the course of hemodynamic variables due to LPS.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Hemodynamics; HSP70 Heat-Shock Proteins; Interleukin-6; Lipopolysaccharides; Shock, Septic; Swine; Thromboxane B2; Zinc

This study investigated metabolic and biochemical consequences of colonic ischemia/reperfusion (I/R) in the rat and evaluated whether antioxidants prevent I/R-induced functional damage in the rat colon. The surgical preparation involved a 10 cm segment of the colon and occlusion of the superior mesenteric artery (SMA) to induce I/R. Arterial blood from the aorta and venous blood from the superior mesenteric vein (SMV) was collected to measure blood gases, lactic acid (LA) and arachidonic acid (AA) metabolites. Tissue xanthine oxidase (XO) and thiobarbituric acid (TBA) derivatives were measured before and after reperfusion. In addition, vascular and mucosal permeability, and the effect of MDL 73404 (a water soluble vitamin E analog) and 5-aminosalicylic acid on LA, AA, XO and TBA was measured. After ischemia, the colon displayed a metabolic shift from aerobic to anaerobic course by increasing lactic acid production in the colon (183% increase in SMV lactate level compared 87% in the SMA; p < 0.03). After 10 minutes of reperfusion, circulating 6-keto-prostaglandin F1 alpha increased by 3.85 fold (p < 0.001) and thromboxane B2 increased by 2 to 3 fold. An Ischemia time longer than 60 minutes was required to cause changes in tissue XO levels. Tissue TBA levels showed a good dose response corresponding with I/R time. I/R (60 minutes) caused a three and 16 fold increase (p < 0.01) in vascular and mucosal permeability, respectively. MDL 73404 and 5-aminosalicylic acid significantly inhibited the vascular permeability and decreased LA, AA, XO and TBA. These observations provide the first direct experimental evidence for I/R-induced damage in the colon and some of its effects can be reversed by conventional and novel antioxidants.

Topics: 6-Ketoprostaglandin F1 alpha; Aerobiosis; Aminosalicylic Acids; Anaerobiosis; Animals; Antioxidants; Arachidonic Acid; Colon; Disease Models, Animal; Glutathione; Lactic Acid; Male; Mesalamine; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thiobarbituric Acid Reactive Substances; Thromboxane B2; Vitamin E; Xanthine Oxidase

We investigated the effects of thromboxane (TX) A2 in rats with ischemia-reperfusion-induced intrauterine growth retardation. A saline solution or OKY-046, a selective TXA2 synthetase inhibitor, was injected into the caudal vein of pregnant rats on gestation day 17 before the induction of 60-min uteroplacental ischemia. The fetuses and placentas were delivered and examined on gestation day 21. Blood from the uterine vein of the occluded horn shortly after uteroplacental ischemia was collected, and plasma concentrations of TXB2 and 6-keto-prostaglandin (PG) F1 alpha were determined in the other rats on gestation day 17. Treatment with OKY-046 prevented the ischemia-induced reduction in the fetal body and placental weights. The ratio of 6-keto-PGF1 alpha to TXB2 was significantly increased in the OKY-046-treated group. We conclude that the action of TXA2 might play a salient role in our model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Embryonic and Fetal Development; Enzyme Inhibitors; Female; Fetal Growth Retardation; Injections, Intravenous; Methacrylates; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Thromboxane B2; Thromboxane-A Synthase

To compare effects of a single dose of pentoxifylline (PTX), flunixin meglumine (FM), and their combination (FM/PTX) in a model of equine endotoxemia.. 24 healthy horses, aged 2 to 15 years.. 4 groups (n = 6/group) received 30 ng of Escherichia coli O55:B5 endotoxin/kg of body weight, i.v., over 30 minutes, and 1 of the following preparations 15 minutes before and 8 hours after endotoxin infusion: FM, 1.1 mg/kg; PTX, 8 mg/kg; FM/PTX, 1.1 mg of FM and 8 mg of PTX/kg; and saline solution bolus (ENDO). Clinical and hematologic variables were measured over 24 hours.. Compared with ENDO, FM given before endotoxin significantly reduced TxB2, and 6-keto-PGF1 concentrations, pulse, rectal temperature, and attitude score. Pentoxifylline given before endotoxin resulted in significantly higher 6-keto-PGF1 concentration at 1.5 hours and significantly lower PAI-1 activity at 12 hours. Tumor necrosis factor and IL-6 activities in horses given PTX alone were not significantly different from values in those given the saline bolus. FM/PTX induced effects similar to those of FM alone on endotoxin-induced changes in temperature and TxB2 concentration, and 6-keto-PGF1 concentration was significantly lower than that in horses of the ENDO group at 1 hour. In horses of the FM group, 6-keto-PGF1 concentration was significantly lower than that in horses of the ENDO group, from 0.5 hour to 2 hours. Horses of the FM and FM/PTX groups had significantly higher IL-6 activity at 1.5 and 2 hours than did horses of the PTX and ENDO groups; those of the FM and FM/PTX groups had significantly lower WBC count than did those of the PTX and ENDO groups.. FM/PTX may help offset deleterious hemodynamic effects of endotoxin more effectively than does either FM or PTX alone.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Clonixin; Disease Models, Animal; Drug Combinations; Endotoxemia; Escherichia coli; Escherichia coli Infections; Hemodynamics; Horse Diseases; Horses; Interleukin-6; Leukocyte Count; Pentoxifylline; Plasminogen Activator Inhibitor 1; Thromboxane B2; Time Factors; Tissue Plasminogen Activator; Tumor Necrosis Factor-alpha; Vasodilator Agents

To evaluate the effect of pentoxifylline on response of horses to in vivo challenge exposure with endotoxin.. 24 healthy horses in 3 treatment groups: pentoxifylline, endotoxin, or endotoxin and pentoxifylline.. Horses of the pentoxifylline group were given a bolus of pentoxifylline (7.5 mg/kg of body weight, i.v.), followed by an infusion (3 mg/kg/h) over 3 hours, and those of the endotoxin group were given 20 ng of endotoxin/kg i.v. over 30 minutes. Those of the combination group were given both of the aforementioned compounds; pentoxifylline was administered immediately after endotoxin. Clinical (rectal temperature, heart and respiratory rates, blood pressure) and hematologic (WBC count; whole blood recalcification time; plasma fibrinogen, thromboxane B2, and 6-keto-prostaglandin F1 alpha concentrations; plasma plasminogen activator inhibitor activity; and serum tumor necrosis factor and interleukin 6 activities) variables were evaluated over 24 hours.. Compared with baseline values, there were no significant changes in any variable over time in the horses receiving only pentoxifylline, with the exception of a significant increase in WBC count. Rectal temperature, heart rate, mean blood pressure, WBC count, whole blood recalcification time, fibrinogen concentration, plasminogen activator inhibitor activity, tumor necrosis factor and interleukin 6 activities, and plasma thromboxane B2 concentration changed significantly over time in horses of the endotoxin and endotoxin-pentoxifylline combination groups. Respiratory rate and plasma 6-keto-prostaglandin F1 alpha concentration changed significantly over time only in horses of the endotoxin group. Compared with values for the endotoxin group, rectal temperature and respiratory rate were significantly lower, and whole blood recalcification time was longer for the endotoxin/pentoxifylline group.. Beneficial effects of pentoxifylline are limited when it is administered i.v. to horses after in vivo challenge exposure with endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Blood Pressure; Body Temperature; Disease Models, Animal; Endotoxemia; Endotoxins; Fibrinogen; Heart Rate; Horse Diseases; Horses; Infusions, Intravenous; Interleukin-6; Leukocyte Count; Pentoxifylline; Plasminogen Inactivators; Respiration; Thromboxane B2; Tumor Necrosis Factor-alpha; Vasodilator Agents

We examined prostaglandin (PG) E2, 6-keto PGF1alpha, and thromboxane B2 (TxB2) production in cortical and medullary tubules from sham-operated control (SOC) rats and rats with bilateral ureteral obstruction (BUO) of 24 h duration. In SOC rats medullary tubules produced significantly greater amounts of the three eicosanoids than cortical tubules. Again, the production of PGE2, 6-keto PGF1alpha, and TxB2 by cortical and medullary tubules was significantly greater in BUO rats than in SOC rats. To elucidate the mechanisms involved, we examined the activity of phospholipase A2 (PLA2) reactive against phosphatidylcholine or phosphatidylethanolamine (PE), the activity of phospholipase C (PLC), and the levels of cyclooxygenase (COX) in cortical and medullary tubules from SOC and BUO rats. In SOC rats the activity of phosphatidylcholine-PLA2 and PE-PLA2, the activity of PLC, and the mass of COX were significantly greater in medullary tubules than in cortical tubules. On the other hand, the activity of PLC in membranes of cortical tubules and the activity of PE-PLA2 and PLC in membranes of medullary tubules, which were in active location, were significantly greater in BUO rats than in SOC rats. COX levels were also significantly greater in cortical and medullary tubules of BUO rats than in those of SOC rats. Thus, we indicate that medullary tubules from SOC rats have greater production of eicosanoids through increased activity of the PLA2 and PLC-COX pathway than cortical tubules from the same group of rats. Again, in rats with BUO, the tubular eicosanoid production may be enhanced via activation of the PLC-COX pathway in cortical tubules or through activation of the PE-PLA2 and PLC-COX pathway in medullary tubules. The enhanced production of tubular eicosanoids observed in rats with BUO may affect tubular function, particularly sodium and water reabsorption.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cell Membrane; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Eicosanoids; Female; Isoenzymes; Kidney Cortex; Kidney Medulla; Kidney Tubules; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipases A; Phospholipases A2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thromboxane B2; Type C Phospholipases; Ureteral Obstruction

To elucidate the mechanism of development of asthma, we tried to develop a model which elicited a late asthmatic response by a combination of systemic and inhaled sensitization with ovalbumin in guinea pigs. Eighty-seven percent of animals elicited both an immediate and late asthmatic response after the third antigen inhalation. Airway eosinophilia and airway hyperresponsiveness (AHR) induced after the third challenge were more severe than those after the first challenge. There was a good correlation between airway eosinophilia and AHR in this model under experimental modulation of the number of eosinophils, such as by interleukin 5 or antieosinophil antibody injection. These results demonstrate that eosinophils play an important role in the development of late asthmatic response and AHR.

Topics: Animals; Antibodies; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Bronchoconstrictor Agents; Disease Models, Animal; Eosinophils; Guinea Pigs; Histamine; Interleukin-5; Leukocyte Count; Leukotriene C4; Male; Methacholine Chloride; Ovalbumin; Passive Cutaneous Anaphylaxis; Pulmonary Eosinophilia; Thromboxane B2; Time Factors

To assess the anti-inflammatory action of lexipafant (BB-882), a platelet activating factor antagonist, in an animal model of acute colitis.. An animal intervention study.. Following the rectal instillation of formalin 0.75% into male New Zealand White (NZW) rabbits, 0.85 ml of aggregated immunoglobulin was administered i.v. Treatment groups (0.8 mg/kg, n = 6; 2.4 mg/kg, n = 13; 3.2 mg/kg, n = 10) were given bolus doses of BB-882 two-hourly i.v. (control group, n = 25). Rectal dialysis was performed before induction of colitis and sacrifice. Dialysate leukotriene B4 (LTB4), prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) levels were determined. Tissue was saved for histology and measurement of myeloperoxidase content.. There was a dose-dependent improvement in macroscopic scores (2.4 and 3.2 mg/kg: P < 0.02, P < 0.001) and myeloperoxidase levels (3.2 mg/kg: P < 0.04). Dialysate LTB4 levels fell (2.4 and 3.2 mg/kg: P < 0.03, P < 0.02) as did PGE2 levels. TXB2 concentrations remained unaffected.. The PAF receptor antagonist BB-882 shows efficacy in treating inflammation in an animal model of acute colitis as evidenced by a dose-dependent fall in macroscopic mucosal damage, neutrophil infiltration and reduced generation of inflammatory mediators.

Topics: Animals; Colitis; Dinoprostone; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Formaldehyde; Injections, Intravenous; Intestinal Mucosa; Leucine; Leukotriene B4; Male; Platelet Membrane Glycoproteins; Rabbits; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Thromboxane B2

Little is known about the pathophysiological processes leading to superimposed preeclampsia. We present an animal model where the uteroplacental blood flow in spontaneously hypertensive rats (SHR) was reduced by a silver clip. Thus, a superimposed preeclampsia-like syndrome could be studied under defined conditions. Urinary excretion of 2,3-dinor-6-keto PGF1 alpha and 11-dehydro-TxB2 were measured by enzyme immunoassays at day 16 and 20 of pregnancy. In gravid, sham-operated animals excretion of 2,3-dinor-6-keto-PGF1 alpha was largely elevated compared to non gravid control animals (day 16: 1259 vs. 258 ng/kg 24h; day 20: 471 vs. 269 ng/kg.24h). However, in the gravid rats with reduced uteroplacental blood flow urinary excretion of 2,3-dinor-6-keto-PGF1 alpha decreased to non gravid levels (day 16: 335 ng/kg.24h; day 20: 238 ng/kg.24h). By antihypertensive therapy with dihydralazin this effect was largely abolished. Only minor alterations were found in the excretion of 11-dehydro-TxB2. Our findings suggest, that a reduction of uteroplacental blood flow in the spontaneously hypertensive rat decreases the systemic prostacyclin synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Dihydralazine; Disease Models, Animal; Female; Placenta; Pre-Eclampsia; Pregnancy; Rats; Rats, Inbred SHR; Thromboxane B2

Bacterial products released within the gut lumen may alter the course of inflammatory bowel lesions. The effect of intraluminal N-formyl methionyl-leucyl-phenylalanine on mucosal release of inflammatory mediators was investigated in normal and colitis rats (at 1 and 7 days after induction of colitis by trinitrobenzenesulfonic acid). Under anesthesia, the distal colon was perfused using an isosmotic solution with or without synthetic N-formyl methionyl-leucyl-phenylalanine (100 nmol/ml). Effluents were assayed for eicosanoid (PGE2, TXB2 and LTB4) concentration. Myeloperoxidase activity was measured in colonic wall homogenates. In normal rats, peptide perfusion did not change mucosal release of PGE2, TXB2 and LTB4. Colitic rats showed high baseline release of eicosanoids. The peptide did not further increase PGE2 and TXB2 release, but significantly stimulated LTB4 both on days 1 and 7 after induction of colitis. Rats with high myeloperoxidase activity in the colonic wall showed a marked LTB4 response to the peptide. Finally, peptide perfusion increased tissue myeloperoxidase activity in colitis at day 7 but not in colitis at day 1 or in normal rats. In conclusion, bacterial products may activate inflammation. This mechanism of lumen-wall interaction might be involved in the perpetuation of inflammatory lesions of the colonic mucosa.

Topics: Animals; Colitis; Dinoprostone; Disease Models, Animal; Eicosanoids; Intestinal Mucosa; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Peroxidase; Rats; Rats, Sprague-Dawley; Thromboxane B2; Trinitrobenzenesulfonic Acid

Myocardial stunning (MS) is a transient contractile dysfunction occurring subsequent to an episode of ischemia followed by reperfusion. NPC 15669 is a leumedin, which inhibits leukocyte adhesion to the endothelium by blocking Mac-1 upregulation. The effect of NPC 15669 supplementation on the hemostasis during MS is unknown. We linked the potential changes in the hemostasis with NPC 15669 therapy during mild MS. Twelve Yorkshire swine underwent coronary artery occlusion for 8 min followed by 90 min of reperfusion. NP 15669 (10 mg/kg loading dose followed by constant infusion a 6 mg kg-1 h-1) was administered to 6 of the animals; another swine received saline and served as the controls. Concentrations of antithrombin III (AT-III), protein C, total protein S, fibronectin, endothelin 1 (ET-1) and the stable metabolites of thromboxane (TxB2) and prostacyclin (6-keto-PGF1 alpha) were measured in the systemic circulation. NPC 15669 therapy was associated with diminished ET-1 (37.4%) and 6-keto-PGF1 alpha (47.1%) levels and increased fibronectin (77.6%) concentrations during MS. There were no changes in the plasma concentrations of TxB2, total protein S, protein C and AT-III in the NPC 15669 group when compared with controls. Mild MS in associated with substantial changes in the hemostatic profile. NPC 15669 administration in a swine model of MS affects certain hemostatic parameters. These data provide support for the involvement of cellular mechanisms in the pathogenesis of MS. The ability of leumedins to modulate hemostasis may have implications for their use in cardiovascular disease.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antithrombin III; Blood Proteins; Disease Models, Animal; Endothelin-1; Female; Fibronectins; Hemostasis; Leucine; Macrophage-1 Antigen; Myocardial Stunning; Protein C; Protein S; Reperfusion Injury; Swine; Thromboxane B2; Up-Regulation

The manipulation of stress gene expression by heavy metals provides protection against the lethal effects of endotoxemia in murine models of septic shock. Recent in vitro studies with alveolar macrophages or monocytes show that induction of the stress response in these cells is followed by a decreased liberation of major cytokines [tumor necrosis factor-alpha (TNF alpha) and interleukin-1 (IL-1)] after endotoxin challenge. These findings suggest that the increased resistance to endotoxin in vivo after stress protein induction could be explained by an altered pattern of inflammatory mediator release. Therefore, we measured the time course of thromboxane-B2 (TxB2), 6-keto-PGF1 alpha, platelet activating factor (PAF), TNF alpha, interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) formation with and without induction of the stress response in an established porcine model of recurrent endotoxemia (Klosterhalfen et al., Biochem Pharmacol 43: 2103-2109, 1992). Induction of the stress response was done by a pretreatment with Zn2+ (25 mg/kg zinc-bis-(DL-hydrogenasparate = 5 mg/kg Zn2+). Pretreatment with Zn2+ prior to lipopolysaccharide (LPS) infusion induced an increased heat shock protein 70 and metallothionein expression in the lungs, liver, and kidneys and increased plasma levels of TNF alpha, IL-1 beta, IL-6, and TxB2 as opposed to untreated controls. After LPS infusion, however, pretreated animals showed significantly decreased peak plasma levels of all mediators as opposed to the untreated group. The time course of mediator release was identical with the decreasing and increasing three peak profiles described previously. Hemodynamic data presented significantly decreased peak pulmonary artery pressures and significantly altered hypodynamic/hyperdynamic cardiac output levels in the pretreated group. In conclusion, the data show that the induction of stress proteins by Zn2+ could be a practicable strategy to prevent sepsis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspartic Acid; Blood Pressure; Cardiac Output; Disease Models, Animal; Endotoxemia; Gene Expression; HSP70 Heat-Shock Proteins; Inflammation Mediators; Interleukin-1; Interleukin-6; Kidney; Lipopolysaccharides; Metallothionein; Platelet Activating Factor; Pulmonary Artery; Recurrence; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha; Zinc

1. The effect of purified crotapotin, a non-toxic non-enzymatic chaperon protein normally complexed to a phospholipase A2 (PLA2) in South America rattlesnake venom, was studied in the acute inflammatory response induced by carrageenin (1 mg/paw), compound 48/80 (3 micrograms/paw) and 5-hydroxytryptamine (5-HT) (3 micrograms/paw) in the rat hind-paw. The effects of crotapotin on platelet aggregation, mast cell degranulation and eicosanoid release from guinea-pig isolated lung were also investigated. 2. Subplantar co-injection of crotapotin (1 and 10 micrograms/paw) with carrageenin or injection of crotapotin (10 micrograms/paw) into the contralateral paw significantly inhibited the carrageenin-induced oedema. This inhibition was also observed when crotapotin (10-30 micrograms/paw) was administered either intraperitoneally or orally. Subplantar injection of heated crotapotin (15 min at 60 degrees C) failed to inhibit carrageenin-induced oedema. Subplantar injection of crotapotin (10 micrograms/paw) also significantly inhibited the rat paw oedema induced by compound 48/80, but it did not affect 5-HT-induced oedema. 3. In adrenalectomized animals, subplantar injection of crotapotin markedly inhibited the oedema induced by carrageenin. The inhibitory effect of crotapotin was also observed in rats depleted of histamine and 5-HT stores. 4. Crotapotin (30 micrograms/paw) had no effect on either the histamine release induced by compound 48/80 in vitro or on the platelet aggregation induced by both arachidonic acid (1 nM) and platelet activating factor (1 microM) in human platelet-rich plasma. The platelet aggregation and thromboxane B2 (TXB2) release induced by thrombin (100 mu ml-1) in washed human platelets were also not affected by crotapotin. In addition, crotapotin (10 microg/paw) did not affect the release of 6-oxo-prostaglandin Fla, and TXB2 induced by ovalbumin in sensitized guinea-pig isolated lungs.5. Our results indicate that the anti-inflammatory activity of crotapotin is not due to endogenous corticosteroid release or inhibition of cyclo-oxygenase activity. It is possible that crotapotin may interact with extracellular PLA2 generated during the inflammatory process thereby reducing its hydrolytic activity.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Arachidonic Acid; Carrageenan; Cell Degranulation; Crotoxin; Disease Models, Animal; Edema; Guinea Pigs; Histamine Release; Humans; Injections, Intraperitoneal; Male; Mast Cells; p-Methoxy-N-methylphenethylamine; Phospholipases A; Phospholipases A2; Platelet Activating Factor; Platelet Aggregation; Rats; Rats, Wistar; Serotonin; Thromboxane B2

The impact of the 2- and 3-series prostanoid precursors arachidonic acid (AA) and eicosapentaenoic acid (EPA) on experimental pulmonary hypertension was investigated. The model of buffer-perfused rabbit lungs was stimulated by infusion of Escherichia coli hemolysin (HlyA), which is known to provoke sustained thromboxane (Tx)-mediated pulmonary hypertension. Release of di- and trienoic Tx into the recirculating perfusate was quantified by a post-high-performance liquid chromatography enzyme-linked immunosorbent assay technique. HlyA at 0.08 hemolytic unit/ml caused a sustained rise in pulmonary arterial pressure (PAP; maximum increase 14 +/- 2 mmHg) accompanied by progressive TxB2 liberation (maximum perfusate concn 33 +/- 4 pg/ml, baseline < 2 pg/ml). Between 5 and 30 nM, AA provoked a transient monophasic rise in PAP (maximum pressor response 1.5-15 mmHg) and concomitant TxB2 release (peak concn 2-30 pg/ml). Simultaneous administration of HlyA and AA exhibited additive effects with regard to mediator release and pressor responses. EPA at 200-2,000 nM caused a transient rise in PAP similar to that provoked by 5-30 nM AA (maximum pressor response 3-18 mmHg). This was accompanied by liberation of TxB2 (peak concn 16 +/- 5 and 28 +/- 4 pg/ml after 1,000 and 2,000 nM EPA) and TxB3 (peak concn 9 +/- 4 and 30 +/- 3 pg/ml). Combined application of HlyA and EPA resulted in approximate addition of the TxB2 release reaction to each single compound, and TxB3 liberation more than doubled (maximum concn 59 +/- 12 pg/ml). The pressor responses to HlyA-EPA (200-2,000 nM) did not, however, surpass those to HlyA-AA (5-30 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonic Acid; Disease Models, Animal; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Escherichia coli; Female; Hemolysin Proteins; Hypertension, Pulmonary; Male; Potassium; Pulmonary Artery; Pulmonary Wedge Pressure; Rabbits; Thromboxane B2; Thromboxanes

1. In previous works we have described the development of hypertension and aggravation of proteinuria in rats who became pregnant after the administration of Adriamycin. This was associated with an increase in the glomerular thromboxane B2-prostaglandin E2 ratio. 2. To assess the pathogenetic role of thromboxane in this model, female Wistar rats were mated 2 weeks after receiving Adriamycin (3.5 mg/kg intravenously). Rats were then treated with the thromboxane-receptor antagonist daltroban, 60 mg day-1 kg-1 orally, beginning on day 11 of pregnancy. Systolic blood pressure, proteinuria and the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 were measured serially before mating, and on days 14 and 21 of pregnancy. The results were compared with those in Adriamycin-(treated) pregnant rats not treated with daltroban, Adriamycin-treated virgin rats and normal virgin or pregnant rats either treated or untreated with daltroban. 3. In daltroban-treated pregnant and virgin rats treated with Adriamycin, systolic blood pressure remained normal, whereas it increased significantly (P < 0.05) in untreated animals. On day 14, blood pressure was higher in non-daltroban-treated Adriamycin-treated pregnant rats than in non-daltroban-treated Adriamycin-treated virgin rats. Treatment had no effect on blood pressure in normal virgin or pregnant rats. Proteinuria was higher in pregnant rats treated with Adriamycin than in Adriamycin-treated virgin rats, but it was not reduced by daltroban.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Doxorubicin; Female; Hypertension; Phenylacetates; Pregnancy; Pregnancy Complications, Cardiovascular; Rats; Rats, Wistar; Receptors, Thromboxane; Sulfonamides; Thromboxane B2; Thromboxanes

Cationic antimicrobial protein of 18 kd (CAP18) is a neutrophil-derived peptide that binds lipopolysaccharide (LPS) with high affinity. We hypothesized that CAP18(106-137), a novel synthetic 32-amino acid C-terminal fragment of CAP18, would neutralize the physiologic derangements induced by LPS in anesthetized swine.. Pigs were randomly allocated into three groups. Those in the LPS group (n = 6) were infused with LPS (3 micrograms/kg/hr for 4 hours). Pigs in the LPS/CAP18 group (n = 6) were challenged with LPS (3 micrograms/kg/hr for 4 hours) and also treated with CAP18(106-137) (4 mg/kg/hr for 4 hours). Pigs in the RL group (n = 4) received neither LPS nor CAP18(106-137).. Treatment with CAP18(106-137) blocked LPS-induced increases in plasma levels of 6-keto-prostaglandin F1 alpha and tumor necrosis factor-alpha and prevented LPS-induced changes in cardiac output, arterial PO2, phagocyte activation, and peripheral leukocyte count. Changes in circulating concentrations of thromboxane B2, mean pulmonary artery pressure, and dynamic pulmonary compliance were attenuated in the LPS/CAP18 group.. Treatment with CAP18(106-137) neutralizes many of the deleterious effects of LPS in pigs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Bacterial Agents; Antimicrobial Cationic Peptides; Blood Pressure; Cardiac Output; Carrier Proteins; Cathelicidins; Disease Models, Animal; Endotoxins; Escherichia coli; Leukocyte Count; Lipopolysaccharides; Lung Compliance; Male; Opsonin Proteins; Oxygen; Phagocytes; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha

The objective of this study was to assess the effects of flaxseed and flax oil diets in the rat renal ablation model. Flaxseed is a rich source of alpha-linolenic acid, an 18:3n3 omega-3 fatty acid, which has anti-atherogenic and anti-inflammatory properties. Flaxseed, but not flax oil, is also rich in lignans, which are platelet-activating factor-receptor antagonists. Rats were subjected to 5/6 nephrectomy, fed a regular laboratory diet (RLD) for 1 week, then divided into three groups to receive either the RLD (n = 8), a 15% flaxseed diet (n = 8), or a 15% flax oil diet (n = 7). Blood pressure, proteinuria, glomerular filtration rate, and urinary prostaglandins (thromboxane B2 and 6-keto prostaglandin F1 alpha) were measured presurgery and at 1 week (before dietary allotment) and 20 weeks postnephrectomy when blood for plasma lipids and kidneys for histology and tissue-phospholipid analyses were obtained. Blood pressure increased progressively in the RLD group but not in the flax diet groups. Plasma triglycerides and cholesterol increased in all groups, but this increase was significantly attenuated by both flax diets. Proteinuria increased 1 week postsurgery and continued to increase in the RLD group but not in the flax diet groups. Glomerular filtration rate decreased progressively, but this decline in renal function was attenuated significantly by the flax diets. Both of the flax diets prevented glomerulosclerosis and mesangial expansion. Renal alpha-linolenic acid was increased by both the flax diets (flax oil > flaxseed), but eicosapentaenoic acid increased in the flax oil group only. The flaxseed group had greater renal-arachidonic acid levels than the flax oil and RLD groups. The total omega-3 fatty acids increased twofold to threefold in the flax oil group compared with the two other groups. The total saturated fatty acids were lower and the polyunsaturated fatty acids were increased in both flax diet groups. A progressive increase in urinary thromboxane B2 occurred in the RLD group but not in the flaxseed group; the level decreased in the flax oil group. The ratio of prostaglandin F1 alpha/thromboxane B2 was preserved in the flax oil group only. In conclusion, the dietary flax seed and flax oil attenuated the decline in renal function and reduced glomerular injury with favorable effects on blood pressure, plasma lipids, and urinary prostaglandins. While we have not proven any specific synergistic effects of the constituents of the flaxseed diet,

Topics: 6-Ketoprostaglandin F1 alpha; alpha-Linolenic Acid; Analysis of Variance; Animals; Blood Pressure; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney; Kidney Failure, Chronic; Ligation; Linseed Oil; Lipids; Male; Nephrectomy; Plants, Edible; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Artery; Seeds; Thromboxane B2

Thromboxane A2 (TxA2) seems to play an important role in bronchial constriction and hypersensitivity in asthmatics. To study the role of TxA2 in allergic rhinitis, we investigated the levels of thromboxane B2 (TxB2), a stable metabolite of TxA2, in nasal lavage fluid from patients with allergic rhinitis and from actively sensitized guinea pigs after antigen challenge by radioimmunoassay (RIA). There was a significant (p < 0.05) rise in TxB2 levels soon after antigen challenge in nasal lavage fluid from both patients (36.4 +/- 7.5 pg/ml, mean +/- SE) and models (55.6 +/- 21.8 pg/ml). In some of the patients and models, there was an dual rise in TxB2 in the 10 hours after antigen challenge. There was a significant (p < 0.03) correlation between the patients whose levels of TxB2 were re-elevated and them whose nasal airway resistance showed dual rises. These results suggest that TxA2 may contribute to the nasal obstruction in later phase in allergic rhinitis.

Topics: Adult; Animals; Antigens; Disease Models, Animal; Female; Guinea Pigs; Humans; Male; Nasal Lavage Fluid; Nasal Obstruction; Radioimmunoassay; Rhinitis, Allergic, Perennial; Thromboxane A2; Thromboxane B2

Topics: Animals; Blood Pressure; Catecholamines; Constriction; Denervation; Disease Models, Animal; Hypertension, Renovascular; Kidney; Male; Nephrectomy; Potassium; Rats; Rats, Sprague-Dawley; Renal Artery; Sodium; Sympathetic Nervous System; Thromboxane A2; Thromboxane B2

The effects of endotoxin pretreatment on induction of in vivo tolerance to endotoxin lethality, and on in vitro stimulated peritoneal macrophage mediators, thromboxane (TX)B2 and interleukin 6 (IL-6) were investigated. Rats were given i.p. injections of S. enteritidis endotoxin on days 1 (100 micrograms/kg) and 2 (500 micrograms/kg), respectively. After 5 days, or after 2-8 weeks of initial pretreatment, either endotoxin-induced mortality was assessed, or peritoneal cells were harvested for the in vitro studies. Endotoxin tolerant rats were resistant (p < .05) to endotoxin lethality for 2 weeks after initial induction of tolerance. In vitro studies with peritoneal macrophages demonstrated that endotoxin or monophosphoryl lipid A stimulated (p < .05) TXB2 production. However, peritoneal cells harvested from endotoxin tolerant rats exhibited suppressed (*p < .05) TXB2 production to both stimuli which persisted for at least 8 weeks. Endotoxin stimulated (p < .05) in vitro levels of IL-6 in control cells, but in contrast to the suppressed TXB2 production in tolerance, also stimulated (p < .05) in vitro IL-6 in the endotoxin tolerant group. Paradoxically, lipid A did not induce IL-6 production in either group. These composite observations suggest that during endotoxin tolerance neither in vitro peritoneal macrophage TXB2 nor IL-6 synthesis temporally correlate with in vivo resistance to lethality.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Drug Tolerance; Interleukin-6; Lipopolysaccharides; Macrophages; Male; Peritoneum; Rats; Salmonella Infections, Animal; Shock, Septic; Thromboxane B2

Compound BW B70C, a selective 5-lipoxygenase inhibitor was tested for its ability to reduce inflammatory damage in an in vivo rabbit model of renal storage and transplantation. Kidneys were stored at 0-2 degrees C for 48 hr prior to autografting. In controls, renal vein LTB4 levels rose significantly after 30 min reperfusion but fell after 2 hr to baseline. TxB2 levels remained at baseline for the 6 hr measured. 6-k-PGF1 alpha levels rose significantly after 1 hr of reperfusion and remained elevated thereafter. Histology after 6 hr reperfusion showed moderate-to-severe cortical edema and mild congestion. Infused colloidal carbon was retained in the perivascular area in a narrow band at the corticomedullary junction, indicating a zone of vascular permeability. At 3 days after transplant, kidneys exhibited widespread tubular necrosis and calcification but little inflammation. Serum creatinine and urea peaked between days 3 and 5. 3/6 rabbits showed no symptoms of renal failure after 3 weeks. Pretreatment with BW B70C prevented the increase in LTB4 but had little effect on TxB2 and 6-k-PGF1 alpha levels. Histology showed no amelioration of cortical edema at 6 hr and congestion and hemorrhage were exacerbated. BW B70C had no effect on either colloidal carbon retention or distribution but did significantly reduce tubular necrosis and calcification at day 3. There was very little inflammatory infiltrate. BW B70C treatment did not improve the long-term viability of transplanted kidneys: 2/6 rabbits showed no symptoms of renal failure after 3 weeks. These data indicate that inhibition of LTB4 synthesis by BW B70C does not prevent the development of acute renal failure following 48 hr hypothermic storage and transplantation.

Topics: Acute Kidney Injury; Animals; Capillary Permeability; Creatinine; Disease Models, Animal; Eicosanoids; Enzyme-Linked Immunosorbent Assay; Female; Graft Rejection; Graft Survival; Hydroxylamines; Hydroxyurea; Kidney Transplantation; Kidney Tubules; Leukotriene B4; Lipoxygenase Inhibitors; Methylurea Compounds; Necrosis; Organ Preservation; Prostaglandins F; Rabbits; Thromboxane B2; Urea

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

As part of our search for novel antiinflammatory drug candidates, we have designed and synthesized a series of 3-pyridylmethyl-substituted 2-amino-6- hydroxybenzothiazoles. Introduction of a 3-pyridylmethyl group into the 2-amino group (type-A) or the benzene ring (type-B) of 2-amino-6-hydroxybenzothiazoles imparted dual inhibitory activity against the production by glycogen-induced peritoneal cells of rat (in vitro) of leukotriene B4 (LTB4) and thromboxane A2 (TXA2), while not significantly inhibiting that of prostaglandin E2 (PGE2). The observed inhibition of the former two arachidonic acid metabolites was indicated to be the result of a direct action on 5-lipoxygenase and TXA2 synthetase by a cell-free in vitro assay. On the other hand, the inhibitory activities against PGE2 production were for most compounds very weak, indicating that they did not inhibit cyclooxygenase. Structure-activity relationship studies concerning the position of the 3-pyridylmethyl group revealed that type-B compounds generally showed about 10-fold stronger inhibitory activity against TXA2 synthetase than type-A compounds. The position of the 3-pyridylmethyl group played an important role in TXA2 synthetase inhibition. When some of these compounds (8, 13a, 26a (E3040), 26b, 27b, and 28b) were orally administered in the rat TNB/ethanol-induced chronic colitis model (100 mg/kg), the production of both LTB4 and TXB2 in the rat colon was reduced (ex vivo). In addition, one type-B compound, 6-hydroxy-5,7-dimethyl-2-(methylamino)-4-(3-pyridylmethyl)benzothiazole (26a), demonstrated a therapeutic effect at treatments of 100 mg/kg po once daily for 11 days and showed almost comparable activity to sulfasalazine at a dose of 500 mg/kg, the reference drug for inflammatory bowel diseases, in this in vivo model.

Topics: Animals; Blood Platelets; Cells, Cultured; Colitis; Dinoprostone; Disease Models, Animal; Humans; Leukotriene B4; Lipoxygenase Inhibitors; Male; Peritoneal Cavity; Rats; Rats, Inbred F344; Sheep; Structure-Activity Relationship; Thiazoles; Thromboxane B2; Thromboxane-A Synthase

In multiple trauma patients with lung contusion, pulmonary complications have been reported that were attributed to intramedullary stabilization of the femur. The reaming procedure of the medullary canal is thought to play a major role. We investigated whether different types of reamers might exert different amounts of fat mobilization into the vascular system and different degrees of pulmonary dysfunction. Adult female Merino sheep were submitted to hemorrhagic shock (2 h, 50 mm Hg) and a unilateral lung contusion; in addition, a lung lymph fistula was created. Pulmonary capillary permeability, central venous triglyceride levels, 11-dehydro-thromboxane B2 (dh-TXB2) levels, and pulmonary artery pressure were determined. After recovery, animals were randomly assigned to intramedullary femoral nailing using several types of reamers: group A, AO reamer (n = 8); group B, Biomet reamer (n = 7); group H, Howmedica reamer (n = 6); group C, controls, no reaming (n = 4). Intramedullary reaming caused a significant (p < 0.05) increase in pulmonary artery pressure in groups A and B; dh-TXB2 levels increased in all groups. Statistically significant (p < 0.05) pulmonary capillary permeability damage was measured in group A only. Intramedullary femoral nailing can cause transient pulmonary hemodynamic and mediator effects as well as increased pulmonary capillary permeability. In the present study, this effect was evident in group A reamer systems only, which may be due to reamer construction.

Topics: Animals; Bone Nails; Capillary Permeability; Contusions; Disease Models, Animal; Embolism, Fat; Equipment Design; Female; Femoral Fractures; Fracture Fixation, Intramedullary; Lung Injury; Multiple Trauma; Pulmonary Circulation; Pulmonary Embolism; Severity of Illness Index; Sheep; Shock, Hemorrhagic; Thromboxane B2; Triglycerides

The effects of ridogrel (a thromboxane synthetase inhibitor/endoperoxide receptor antagonist) were assessed in an ovine model of pregnancy-induced hypertension. Maternal serum prostacyclin and thromboxane levels were quanitiated using RIA, and maternal and neonatal coagulation status was assessed. Pregnancy and neonatal outcome were recorded. Ridogrel, (E)-5-[[[3-pyridinyl)[3-(trifluoromethyl)phenyl]methylen]amin++ +] oxy]pentanoic acid, was administered in one bolus dose at 0.1 or 1.0 mg/kg IV, three hours following the onset of a 27 hour magnesium sulfate infusion given hypertensive ewes to prevent maternal seizures. At both doses, ridogrel improved neonatal outcome (0% neonatal mortality in each ridogrel group versus 67% neonatal mortality in the magnesium sulfate group), and ridogrel at 0.1 mg/kg IV normalized birth weights. Abnormalities of maternal platelet function (abnormal or no response to collagen), occurring during the ovine syndrome, resolved following ridogrel treatment. Ridogrel's effects on maternal and neonatal coagulation were more dramatic at the 0.1 mg/kg IV dose. Ridogrel appeared to be beneficial in this model of pregnancy-induced hypertension.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Female; Fetus; Homeostasis; Hypertension; Pentanoic Acids; Placebos; Pregnancy; Pregnancy Complications, Cardiovascular; Pyridines; Radioimmunoassay; Sheep; Thromboxane B2; Thromboxane-A Synthase

Pregnancy-induced hypertension is no uniform disease with one cause and one pathophysiologic course. On the contrary it seems to be a multifactorial event with a very different symptomatology and a variable damage of various organs. Because of the heterogeneity of the disease and the difficulty of differentiation these various kinds of courses clinical studies, mostly retrospectively done, have to be criticized. The aim of this study is to examine vasoactive regulation systems by means of a standardized animal model, using wistar rats. A systemic hypertension could be achieved only in pregnant animals with aid a infrarenal aortic stenosis. Non pregnant and simulated operated pregnant animals are the control group. In the normotensive pregnant rats there was an elevation of all renal prostanoids: PGI2, TxB2 and PGE2. On the contrary hypertensive pregnant rats showed a decrease of all eicosanoids, prononcigated of PGE2.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Epoprostenol; Female; Gestational Age; Homeostasis; Hypertension; Kidney; Pre-Eclampsia; Pregnancy; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2

The combination of thromboxane (TX) synthase inhibition and prostaglandin (PG) H2/TXA2 receptor antagonism yields enhanced antithrombotic effects as compared with either intervention alone. However, it is not known whether the enhancing effect of TX synthase inhibition is expressed also in the presence of complete blockade of PGH2/TXA2 receptors. Thus we evaluated the antithrombotic effects of increasing doses of the PGH2/TXA2 receptor antagonist L 670596 alone and in combination with a dose of the TX synthase inhibitor FCE 22178 causing > 95% inhibition of platelet TXB2 production. In the dog model of electrically induced coronary thrombosis, occlusion time in control animals (n = 14) averaged 72 +/- 29 min. L 670596 alone dose-dependently antagonized platelet PGH2/TXA2 receptors and prolonged occlusion time. The addition of FCE 22178 displaced the dose-occlusion time relation of L 670596 in a parallel fashion without modifying receptor occupancy. In the rabbit model of copper coil-induced carotid artery thrombosis, occlusion was very rapid (14 +/- 4 min) in control animals (n = 17) and was not modified by either aspirin or FCE 22178. L 670596 caused a dose-related receptor blockade and prolongation of occlusion time. The association with FCE 22178 enhanced significantly the antithrombotic effect of L 670596 at all doses. We conclude that the full therapeutic potential of PGH2/TXA2 receptor antagonism is expressed at > 90% platelet receptor occupancy. The additive effect of TX synthase inhibition suggests that conversion of PGH2 to platelet-inhibitor and vasodilator prostaglandins might be of therapeutic importance, irrespective of the extent of PGH2/TXA2 receptor blockade.

Topics: Animals; Carbazoles; Carotid Artery Thrombosis; Copper; Coronary Thrombosis; Disease Models, Animal; Dogs; Evaluation Studies as Topic; Imidazoles; Male; Naphthalenes; Platelet Aggregation; Prostaglandin H2; Prostaglandins H; Rabbits; Receptors, Prostaglandin; Receptors, Thromboxane; Receptors, Thromboxane A2, Prostaglandin H2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Cytochrome P450 induction is believed to be important in the pathogenesis of alcoholic hepatic disease. Because cimetidine is a general inhibitor of cytochrome P450 enzymes, it was hypothesized that it could be useful in preventing alcoholic hepatic injury. An intragastric feeding model was used these studies. Experimental animals were divided into groups of four to five rats/group and fed the following diets: corn oil+dextrose, corn oil+ethanol (CE) and corn oil+ethanol+cimetidine (250 mg kg-1 day-1) (CEC). The rats in each group were sacrificed at the following time intervals: 2 weeks, 1 month and 2 months. For each animal, the severity of the pathologic findings and relative protein levels of cytochromes P450 2E1, 2B and 4A were measured. In addition, plasma levels of thromboxane B2, 6-ketoprostaglandin F1 alpha and 8-isoprostane were also measured. The most significant finding was that cimetidine completely prevented alcoholic hepatic injury in this model system. The pathologic scores (an indication of the severity of injury) were significantly lower in the CEC groups compared with the CE group. There was however, no significant difference in cytochrome P450 2E1, 2B or 4A protein levels between CE and CEC groups. Thromboxane B2 and 8-isoprostane levels were significantly lower and 6-ketoprostaglandin F1 alpha, significantly higher in the CEC group than in the CE group. These results indicate that possible mechanisms involved in the protective action of cimetidine include inhibition of thromboxane production and lipid peroxidation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Cimetidine; Cytochrome P-450 Enzyme System; Dinoprost; Disease Models, Animal; Endotoxins; F2-Isoprostanes; Lipid Peroxidation; Liver Diseases, Alcoholic; Male; Rats; Rats, Wistar; Thromboxane B2

The etiology of pregnancy induced hypertension (PIH) is still unknown. The pathophysiology must be clarified. In this paper we present an animal model where hypertension in pregnant and non-pregnant rats was induced by an experimental reduction of uteroplacental blood flow. Thus, a preeclampsia-like syndrome could be studied under defined conditions. The eicosanoid system was investigated for pathophysiological alterations of the kidney by measuring urinary excretion of 6-keto-PGF1 alpha, TxB2 and PGE2 with radioimmunoassay at day 18 of pregnancy. First, in gravid control animals concentrations of all three prostaglandins were significantly elevated compared to non-gravid controls. However, in hypertensive gravid rats urinary concentrations of these prostaglandins fell even below the levels of non-gravid controls. The observed decrease was more pronounced for the vasodilatory 6-keto-PGF1 alpha and PGE2 than for the vasoconstrictive TxB2. Our results demonstrate that an experimental reduction of uteroplacental blood flow in the rat culminates in symptoms which clinically (hypertension, proteinuria) and pathophysiologically (eicosanoid system) resemble to preeclampsia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Female; Pre-Eclampsia; Pregnancy; Rats; Rats, Wistar; Thromboxane B2

To evaluate the hypothesis that treatment with LY255283, a novel leukotriene B4-receptor antagonist, is beneficial in an animal model of the adult respiratory distress syndrome induced by endotoxin.. Prospective, randomized, controlled trial.. Laboratory at a large university medical center.. Twenty-five, immature, random-bred swine.. Four groups of pigs were studied: the LPS group of animals (n = 6) were infused with Escherichia coli lipopolysaccharide (strain 0111:B4, 250 micrograms/kg) from 0 to 60 mins; the LPS + 255283 group of animals (n = 6) were infused with lipopolysaccharide as above, but were also treated with LY255283 (30 mg/kg, then 10 mg/kg/hr), beginning at -15 mins; the 255283 group of animals (n = 6) were infused with the same dose of LY255283, but were not challenged with lipopolysaccharide; and the RL control group of subjects (n = 7) received only the lactated Ringer's solution vehicle. Beginning at 30 mins, all groups were infused with dextran-70 solution as needed to maintain cardiac output at 90% to 110% of baseline value.. Treatment with LY255283 significantly (p < .05) ameliorated lipopolysaccharide-induced systemic arterial hypotension, pulmonary arterial hypertension, and arterial hypoxemia. Treatment with this drug also abrogated lipopolysaccharide-induced increases in pulmonary extravascular water content and bronchoalveolar lavage fluid protein concentration.. These data suggest that leukotriene B4 may be an important mediator of acute lung injury in this porcine model of septic shock and acute lung injury. Further studies to assess the specificity of LY255283 as a leukotriene B4 antagonist are necessary in order to exclude the possibility that the beneficial effects of this compound are due to pharmacologic actions other than the blockade of LTB4 receptors.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Drug Evaluation, Preclinical; Escherichia coli Infections; Extravascular Lung Water; Hemodynamics; Leukotriene B4; Male; Peroxidase; Proteins; Random Allocation; Respiratory Distress Syndrome; Shock, Septic; Swine; Tetrazoles; Thromboxane B2

A simple and humane model of inflammation, induced by the intradermal injection of 0.3 mL of sterile 2% carrageenan, was characterized in calves by measuring the volume of skin swelling plus histological analysis of skin biopsies. Carrageenan produced a biphasic increase in skin swelling, with an early edematous response followed by a more chronic cellular infiltrate. The swelling and sensitivity to pressure observed in the early response were suitable for testing the antiedematous and analgesic activity of a new nonsteroidal anti-inflammatory drug (NSAID), oxindanac. Pretreatment with intravenous oxindanac at doses from 0.5 to 8.0 mg/kg reduced the volume of swelling and this reached statistical significance (p < 0.05) at 2 mg/kg. The ED50 and ED90 values for inhibition of the peak swelling volume (4 h) were estimated to be 1 mg/kg and 2 mg/kg, respectively. These compare with an ED90 of 2.0 mg/kg for inhibition of serum TxB2 production, an index of platelet cyclo-oxygenase activity. The dose of oxindanac required for antiedematous activity correlated, therefore, with maximal inhibition of serum TxB2. The analgesic activity of oxindanac reached no clear maximum response, but statistically significant difference (p < 0.05) from placebo was reached with doses of 2 mg/kg and above. It is concluded that intradermal carrageenan produced a simple, humane and useful model for dose estimation of a new NSAID in calves.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Cattle; Cattle Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Indenes; Inflammation; Injections, Intradermal; Male; Pressure; Skin; Thromboxane B2

Use of the CTT model provides insight into the inflammatory mediator contribution in the pathogenesis of idiopathic colitis. To evaluate anti-colitic efficacy, the leukotriene B4 receptor antagonist and anti-inflammatory agent, SC-41930, was administered (10 mg/kg BW by gavage BID) for 8 weeks to CTTs with histologically confirmed persistent and defined active colitis. The inflammatory mediators LTB4, PGE2, TXB2, and PAF were assayed in colonic dialysate that was collected after 1 1/2 h from four CTTs pre-, mid-, and post-treatment, frozen at -70 degrees C, and analyzed by RIA after HPLC purification. LTB4 levels were lower at mid- and post-treatment and had little inter-animal variation post-treatment. PGE2 and PAF levels were elevated during SC-41930 treatment, but there was a trend towards lower thromboxane B2 levels. Reduced LTB4 (PMN degranulation and chemotaxis) and increased PGE2 (mucosal-protective effect) may, in part, explain the observed efficacy of SC-41930 in active tamarin colitis.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Benzopyrans; Colitis; Colon; Dinoprostone; Disease Models, Animal; Leukotriene B4; Platelet Activating Factor; Radioimmunoassay; Saguinus; Thromboxane B2

Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Bacterial Capsules; Disease Models, Animal; Drug Evaluation, Preclinical; Hemodynamics; Hypertension, Pulmonary; Imidazoles; Polysaccharides, Bacterial; Streptococcal Infections; Streptococcus agalactiae; Swine; Thromboxane B2; Thromboxane-A Synthase

Because of their angular conformation, short hair, and thin skin, greyhounds are particularly subject to development of pressure ulcers. Greyhounds, therefore, can serve as a model to study pressure ulcers, either naturally occurring pressure ulcers or induced dermal pressure lesions. A method for inducing dermal pressure lesions was developed using a short-limb walking cast on one pelvic limb of the dog. Physical characteristics, dermal thromboxane B2 concentrations, and histopathologic changes were used to determine the severity of the lesions. Different lesion severities can be induced over the calcaneal tuberosity depending upon the amount of padding in the cast and the length of time the cast is in place. The technique for inducing a mild dermal pressure lesion is described.

Topics: Animals; Casts, Surgical; Disease Models, Animal; Dogs; Pressure; Pressure Ulcer; Thromboxane B2

We recently reported that the combined administration of lipopolysaccharide (LPS) and platelet-activating factor (PAF) in rats, at doses that are completely devoid of any effect when given alone, caused lung injury characterized by neutrophil adhesion to lung capillaries and postcapillary venules, neutrophil accumulation in the lung parenchyma, platelet-fibrin deposits in postcapillary venules, and pulmonary edema. A marked increase in lung myeloperoxidase activity and an elevation of serum tumor necrosis factor-alpha and thromboxane B2, along with leukopenia and thrombocytopenia, were also noticed. The present study aimed to examine whether repeated LPS-PAF stimulus can cause progressive lung injury reminiscent of adult respiratory distress syndrome (ARDS). A second LPS-PAF challenge, 4 h (n = 11) after the original challenge, induced mortality (69% at 24 h, P < 0.01) and some of the pathological changes seen in clinical ARDS, including severe pulmonary edema, alveolar proteinaceous exudates, monocytic infiltration, and a further increase in lung myeloperoxidase activity (700%, P < 0.01). Repeated LPS-PAF dosing also resulted in sustained increased serum tumor necrosis factor-alpha levels (1,610 +/- 470 pg/ml, P < 0.01) and further exacerbation of the leukopenia (-68 +/- 6%, P < 0.01) and thrombocytopenia (-65 +/- 8%, P < 0.01). These data suggest that repeated LPS-PAF actions are sufficient to elicit pathophysiology of ARDS-like lung injury.

Topics: Animals; Disease Models, Animal; Endotoxins; Hemodynamics; Lipopolysaccharides; Lung; Lung Injury; Male; Microscopy, Electron; Platelet Activating Factor; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Thromboxane B2; Tumor Necrosis Factor-alpha

Non-immunosuppressed rat aortic allografts from DA (RT1av1) to WF (RT1u) strain develop, after a short reversible acute rejection episode, chronic arteriosclerotic changes in the vascular wall, which are indistinguishable from those seen in human allografts during chronic rejection. Incubation of the aortic wall segments in vitro and immunochemical assays demonstrated that the allografts synthesized increased amounts of TxB2, but not 6-keto-PGF1alpha, or LTB4, compared to syngenic or normal aortas. The two major cellular components of the vascular wall, intima and adventitia, were incubated separately after microdissection. TxB2 was produced in the adventitia, whereas most of the 6-keto-PGF1alpha was synthesized in the intima. Administration of a specific TxA2 receptor inhibitor to the recipient rat reduced significantly the proliferation of adventitial inflammatory cells and the intimal smooth muscle cells. Nevertheless, it only delayed but did not inhibit the overall sclerosis of the intima.

Topics: Animals; Biphenyl Compounds; Disease Models, Animal; Graft Rejection; Heptanoic Acids; Prostaglandin Antagonists; Rats; Rats, Inbred Strains; Rats, Inbred WF; Thromboxane B2; Thromboxanes; Transplantation, Homologous

Biofor 389 (BF389), dihydro-4-[[3,5-bis(1,1-dimethyl)-4-hydroxyphenyl] methylene]-2-methyl-2H-1,2-oxazin-3(4H)-one, was tested for anti-inflammatory activity in various animal models of arthritis. Initial evaluation in the lipoidalamine (LA) arthritis model in rats (5-day dosing protocol) resulted in an oral ED50 of 4.9 mg/kg for inhibition of paw swelling. No effects on splenomegaly were observed, suggesting that the compound was efficacious as a result of anti-inflammatory rather than immunomodulatory effects. BF389 was efficacious in interleukin 1 (IL-1)-enhanced type II collagen arthritis in rats (oral ED50 less than 1.0 mg/kg) as assessed by paw volume measurement and histologic evaluation of joints. Mice with IL-1-enhanced type II collagen arthritis given 30 mg/kg of BF 389 had significantly lower histological scores for joint damage than did untreated controls. Normal rats given single oral doses of BF389 had significant suppression of arachidonate-stimulated whole blood prostaglandin E2 and thromboxane B2 production 2 hr postdosing (ED50 = 0.1 mg/kg). Leukotriene B4 production in these animals was not decreased. After it became apparent that the compound was a potent inhibitor of prostaglandin production in vivo, a study was done to compare the efficacy and toxicity of BF389 with several currently marketed nonsteroidal anti-inflammatory drugs, piroxicam, naproxen and diclofenac. Lipoidalamine-injected rats were given daily oral doses of BF389 or the comparators for 21 days. Quantitation of effects on arthritis on day 21 resulted in ED50 values of 0.9 mg/kg (BF389), 3.9 mg/kg (naproxen), 4.9 mg/kg (diclofenac) and 0.6 mg/kg (piroxicam).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Arthritis, Experimental; Collagen; Diamines; Diclofenac; Dinoprostone; Disease Models, Animal; Female; Interleukin-1; Leukotriene B4; Male; Naproxen; Oxazines; Phenols; Piroxicam; Rats; Rats, Inbred Lew; Thromboxane B2

1. This paper describes the pre-clinical pharmacology of ICI D2138, a potent orally-active non-redox inhibitor of 5-lipoxygenase which is undergoing clinical evaluation. 2. ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nM) and human blood (IC50 = 20 nM). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 microM, thus the selectivity ratio (cyclo-oxygenase: 5-lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5-lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15-100. 3. ICI D2138 potently and dose-dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg-1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan-inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg-1 at 3 and 10 h respectively. 4. Oral administration of 1, 3 or 10 mg kg-1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg-1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h. 5. Oral administration of 10 mg kg-1 ICI D2138 caused total inhibition of LTB4 production in zymosan-inflamed rabbit knee joint. 6. Topical administration of ICI D2138 to rabbit skin caused a dose-related inhibition of arachidonic acid-induced plasma extravasation with an ID30 of 1.08 nmol per site. Zileuton was approximately 40 times less potent.7. Oral anti-inflammatory activity was assessed in an arachidonic acid-induced mouse ear oedema model in animals treated with indomethacin to block pro-inflammatory prostanoids. ICI D2138, given orally, caused dose-dependent inhibition of oedema with an approximate ID50 of 1.8 mg kg'. Zileuton was approximately 10 times less potent.8. ICI D2138 caused a dose-dependent inhibition of antigen-induced broncho-constriction in guineapigs with an approximate ID50 of 0.1 mg kg-', i.v. Zileuton was approximately 10 times less potent.9. In view of the pharmacological profile described here, ICI D2138 has the potential to provide improved clinical efficacy compared to existing lipoxygenase inhibitors such as zileuton.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Bronchoconstriction; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Guinea Pigs; Hydroxyurea; Inflammation; Knee Joint; Leukotriene B4; Lipoxygenase Inhibitors; Macrophages; Male; Mice; Oxidation-Reduction; Pyrans; Quinolones; Rabbits; Rats; Thromboxane B2

For the past half-century, several high molecular weight compounds have been used for volume expansion during cardiopulmonary resuscitation. However, the effectiveness and side effects of these different expanders are varied. We have compared plasma, pentastarch, and a new product, pentafraction, for effective plasma volume expansion before and after tissue injury with endotoxin administration. In each group, eight range ewes instrumented with a Swan-Ganz, arterial, and venous catheters, and lung and flank lymphatic cannulas were compared. Each group received 15 ml/kg of either 6% pentafraction, 6% pentastarch, or plasma followed two hours later by 1.5 micrograms/kg/0.5 hr E. Coli endotoxin over 30 min. Data were collected for an additional 24 hr after endotoxin administration. Our results indicated a plasma volume expansion in all three groups. However, the prior administration of pentafraction significantly attenuated the increase in the lung lymph flow and early evaluation of systemic vascular resistance noted with endotoxin in comparison to the other two groups.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Capillary Permeability; Disease Models, Animal; Hydroxyethyl Starch Derivatives; Lymph; Molecular Weight; Pulmonary Edema; Sheep; Shock, Septic; Thromboxane B2

1. The role of prostanoids in experimental colitis with trinitrobenzene sulfonic acid (TNBS) in rats was investigated. The effects of cyclosporine A (CsA) on the development of experimental colitis were also examined. 2. Five kinds of prostanoids were detected in rat colonic tissue by high performance liquid chromatography. These were 6-keto-prostaglandin (PG) F1 alpha, PGF2 alpha, PGE2, PGD2 and thromboxane B2. 3. In TNBS-induced experimental colitis, all prostanoid concentrations except PGD2 increased, although the time courses differed from each other. 4. Medication with indomethacin markedly reduced prostanoid concentrations in TNBS-induced colitis. However, indomethacin did not show any effect on damage scores. 5. Cyclosporine A reduced damage scores 14 days after TNBS treatment, and the protective effects were observed, whereas CsA did not affect colonic tissue prostanoid concentrations. 6. Prostanoids might be produced secondarily in the genesis of TNBS-induced colitis, although they may attenuate the inflammatory response. It was also suggested that CsA was likely to have therapeutic effects on experimental colitis by inhibiting the immune reaction with TNBS, which induced the chronic inflammation.

Topics: Animals; Chromatography, High Pressure Liquid; Chronic Disease; Colitis; Colon; Cyclosporine; Disease Models, Animal; Indomethacin; Male; Prostaglandins; Rats; Rats, Wistar; Thromboxane B2; Trinitrobenzenesulfonic Acid

We studied the changes in myocardial and aortic concentrations of prostacyclin and thromboxane A2 during acute coronary occlusion with or without reperfusion in rabbits fed with a cholesterol-enriched diet with or without fish oil supplementation for a short (5 days) or long period (6 weeks). New Zealand white male rabbits were divided into 5 groups: Group I, 15 control rabbits fed with a laboratory standard rabbit chow. In addition to the standard chow, the 4 study groups were treated with cholesterol or fish oil. Group II, 17 rabbits fed with a 1% high cholesterol diet for 5 days. Group III, 16 rabbits fed with a diet containing 1% cholesterol and 10% fish oil for 5 days. Group IV, 17 rabbits fed with the same diet as group II for 6 weeks. Group V, 18 rabbits fed with the same diet as group III for 6 weeks. Each group of rabbits was randomly divided into the coronary occlusion or occlusion-reperfusion mode of experiment. Acute coronary occlusion was induced by ligating the marginal branch of the left circumflex coronary artery for 1 h. Subsequent reperfusion for 4 h was performed in the occlusion-reperfusion rabbits. The aortic tissue above the aortic valve and the ischemic and normal (nonischemic) areas of the left ventricle were excised for the measurement of 6-keto-PGF1 alpha and thromboxane B2 levels by radioimmunoassay. Both during coronary occlusion and occlusion-reperfusion, rabbits showed higher myocardial concentrations of 6-keto-PGF1 alpha and thromboxane B2 in the ischemic area than in the normal myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aorta; Cholesterol, Dietary; Coronary Disease; Disease Models, Animal; Evaluation Studies as Topic; Fish Oils; Hypercholesterolemia; Lipoproteins; Male; Myocardial Reperfusion; Myocardium; Prostaglandins; Prostaglandins F; Rabbits; Radioimmunoassay; Thromboxane B2; Triglycerides

The effects of Y-20811, a selective inhibitor of thromboxane A2 (TXA2) synthetase, on blood flow and local levels of immunoreactive thromboxane B2 (i-TXB2) and 6-keto prostaglandin F1 alpha (i-6-keto PGF1 alpha) in the coronary artery were investigated in the canine model of coronary thrombosis. Thrombosis was induced by applying an electric current to the intraluminal surface of the coronary artery. The plasma levels of i-TXB2 and i-6-keto PGF1 alpha were measured distal to the electrode. In the control group, coronary blood flow decreased and finally stopped 207 +/- 53 min (mean +/- S.E.M., n = 5) after the start of current application. The level of i-TXB2 rose before the coronary occlusion. Coronary blood flow did not change significantly in the Y-20811-treated group (1 mg/kg i.v.). The level of i-TXB2 decreased and remained significantly lower than that in the control group. The level of i-6-keto PGF1 alpha tended to increase slightly in the Y-20811-treated, but not in the control group. The weight of the thrombus in the Y-20811-treated group was significantly less than that in the control group (P less than 0.01). These results suggest that Y-20811 prevents coronary thrombosis by the inhibition of TXA2 production around the electrically injured lumen of the coronary artery.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Circulation; Coronary Thrombosis; Disease Models, Animal; Dogs; Electric Stimulation; Imidazoles; Male; Thromboxane B2; Thromboxane-A Synthase

Interleukin-1 and thromboxane are known to mediate the host response to sepsis, trauma, and myocardial ischemia. A well-established model of canine isolated gracilis muscle was used to evaluate whether cytokine (interleukin-1) played a role in skeletal muscle ischemia-reperfusion injury. Six adult mongrel dogs (25-30 kg) were subjected to six hours of muscle ischemia followed by reperfusion. Gracilis venous samples were collected pre-ischemia and at one hour of reperfusion. Systemic (arterial) blood samples were taken at one hour of reperfusion. Sera were analyzed for interleukin-1 by bioassay and thromboxane (B2) by radio-immunoassay. The gracilis muscle of the operated limb was harvested in all the animals for assessment of the percentage of muscle necrosis. This was found to be 56.2 +/- 14.8% by serial transections, nitroblue tetrazolium staining, and computerized planimetry. Interleukin-1 levels in the gracilis venous effluent increased from 21.88 +/- 7.13 units/ml during pre-ischemic baseline to 50.42 +/- 9.12 units/ml after six hours of ischemia followed by one hour of reperfusion (p less than 0.04). Thromboxane B2 levels were 2983 +/- 1083 pg/ml and 9483 +/- 2218 pg/ml at pre-ischemia and at one hour of reperfusion respectively (p less than 0.04). Systemic levels of both interleukin-1 and thromboxane B2 at one hour of reperfusion were 0 units/ml and 1584 +/- 520 pg/ml respectively, which were significantly lower than the one hour reperfusion gracilis venous effluent levels (p less than 0.04). This is the first report in which cytokines have been implicated in skeletal muscle ischemia-reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biological Assay; Disease Models, Animal; Dogs; Hindlimb; Interleukin-1; Ischemia; Muscles; Radioimmunoassay; Reperfusion Injury; Thromboxane B2

The effect of testosterone administration on plasma lipoproteins and eicosanoids was studied in 24 male cynomolgus monkeys. We hypothesized that elevated plasma testosterone would unfavorably alter plasma lipids as well as thromboxane A2 (TxA2) and prostacyclin (PGI2), two eicosanoids that have been linked to the increased incidence of atherosclerosis, myocardial ischemia, and thrombosis. To test our hypothesis, half of the monkeys (N = 12) were subjected to 10 wk of testosterone treatment, whereas the remaining monkeys (N = 12) received a sesame oil vehicle. The plasma concentrations of thromboxane B2 (TxB2) and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and PGI2, respectively, were determined. Additionally, assays were conducted on total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG). Distribution of the HDL subfraction protein was measured by gradient gel electrophoresis. All monkeys exhibited significant increases in TC (P less than 0.001) and low density lipoprotein cholesterol (LDL-C) (P less than 0.001); however, monkeys who received testosterone also displayed significant increases in TxB2 (P less than 0.03) and decreases in HDL-C (P less than 0.03) compared with control monkeys. There was a trend in the HDL-C subfraction data, indicating that testosterone treatment may be associated with a decrease in the larger HDL2b subfraction and a corresponding increase in HDL3c. These results demonstrate that exogenous testosterone adversely alters cardiovascular risk profiles by increasing TXB2 production and decreasing HDL-C. Athletes who use testosterone as an anabolic androgenic steroid may have an increased risk for coronary heart disease.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Disease Models, Animal; Eicosanoids; Epoprostenol; Lipids; Macaca fascicularis; Male; Testosterone; Thromboxane A2; Thromboxane B2

1. The burst of damaging oxygen free-radicals at the time of reperfusion is one of the crucial factors affecting skin flap survival after an ischaemic interval. In these experiments the efficacy of the antioxidant and free-radical scavenger N-acetylcysteine in improving the survival of ischaemic rabbit epigastric skin flaps was tested. 2. At the time of reperfusion flaps were given: (1) balanced salt solution by intravenous whole-body administration, (2) N-acetylcysteine (200 mg/kg) by intravenous whole-body administration, (3) balanced salt solution by intra-arterial infusion into the flap, (4) N-acetylcysteine (20 mg/kg) by intra-arterial infusion into the flap, or (5) N-acetylcysteine (200 mg/kg) by intra-arterial infusion into the flap. Flap survival at 1 week, and tissue levels of parameters related to free-radical production, blood levels of thromboxane B2 and peripheral resistance during reperfusion were determined. 3. Compared with controls (groups 1 and 3) which had flap survival rates (expressed as percentage surface area surviving) of 27.1% and 31.6%, respectively. N-acetylcysteine treatment in group 2 (55.2%) and group 4 (51.9%) resulted in significant (P less than 0.05) improvements in flap survival. The survival rate in group 5 (37.7%) was not significantly better than that of the controls. 4. N-Acetylcysteine significantly reduced parameters related to free-radical production in the skin flap after 30 min of reperfusion, determined as tissue levels of malonyldialdehyde and protein oxidation products. There was also a significant decrease in peripheral resistance when low-dose N-acetylcysteine (group 4) was infused intra-arterially into the flap.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcysteine; Animals; Antioxidants; Disease Models, Animal; Free Radical Scavengers; Graft Survival; Ischemia; Malondialdehyde; Phenylhydrazines; Rabbits; Reperfusion Injury; Skin; Surgical Flaps; Thromboxane B2; Vascular Resistance

The role of metabolites of arachidonic acid (AA) in experimental autoimmune uveoretinitis was studied using inhibitors of AA metabolism. Nordihydroguaiaretic acid (NDGA), which inhibits predominantly the lipoxygenase (LO) pathway, or indomethacin, a specific cyclo-oxygenase (CO) inhibitor, was administered to rats immunized with retinal S antigen. Levels of various AA metabolites were measured in the inflamed uvea, and the severity of intraocular inflammation was quantitated by morphometric analysis. Histopathologically, the uveoretinitis was significantly suppressed following treatment with NDGA, while indomethacin treatment resulted in augmentation of the disease (p less than 0.05). These results tend to indicate that the inhibition of the LO rather than the CO pathway may be more beneficial in the treatment of autoimmune uveitis.

Topics: Animals; Anthropometry; Anti-Inflammatory Agents, Non-Steroidal; Antigens; Arrestin; Dinoprostone; Disease Models, Animal; Eye Proteins; Female; Indomethacin; Leukotriene B4; Masoprocol; Radioimmunoassay; Rats; Rats, Inbred Lew; Retinitis; Thromboxane B2; Uveitis, Posterior

The beige (bgJ/bgJ) mouse is a well-described murine model of Chediak-Higashi syndrome. Platelet function was examined in normal and beige mice to better characterize the defective aggregation response in platelets from mice with Chediak-Higashi syndrome. Platelet aggregation after collagen, thrombin, and phorbol-12-myristate 13-acetate stimulation was significantly (P less than 0.025) decreased in platelets from beige mice, relative to platelets from normal mice. Compared with beige and normal mice, those heterozygous for the bg trait had intermediate responses to collagen and thrombin, but not phorbol-12-myristate 13-acetate. The defect(s) in aggregation of platelets from beige mice was associated with a dense granule storage pool deficiency and decreased stores of serotonin and adenine nucleotides in platelets. Mice heterozygous for the bg trait had normal platelet serotonin and adenine nucleotide concentrations. Platelets from beige mice were approximately 10 times more sensitive to prostacyclin inhibition of collagen-induced aggregation than were platelets from control mice. However, a significant difference in platelet cyclic AMP concentration was not apparent between beige and normal mice after prostacyclin stimulation. Platelet endoperoxide synthesis measured by quantification of thromboxane B2, was normal in beige mice. Protein phosphorylation patterns in mouse platelets were similar to those seen in human platelets. Thrombin and collagen-induced [32P] phosphorylation of 40- and 20-kD proteins in platelets from normal and beige mice was similar. Results indicate that the biochemical defect(s) in platelet function in beige mice is partially attributable to storage pool deficiency and does not result in an absolute defect in phosphorylation of 40- and 20-kD proteins.

Topics: Animals; Blood Platelets; Blood Proteins; Chediak-Higashi Syndrome; Cyclic AMP; Disease Models, Animal; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nucleotides; Phosphorylation; Platelet Aggregation; Platelet Storage Pool Deficiency; Serotonin; Thromboxane B2

Rats were treated with the platelet activating factor receptor antagonist WEB 2170 (15 mg/kg/day) in three different protocols to evaluate a possible role of platelet activating factor in an experimental proliferative model of glomerular disease. The glomerular immune injury was initiated by the i.v. administration of a rabbit anti-rat thymocyte antiserum. Anti-rat thymocyte antiserum induces a proliferative glomerulonephritis with reduction of glomerular filtration rate (614 +/- 94) compared with controls (1,120 +/- 192 microL/min/100 g body wt) when studied at day 7. Treatment of rats with WEB 2170 over 8 days (starting at day -1; protocol 1) ameliorated the loss in glomerular filtration rate (936 +/- 82 microL/min/100 g body wt) in nephritic rats at day 7; however, it had no effect on controls (1,142 +/- 104 microL/min/100 g body wt). Interventional treatment with WEB 2170 (starting at day 4 after anti-rat thymocyte antiserum; protocol 2) also improved glomerular function when glomerular filtration rate was already reduced (410 +/- 41 microL/min/100 g body wt) at day 4. The platelet activating factor receptor antagonist given at day 7 after induction of disease (protocol 3) did not improve impaired glomerular filtration rate. Preinterventional and interventional treatment with WEB 2170 reduced the infiltration of polymorphonuclear granulocytes in glomeruli. Interventional treatment with WEB 2170 also reduced glomerular morphologic damage in nephritic glomeruli. The data demonstrate a beneficial effect of the platelet activating factor receptor antagonist in this animal model of proliferative glomerulonephritis which suggests that platelet activating factor might play an important role in the mediation of this disease.

Topics: Animals; Antilymphocyte Serum; Azepines; Dinoprostone; Disease Models, Animal; Glomerular Filtration Rate; Glomerular Mesangium; Glomerulonephritis; Inulin; Male; Platelet Membrane Glycoproteins; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Thromboxane B2; Triazoles

The anti-inflammatory effects of vitamin E were investigated using the S antigen model of uveoretinitis. Thirty-six 3-week-old Lewis rats were separated into three groups and maintained on a specially formulated diet. One group of animals received a diet deficient in vitamin E; a second group received a normal diet containing vitamin E, and the third group, in addition to receiving the normal diet, received vitamin E supplementation. At 9 weeks of age, all rats were sensitized to S antigen. Six animals in each group were killed on day 14 and the remaining animals on day 21 following immunization. Both histopathologic and biochemical studies were conducted to evaluate the tissue damage observed in animals maintained on different dietary levels of the vitamin. The intraocular inflammation in the vitamin E-supplemented group was considerably smaller than in the other two groups (p less than 0.01). The former group had the highest level of vitamin E in both the eye and plasma (mean value 1.13 micrograms/mg protein and 23.9 micrograms/ml, respectively), while the vitamin E-deficient group had the lowest levels (mean values of 0.16 micrograms/mg protein and 0.48 micrograms/ml in the eye and plasma, respectively). Results of the radioimmunoassay for the determination of the arachidonic acid metabolites revealed significantly lower levels of thromboxane B2 in the vitamin E-supplemented group (2.04 +/- 0.45 pg/mg) than in the normal (4.33 +/- 0.98 pg/mg) or the vitamin E-deficient (5.21 +/- 1.12 pg/mg) groups (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antigens; Arrestin; Autoantigens; Choroid; Diet; Dinoprostone; Disease Models, Animal; Eye Proteins; Female; Leukotriene B4; Membrane Proteins; Phosphodiesterase Inhibitors; Radioimmunoassay; Rats; Rats, Inbred Lew; Retinitis; Thromboxane B2; Uveitis; Vitamin E

It was found, that adaptation of rats to cold and physical exercise prevented ventricular fibrillation, caused by the occlusion of the left anterior coronary artery. An adaptation to cold only or to physical exercise do not prevent ventricular arrhythmias. An significant increase of prostacyclin/thromboxane index in plasma and heats was estimated in rats adapted to cold and physical exercise in relation to control non-adapted group in condition of functional rest or acute myocardial ischemia. It was assumed that an increase of prostacyclin/thromboxane ratio has a significant role in antiarrhythmic action of adaptation.

Topics: 6-Ketoprostaglandin F1 alpha; Adaptation, Physiological; Animals; Cardiac Complexes, Premature; Cold Temperature; Coronary Disease; Disease Models, Animal; Male; Rats; Swimming; Thromboxane B2; Ventricular Fibrillation

Guinea pigs were intravenously injected with icterhemorrhagiae serogroup Lai serovar strain 017 leptospirosis to model the pulmonary diffuse hemorrhage (PDH) in leptospirosis. Thirty-eight hours after the injection, the jugular arteries were catheterized to collect blood sample. The plasma was prepared for radioimmunoassay of TXB2 and 6-keto-PGF1a, the stable metabolites of TXA2 and PGI2 respectively. The plasma level of TXB2 in the experimental group, 107.15 +/- 41.65 pg/ml (n = 7), almost doubled that of the control, 54.05 +/- 12.93 pg/ml (n = 7), with significant difference (P less than 0.01); meanwhile, no significant difference was observed of 6-keto-PGF1a, 67.97 +/- 16.89 pg/ml (n = 6) vs. 98.06 +/- 40.63 pg/ml (n = 9) with P greater than 0.1. The fact that TXA2 causes vasoconstriction and increases vessel permeability suggests that TXA2 elevation should play a role in the mechanism of PDH in leptospirosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Epoprostenol; Guinea Pigs; Hemorrhage; Lung Diseases; Thromboxane B2; Weil Disease

Changes of plasma thromboxane level in subarachnoid haemorrhage (SAH) were studied clinically and experimentally using 11-dehydro-thromboxane B2 (11 DTX) as a measuring index. 11 DTX is a major long-lived metabolite formed from thromboxane (TX) B2, and is said to be a more reliable parameter for detecting TXA2 production in biological systems. In this clinical study, blood was sampled from the cubital vein of 10 SAH patients on the earliest possible day (day 0 or 1), during the vasospasm predilection period (day 7 approximately 11) and in the chronic stage (day 16 approximately 32). Plasma concentrations of 11 DTX and 6-keto-PGF 1 alpha were measured in clinical cases. A canine SAH model was produced by the two haemorrhage methods and blood was sampled from the superior sagittal sinus before and on day 4 of the first cisternal blood injection. 11 DTX, TXB2 and platelet function were examined in each sample. In the clinical studies, plasma 11 DTX levels tended to be higher in the early stage of SAH but decreased thereafter to the normal or lower level. Plasma concentrations of 6-keto-PGF1 alpha tended to decrease mildly during the vasospasm predilection period. In the experimental study, neither definite change of plasma 11 DTX level nor neurological deficit could be induced by the mimic SAH, while an increase in platelet aggregability and narrowing of the basilar artery were observed. 11 DTX was inferred to be a more reliable parameter of TX biosynthesis than TXB2.

Topics: Adult; Aged; Animals; Disease Models, Animal; Dogs; Female; Humans; Ischemic Attack, Transient; Male; Middle Aged; Platelet Aggregation; Subarachnoid Hemorrhage; Thromboxane B2

To determine the role of thromboxane A2 in the pathogenesis of experimentally induced immune complex glomerulonephritis, 12 concanavalin A-immunized Beagles were infused with 1 mg of concanavalin A via each renal artery and treated twice daily for 8 days with either 30 mg of CGS 12970/kg, PO, a specific thromboxane synthetase inhibitor, or placebo. The effect of treatment was assessed by measuring endogenous creatinine clearance and urine protein and eicosanoid excretion, and by evaluating changes in glomerular morphometric characteristics. On postinfusion day 8, urine protein, thromboxane B2, and 11-dehydro-thromboxane B2 excretion, glomerular epithelial crescent formation, and glomerular cell proliferation in the CGS 12970-treated dogs were significantly decreased when compared with values in the placebo-treated group. Differences were not observed in endogenous creatinine clearance, urine prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion, or glomerular polymorphonuclear leukocyte infiltration between groups in this study. These findings suggest thromboxane A2 has a role in the development of immune complex glomerulonephritis and that thromboxane synthetase inhibition may be beneficial in attenuating some of the functional and histological changes associated with immune complex glomerulonephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Concanavalin A; Dinoprostone; Disease Models, Animal; Dogs; Glomerular Filtration Rate; Glomerulonephritis; Immune Complex Diseases; Kidney; Kidney Glomerulus; Male; Pyridines; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

To test the hypothesis that the effect of steroids on hydrochloric acid aspiration may be involved in the metabolism of eicosanoids, we investigated the effects of an iv bolus of prednisolone on the metabolism of 15-hydroxyeicosatetraenoic acid and 11-dehydrothromboxane B2 (11-dehydro-TxB2) in the rat model of acid aspiration. Wistar rats were randomly selected for three groups and treated with either a) an iv bolus of saline after intratracheal injection of saline (control group), b) an iv bolus of saline after intratracheal injection of acid (acid-saline group), or c) an iv bolus of prednisolone after intratracheal injection of acid (acid-prednisolone group). The concentrations of 15-hydroxyeicosatetraenoic acid and 11-dehydro-TxB2 in bronchoalveolar lavage fluid were measured by radioimmunoassay.. The concentration of 15-hydroxyeicosatetraenoic acid in bronchoalveolar lavage fluid of either acid-saline group (804 +/- 129 pg/mL) or acid-prednisolone group (748 +/- 112 pg/mL) was significantly greater than that of the control group (143 +/- 27 pg/mL, p less than .01) 1 hr after the administration. The iv bolus of prednisolone caused a significant decrease in 15-hydroxyeicosatetraenoic acid (acid-saline group 1027 +/- 43 pg/mL; acid-prednisolone group 514 +/- 62 pg/mL; p less than .01) and cell counts of bronchoalveolar lavage fluid 48 hrs after intratracheal injection of acid, while there was no significant change in 11-dehydro-TxB2.. These findings suggest that corticosteroid administration may contribute to the inhibition of the inflammatory process of lungs after acid aspiration by decreasing the release of 15-hydroxyeicosatetraenoic acid in the distal lung unit.

Topics: Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Female; Hydroxyeicosatetraenoic Acids; Injections, Intravenous; Pneumonia, Aspiration; Prednisolone; Rats; Thromboxane B2

The effects of combined thromboxane synthetase inhibition and thromboxane receptor antagonism (TSI/TRA) were studied in conscious and in anesthetized canine models of sudden cardiac death. Administration of the TSI/TRA, R68070 10 mg/kg intravenously (i.v.), decreased thrombin-stimulated thromboxane synthesis and significantly antagonized platelet aggregation in response to the thromboxane-mimetic U46,619. In the conscious canine model, R68070 did not change ventricular refractoriness, did not prevent induction of ventricular arrhythmias by programmed electrical stimulation, and failed to prevent development of spontaneous ventricular fibrillation (VF) in response to ischemia produced at a site remote from the area of previous myocardial infarction (R68070 mortality = 70%, vehicle = 100%, p = NS). In the anesthetized canine model, R68070 prevented development of ischemia in 7 of 11 animals and reduced mortality significantly (R68070 27% and vehicle 73%; p = 0.038). R68070 inhibited thrombus formation in both models (R68070 conscious 7.0 +/- 2.6 mg and vehicle conscious 15 +/- 7.6 mg, p = NS; R68070 anesthetized 5.9 +/- 1.9 mg and vehicle anesthetized 17.7 +/- 4.3 mg; p less than 0.05). The results suggest that inhibition of thromboxane-dependent activity during acute recovery from infarction was able to protect the myocardium from developing ischemia in response to current-mediated intimal damage in a noninfarct-related artery. In the subacute phase of recovery from infarction, when the underlying myocardial substrate is susceptible to electrical derangement induced by transient ischemia, thromboxane inhibition in itself was unable to prevent ischemia-induced sudden cardiac death. Although R68070 may delay onset of ischemia due to thrombotic occlusion of the coronary artery, there does not appear to be an antiarrhythmic/antifibrillatory action to be derived from interfering with the synthesis or receptor-mediated action of thromboxane. Furthermore, R68070 does not alter the electrophysiologic properties of the heart which would result in an antiarrhythmic or antifibrillatory action.

Topics: Adenosine Diphosphate; Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Collagen; Coronary Disease; Death, Sudden; Disease Models, Animal; Dogs; Electric Stimulation; Electrophysiology; Female; Heart Rate; Male; Pentanoic Acids; Platelet Aggregation; Prostaglandin Endoperoxides, Synthetic; Pyridines; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

A hyperdynamic sepsis model was developed in dogs. It is based on a 3-hour clamping of the arteries supplying the middle portion of the jejunum. The ensuing sepsis has a course of several days, during which the animals were studied in the conscious state. 2/3 of the animals developed a sustained 32-108 per cent increase in cardiac output, and survived 7 days or more. In the other 1/3 of the animals, the cardiac output was lower than the control value and all these animals died within 5 days. There were no differences between the two groups in other parameters examined. Sepsis caused a steady, slight decrease in mean arterial pressure, an increase in heart rate, and leukocytosis. The plasma levels of epinephrine and norepinephrine showed a sustained, significant elevation. The level of thromboxane B2 was high only on the first day of sepsis, and that of plasma renin activity on the first 2 days. Necrosis and edema of jejunal villi were demonstrated histologically in the early period. Hemocultures were positive in only 5 of 11 animals examined, suggesting the predominant role of absorbed toxins. This model simulates human sepsis well and is suitable for the study of pathophysiologic mechanisms in hyperdynamic sepsis.

Topics: Alkaline Phosphatase; Animals; Bacterial Infections; Blood Pressure; Cardiac Output; Disease Models, Animal; Dogs; Epinephrine; Female; Heart Rate; Hematocrit; Hemodynamics; Ischemia; Jejunum; Leukocyte Count; Male; Norepinephrine; Renin; Thromboxane B2

The neutralisation of heparin by protamine can cause life-threatening pulmonary hypertension. We studied this reaction in animal experimental models (sheep and rat) to determine the cellular mechanisms of the pulmonary vasoconstriction. The heparin-protamine reaction (H-P) with pulmonary hypertension (peak of mean pulmonary artery pressure = 57.3 +/- 2.2 mmHg), decreased cardiac output (-20%), leukopenia (-30%) and plasma release of high concentrations of thromboxane B2 (6.03 +/- 0.03 ng/ml) was constantly observed in sheep. The reaction was identical in sheep with induced thrombocytopenia by administration of antiplatelet antibodies. On the other hand, the neutralisation of heparin by protamine in rats did not cause thromboxane release or pulmonary vasoconstriction although the leukopenia was identical to that observed in sheep. Therefore, the platelets and white blood cells did not seem to cause the pulmonary vasoconstriction induced by the H-P complexes. The inter-species difference observed suggests that pulmonary intravascular macrophages may be responsible for the liberation of eicosanoids and acute pulmonary vasoconstriction occurring during the neutralisation of heparin by protamine.

Topics: Animals; Disease Models, Animal; Heparin Antagonists; Hypertension, Pulmonary; Leukocyte Count; Macrophages; Protamines; Pulmonary Artery; Pulmonary Wedge Pressure; Rats; Rats, Inbred Strains; Sheep; Thromboxane B2; Vasoconstriction

Dimethylthiourea (DMTU), a putative hydroxyl radical scavenger, attenuates thromboxane generation and pulmonary hypertension in the piglet model of group B streptococcal (GBS) sepsis. This study tested the hypothesis that DMTU reverses ongoing GBS-induced pulmonary hypertension coincident with decreased thromboxane production. Piglets (n = 15) received a 60 min infusion of GBS (10(-8) cfu/kg/min). Mean pulmonary artery pressure (Ppa), arterial blood gases (ABGs), and thromboxane B2 (TXB) levels were measured at 10 min intervals throughout the study. GBS infusion resulted in a marked increase in pulmonary artery pressure (mean delta Ppa = 31 mm Hg) and a significant decline in PaO2 (mean = -80 torr) within 10 min of beginning the infusion. pH decreased from a mean of 7.47 to 7.37. DMTU, 750 mg/kg, or normal saline vehicle was infused over 10-15 min beginning 10 min after initiating GBS. Ppa decreased significantly within 10 min of DMTU infusion. Piglets receiving vehicle had a slow decline in Ppa. Piglets receiving DMTU also had an improvement in PaO2 and showed no further drop in pH. Piglets receiving vehicle had no improvement in PaO2 and demonstrated a continued decline in pH. TXB levels did not differ between the groups at any time interval. We conclude that DMTU can partially reverse GBS-induced pulmonary hypertension, but may function through mechanisms independent of thromboxane generation.

Topics: Animals; Animals, Newborn; Blood Pressure; Disease Models, Animal; Hypertension, Pulmonary; Oxygen; Partial Pressure; Pulmonary Circulation; Sepsis; Streptococcal Infections; Swine; Thiourea; Thromboxane B2

To clarify the role of thromboxane (TX) A2 in arterial thrombus formation, we examined the antithrombotic effects of both a TXA2 synthetase inhibitor (CV-4151) and a TXA2 receptor antagonist (AA-2414) on the rabbit common carotid artery thrombosis which was induced by injury of the endothelium by treatment with 0.25% pronase solution. CV-4151 (1,10 mg/kg, p.o.) and AA-2414 (10 mg/kg, p.o.) significantly inhibited thrombus formation. Furthermore, the combined use of CV-4151 and AA-2414 (0.1 mg/kg, p.o. each) significantly inhibited thrombus formation, though these drugs at the same doses had no effect when administered singly. The plasma level of 11-dehydro TXB2 increased significantly during thrombus formation, and CV-4151 (10 mg/kg) markedly inhibited this increase. There was a significant correlation between the in vivo antithrombotic effects of these drugs and their ex vivo inhibitory effects on arachidonic acid-induced platelet aggregation. The antithrombotic effect of CV-4151 also correlated significantly with its ability to inhibit the production of serum TXA2. These results show that TXA2 may play an important role in the thrombus formation in arterial thrombosis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Benzoquinones; Carotid Artery Thrombosis; Disease Models, Animal; Endothelium, Vascular; Fatty Acids, Monounsaturated; Heptanoic Acids; Male; Platelet Aggregation; Pyridines; Quinones; Rabbits; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

We hypothesized that streptozocin-induced ovine diabetes would cause alterations in the placental production of thromboxane and prostacyclin. With a tissue incubation technique, we examined the placental production of thromboxane and prostacyclin in cotyledons from seven normal near-term ewes (127 +/- 3 days' gestation) and six streptozocin-induced diabetic ewes (125 +/- 3 days' gestation). Diabetic status was verified with serial fasting blood glucose assessments. Placental tissue was incubated in Dulbecco's modified Eagle's medium for 48 hours at 37 degrees C with 95% oxygen and 5% carbon dioxide. Samples were collected at 0, 1, 2, 4, 8, 20, 32, and 48 hours. Radioimmunoassay of the stable metabolites thromboxane B2 and 6-keto-prostaglandin F1 alpha were used to determine thromboxane and prostacyclin production, respectively. Placental thromboxane production was reduced in diabetic animals when compared with control animals (5.63 +/- 2.81 vs 7.32 +/- 1.37 pg/mg per hour, respectively; p less than 0.05). Prostacyclin production was also significantly reduced in the diabetic placentas compared with control placentas (11.44 +/- 4.06 vs 16.29 +/- 4.59 pg/mg per hour, respectively; p less than 0.05). We conclude that the ovine placenta produces thromboxane and prostacyclin. The ovine thromboxane production rate is comparable to that of the human placenta but the prostacyclin production rate is approximately two to three times higher. The observed decrease in the placental production of thromboxane and prostacyclin may reflect an adverse effect of hyperglycemia directly on eicosanoid production or indirectly through decreased placental cellular proliferation.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Female; In Vitro Techniques; Placenta; Pregnancy; Pregnancy in Diabetics; Regression Analysis; Sheep; Streptozocin; Thromboxane B2

We have previously characterized the new antiplatelet agent picotamide as a dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. We have now studied the antithrombotic activity of this drug in a simple animal model of lung platelet thromboembolism in the mouse. Picotamide, given i.p. 1 hr before the thrombotic challenge, protected mice from death caused by the i.v. injection of collagen plus epinephrine in a dose-dependent way; the dose reducing mortality by 50% was 277 mg/kg while for aspirin it was 300 mg/kg. Picotamide was also able to reduce the mortality provoked by the i.v. injection of the stable TxA2 mimetic U46619; BM 13.505, a pure TxA2-receptor blocker, was also effective while aspirin was totally inactive. Picotamide, finally, reduced the lethal consequences of the i.v. injection of a 12.5% suspension of hardened rat red blood cells, a model in which platelets are not involved; aspirin was totally ineffective in this model while nicardipine, a calcium channel blocker, was active. Picotamide did not inhibit the formation of TxB2 in serum at any of the doses tested (100 to 750 mg/kg i.p.) while it did enhance significantly PGI2-synthesis from mice aortae and, even more, from mice lungs. The i.v. administration of picotamide (250 mg/kg 2 min before the thrombotic challenge) lead to a strong inhibition of serum TxB2 (-84.6%) and was associated with a higher antithrombotic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Aspirin; Disease Models, Animal; Epoprostenol; Male; Mice; Phthalic Acids; Platelet Aggregation Inhibitors; Platelet Count; Pulmonary Embolism; Thromboxane B2

Clinical and animal data suggest that the pathogenesis of CO poisoning extends beyond the inhibition of hemoglobin function, but no mechanism has been identified. Evidence of neurological compromise, particularly loss of consciousness, has been implicated as a marker for increased mortality and morbidity in clinical reports. Experiments were carried out with rats to assess whether CO exposure may cause brain lipid peroxidation. With the use of two methods, measurement of conjugated dienes and thiobarbituric acid reactivity, brain lipid peroxidation could be documented as a result of exposure to CO at a concentration sufficient to cause unconsciousness. Products of lipid peroxidation were increased by 75% over the base-line values 90 min after CO exposure. Unconsciousness was associated with a brief period of hypotension, so brief that in itself it caused no apparent insult. Lipid peroxidation occurred only after the animals were returned to CO-free air, and there was no direct correlation with the carboxyhemoglobin level. This work may provide an explanation for a number of currently poorly understood clinical observations regarding CO poisoning.

Topics: Animals; Brain; Carbon Monoxide Poisoning; Carboxyhemoglobin; Cardiovascular System; Disease Models, Animal; Hemorrhage; Hypotension; Lipid Peroxidation; Male; Rats; Rats, Inbred Strains; Thromboxane B2

In a porcine endotoxin shock model employing a continuous intravenous administration of Salmonella abortus equi endotoxin the cardiorespiratory and metabolic parameters were studied with main emphasis on the effect of hemofiltration (HF) as the only therapeutical measurement on the enhancement of survival time. Arachidonic acid (AA) metabolites Thromboxan B2 and 6-Keto-PGF 1-alpha could be lowered significantly by hemofiltration. Measuring the inadequacy of the supply and delivery systems in terms of O2-uptake, CO2 production, lung mechanics, TPR, CO, heart rate and MAP the control group seemed to be more severely compromised than the hemofiltrated groups, although the final outcome as for survival time could not be increased significantly. HF can nonselectively counteract some toxic effects of shock mediators without depriving the organism of beneficial components of a protective system being stimulated at the same time. Once the AA cascade is initiated, pharmacologic inhibition is of limited value as long as a direct specific therapeutic manipulation is still not available. Elimination of mediators by HF helps to combat the overstimulation of host defense mechanisms in ET shock which represents the ultimate threat to the host.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Body Water; Carbon Dioxide; Cardiac Output; Disease Models, Animal; Heart Rate; Hemofiltration; Oxygen Consumption; Pulmonary Wedge Pressure; Shock, Septic; Swine; Thromboxane B2; Vascular Resistance

Sodium arachidonate (NaAr) at a dose of 1.1 mg/kg injected i.v. is uniformly lethal in rabbits within 5 min. This sudden death is typified by a precipitous drop in mean arterial blood pressure, a dramatic decrease in the circulating platelet count, and by a marked rise in plasma thromboxane A2 (TxA2) concentration as measured by radioimmunoassay of its breakdown product, TxB2. Pretreatment with S-145, a new thromboxane receptor antagonist, at doses ranging from 50 to 500 micrograms/kg resulted in 100% survival of all the rabbits subjected to sodium arachidonate injection. However, at 20 micrograms/kg S-145 only 25% of the rabbits challenged with NaAr survived. S-145 pretreatment also inhibited the decreases in circulating platelet count and in blood pressure associated with the i.v. injection of sodium arachidonate (NaAr). S-145 blunted the rise in plasma TxB2 concentration at all doses. S-145 was also shown to be a potent and long-lasting antagonist of TxA2 receptors in isolated rabbit aortic rings. Our data show that S-145 is a very effective protective agent against NaAr-induced sudden death in rabbits.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Aorta, Thoracic; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Death, Sudden; Disease Models, Animal; Fatty Acids, Monounsaturated; In Vitro Techniques; Male; Platelet Count; Prostaglandin Endoperoxides, Synthetic; Rabbits; Radioimmunoassay; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane B2

Topics: Animals; Biological Assay; Disease Models, Animal; Enterocolitis, Pseudomembranous; In Vitro Techniques; Indomethacin; Intestinal Mucosa; Leukotriene B4; Male; N-Formylmethionine Leucyl-Phenylalanine; Perfusion; Prostaglandins; Rabbits; SRS-A; Thromboxane B2; Vascular Resistance

The purpose of this study was to investigate whether procaterol (beta 2 agonist) inhibits the release of cyclooxygenase products in bronchoalveolar lavage fluid (BALF) during in vivo allergic bronchoconstriction in passively sensitized guinea pigs. Antigen-induced bronchoconstriction was significantly inhibited by pretreatment with procaterol. The concentrations of 6-keto-PGF1 alpha, PGF2 alpha and TXB2 in BALF significantly decreased in guinea pigs pretreated with inhaled procaterol. The concentration of TXB2, which is the stable metabolite of TXA2, a strong bronchoconstrictor, was especially markedly decreased compared with that in the control animals. These data indicate that procaterol (beta 2 agonist) may inhibit the release of chemical mediators during allergic reactions as well as directly decrease the contractility of airway smooth muscle. Consequently, regular inhalation of procaterol may be clinically useful for prophylaxis of bronchial asthma.

Topics: Administration, Inhalation; Adrenergic beta-Agonists; Animals; Asthma; Bronchial Provocation Tests; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Ethanolamines; Guinea Pigs; Male; Premedication; Procaterol; Prostaglandins; Thromboxane B2

During Shay-ulcer formation damages to the barrier of the gastric mucosa develop even before the appearance of macroscopic ulceration. Proximal selective vagotomy prevents these damages. Following pyloric ligation the prostaglandin content of the mucosa changes in parallel with the injuries of the mucosal barrier: TXB2 content of the forestomach increases, while PGF2 alpha content of both the forestomach and the antrum decreases. Following PSV operation the 6-keto-PGF1 alpha content of the mucosa decreases, whereas PGF2 alpha and TXB2 contents exhibit no alteration. As a combined effect of proximal selective vagotomy pretreatment and pyloric ligation the 6-keto-PGF1 alpha and PGF2 alpha contents of the mucosa remain low and the TXB2 increase, otherwise detectable after pyloric ligation, does not take place.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Disease Models, Animal; Gastric Mucosa; Prostaglandins; Pyloric Antrum; Radioimmunoassay; Rats; Stomach Ulcer; Thromboxane B2; Vagotomy, Proximal Gastric

Ischemia-induced renal injury is prevented by inhibition of thromboxane (Tx) synthesis. This protection was believed to be secondary to a high prostaglandin (PG)/TxA2 ratio. This study tests whether increasing the PG/Tx ratio by administration of vasodilating PGs protects the reperfused ischemic kidney. Anesthetized rats underwent right nephrectomy and 45 minutes of left renal pedicle clamping. Beginning 10 minutes before clamp release, animals were treated intravenously with the following: saline placebo (n = 10); the cyclooxygenase inhibitor ibuprofen (Ibu), 12.5 mg/Kg in a bolus (n = 8); a stable analogue of prostacyclin (PGI2), 500 ng/kg/minute for 2 hours (n = 9); PGE1, 400 ng/kg/minute for 2 hours (n = 8); the combination Ibu and PGI2 (n = 8) or PGE1 (n = 8). In saline treated ischemic controls, 5 minutes after reperfusion plasma, thromboxane (TxB2) and 6-keto-PGF1 levels were 2537 and 317 pg/ml, respectively--higher than the TxB2 and 6-keto-PGF1 levels of 750 and 80 pg/ml, respectively, in nephrectomized but nonischemic sham controls (n = 7) (p less than 0.05). In ischemic control animals at 24 hours, creatinine levels were 4.6 mg/dl, relative to 0.9 ml/dl in sham animals (p less than 0.05); the weight of the left (L) ischemic kidney relative to the right (R) normal kidney was 118%, compared with 99% in sham animals (p less than 0.05); and renal histology of ischemic control animals at 24 hours showed acute tubular necrosis (ATN) relative to normal findings in sham animals. Pretreatment with Ibu led to: TxB2 and 6-keto-PGF1 levels of 116 and 40 pg/ml, lower than those of sham animals (p less than 0.05); creatinine levels of 4.6 mg/dl, L/R renal weight of 119%; and ATN similar to that of ischemic controls. Treatment with a PGI2 analogue or PGE1 was not protective and led to increases in TxB2, 6-keto-PGF1, creatinine, L/R renal weight, and ATN similar to that of ischemic controls. The combination of Ibu and either PGI2 or PGE1 led to: reduced levels of TxB2 and 6-keto-PGF1 (p less than 0.05); attenuated increases in creatinine to 2.2 and 2.3 mg/dl, respectively (p less than 0.05); and limited ATN (p less than 0.05). These data indicate that the vasodilating PG protect the ischemic reperfused kidney only when Tx is inhibited.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Animals; Creatinine; Disease Models, Animal; Drug Combinations; Drug Evaluation, Preclinical; Epoprostenol; Ibuprofen; Ischemia; Kidney; Male; Organ Size; Prostaglandins E; Rats; Rats, Inbred Strains; Thromboxane B2; Vasodilator Agents

A persisting incidence of acute renal failure has been observed after operative treatment of thoracoabdominal aortic aneurysm, ruptured abdominal aortic aneurysm and renal artery occlusive disease in patients with preoperative impairment of renal function. Because preservation of kidney function can play an important role in the outcome of these patients, the effects of prostaglandin E1 (PGE1) to prevent ischaemic renal failure were studied in an experimental model. Twenty dogs were exposed to 3 h warm ischaemia by clamping of the supra- and infrarenal aorta and both renal arteries. In 10 dogs PGE1 was given intravenously (100 ng/kg/min) for 15 min before clamping. Ten dogs treated with normal saline served as controls. Glomerular filtration rate, renal plasma flow, plasma creatinine, blood urea nitrogen, urine volume, free water clearance and renovascular resistance were calculated before and after renal ischaemia for both groups. The dogs were followed-up for 2 weeks and radionuclide studies with Tc-99m-MAG3, I-131-OIH and In-113m-DTPA were performed on the third postoperative day to calculate global and split renal clearance, tracer extraction fraction and mean transport time. After renal ischemia 9 dogs of the control group and 3 dogs of the PGE1-group developed acute renal failure (P less than 0.05 due to Fisher's exact text). PGE1 infusion significantly attenuated the postischaemic fall in glomerular filtration rate and renal concentrating ability as well as the postischaemic increase of plasma creatinine and blood urea nitrogen induced by 3 h warm renal ischaemia (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Kidney Injury; Alprostadil; Animals; Awards and Prizes; Blood Urea Nitrogen; Disease Models, Animal; Dogs; Europe; Female; Glomerular Filtration Rate; Ischemia; Kidney; Kidney Concentrating Ability; Radionuclide Imaging; Renin; Societies, Medical; Thromboxane B2; Vascular Resistance; Vascular Surgical Procedures

We tested the hypothesis that complement (C')-dependent release of prostaglandin (PG) I2 is an important factor contributing to the development of hypotension and low systemic vascular resistance index (SVRI) in endotoxic shock. Two groups (n = 7) of pentobarbital-anesthetized pigs (12-15 kg) were infused over 40 min with Escherichia coli lipopolysaccharide (LPS; 200 micrograms/kg) and continuously resuscitated with normal saline (1 ml/kg min): LPS-Control (no pretreatment) and LPS-Decomplemented (pretreatment 18 hr before study with 500-1,500 units of Naje haje cobra venom factor, CVF). Prior treatment with CVF: i) decreased the mean titer of total hemolytic C' to 15.9% of pretreatment levels; ii) significantly decreased post-LPS plasma concentrations of immunoreactive TxB2 (TxA2 metabolite) and 6-keto-PGF1 alpha (PGI2 metabolite); iii) abrogated the early transient decrease in cardiac index observed in the LPS-Control group; iv) tended to improve post-LPS visceral perfusion assessed using radioactive microspheres; and v) had no discernible effect on the late sustained decrease in SVRI observed following infusion of LPS. We conclude that C' activation is a major determinant of LPS-induced prostanoid release in vivo, although our results do not support the view that C'-dependent release of PGI2 is an important factor contributing to low SVRI in resuscitated endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Complement System Proteins; Disease Models, Animal; Elapid Venoms; Epoprostenol; Escherichia coli; Hemodynamics; Lipopolysaccharides; Male; Regional Blood Flow; Shock, Septic; Swine; Thromboxane B2; Viscera

The kallikrein-kinin system is activated during endotoxic shock, suggesting that bradykinin plays a role in the pathology of this disease. To test this hypothesis, a bradykinin antagonist, D-Arg-Hyp3-D-Phe7-bradykinin (NPC 567), was studied in conscious, chronically catheterized rats undergoing lipopolysaccharide (LPS)-induced endotoxic shock. LPS treatment resulted in an increase in circulating bradykinin from less than 23 pg/ml to 144 +/- 18 pg/ml at 1 hr. Intravenous administration of LPS resulted in a 38% drop in mean arterial pressure at 1 hr which was partially reversed by NPC 567. NPC 567 did not affect the moderate tachycardia observed following LPS. NPC 567 infusion at 8 nmol/kg/min dramatically reduced mortality from 100% to 50% at 24 hr (P less than 0.01). In response to LPS, blood thromboxane B2 (TXB2) rose from less than 200 pg/ml to 2,298 +/- 64 pg/ml, while 6-keto-prostaglandin-F1 alpha (6kPGF1 alpha) rose from 289 +/- 23 pg/ml to 7,927 +/- 822 pg/ml. NPC 567 reduced the rise in 6kPGF1 alpha by 42% (P less than 0.05), without affecting TXB2. In summary, NPC 567 reduced mortality in rats treated with LPS, reduced the rise in 6kPGF1 alpha and partially reversed the hypotensive effects. These results suggest that bradykinin plays a significant role in the pathology of endotoxic shock.

Topics: Analgesics; Animals; Bradykinin; Disease Models, Animal; Hemodynamics; Lipopolysaccharides; Male; Prostaglandins F; Radioimmunoassay; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

Mucosa damage, these appear in the Shay ulcer model before the macroscopic ulceration, can be prevented by the selective proximal vagotomy. Changes of the potential difference and the prostaglandin content were discovered after pylorus ligation, and Thromboxane was increased, PGF2 alpha and TXB2 were nearly constant, whereas 6-keto-PGF1 alpha increased clearly in the rumen. The 6-keto-PGF1 alpha and the PGF2 alpha content and Thromboxane remained unchanged and the potential difference was normalized in case of selective proximal vagotomy and pylorus ligation. The SPV is significant as you know for the secretion of H+ion and bicarbonate, but also for the normalization of increased TXB2 on the basis of our investigation results.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Disease Models, Animal; Gastric Mucosa; Male; Prostaglandins; Rats; Stomach Ulcer; Thromboxane B2; Thromboxanes; Vagotomy, Proximal Gastric

Topics: Animals; Cerebrovascular Disorders; Disease Models, Animal; Edema; Ischemia; Male; Motor Activity; Prostaglandins; Rabbits; Reperfusion; Spinal Cord; Thromboxane B2

The clinical use of interleukin-2 (IL-2) is limited by severe cardiopulmonary dysfunction. This study examines the mechanism of respiratory failure related to IL-2, using sheep with chronic lung lymph fistulae. Awake animals were infused with an intravenous (I.V.) bolus of IL-2 10(5) U/kg (n = 5) or its excipient (EXC) control (n = 3), every 8 hours for 4 to 5 days. Cardiopulmonary function was monitored daily for at least one 8-hour period. Within 2 hours after each IL-2 administration, mean pulmonary arterial pressure (MPAP) rose. On Day 1, the mean rise was from 13 to 26 mmHg (p less than 0.05), and on Day 5, to 29 mmHg (p less than 0.05). MPAP returned to baseline levels after 2-3 hours. Pulmonary arterial wedge pressure was unchanged from 4 mmHg. There were transient falls in arterial oxygen tension, from 88 to 77 mmHg on Day 1 and to 73 mmHg (p less than 0.05) on Day 5. Lung lymph flow (QL) rose from 2.4 to 6.8 ml/30 minutes (p less than 0.05) on Day 1, and from 4.7 to 10.2 ml/30 minutes (p less than 0.05) on Day 5, whereas the lymph/plasma protein ratio increased on Day 1 from 0.69 to 0.83 (p less than 0.05) and from 0.63 to 0.71 (p less than 0.05) on Day 5. This documents an increase in pulmonary microvascular permeability. Thromboxane (Tx)B2 levels increased transiently after each IL-2 injection in plasma from 195 to 340 pg/ml (p less than 0.05) and in lung lymph from 222 to 772 pg/ml (p less than 0.05) on Day 1, and to similar levels on Day 5. There was a progressive rise in cardiac output from 5.7 to 8.6 1/minute (p less than 0.05) during the 5 days of infusion. Systemic blood pressure did not change. Temperature rose from 39.1 to 41.2 C (p less than 0.05), and shaking chills were common. There was a progressive fall in leukocyte count, from 8.4 to 3.2 X 10(3)/mm3 (p less than 0.05) by Day 5, reflecting a 77% fall in lymphocytes. Lung lymph lymphocyte counts rose, and lymphocyte clearance increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Capillary Permeability; Disease Models, Animal; Female; Fistula; Hemodynamics; Interleukin-2; Leukocyte Count; Lung; Lymph; Lymph Node Excision; Lymphocytes; Proteins; Recombinant Proteins; Respiratory Insufficiency; Sheep; Thromboxane B2; Time Factors

Among the various inflammatory mediators of otitis media (OM), metabolites of arachidonic acid (AA) such as prostaglandins (PGs) and leukotrienes (LTs) appear to play an important role in the pathogenesis of otitis media. In an effort to investigate the role of AA metabolites on the pathogenesis of otitis media, concentrations of AA metabolites were measured in middle ear effusion (MEE) from human and paralleling animal models of otitis media and the effects of inhibitors of AA metabolism, antibiotics, and tympanostomy tube (TT) on the outcome of animal models of OM were studied. Concentrations of AA metabolites in MEE were higher in the younger age group. Levels of PGE2 and LTB4 in MEE seem to represent the degree of inflammation of OM best. Lipoxygenase products seem to be associated with the mucoid type of MEE. In the study of animal models of OM, combined models and ears with TT showed more inflammation than single models and ears without TT. Study of the therapeutic use of inhibitors of AA metabolism, penicillin, and TT showed that lipoxygenase products may be more important in the pathogenesis of OM than the cyclo-oxygenase products, and that the use of a combination of penicillin and corticosteroid produces the best results. It is clear from these studies that arachidonic acid metabolites are important inflammatory mediators in the pathogenesis of otitis media.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Chinchilla; Dinoprostone; Disease Models, Animal; Humans; Hydrocortisone; Hydroxyeicosatetraenoic Acids; Ibuprofen; Leukotriene B4; Middle Ear Ventilation; Otitis Media with Effusion; Penicillin G; Prostaglandins; Prostaglandins E; SRS-A; Temporal Bone; Thromboxane B2

Necrotizing enterocolitis (NEC) was produced in anesthetized rabbits by transmural injection of intestinal loops with an acidified solution of casein and calcium gluconate, mimicking the luminal milieu of afflicted neonates. Intravenous infusion of superoxide dismutase (SOD) 15 min after NEC induction prevented intestinal damage. In ex vivo perfused intestinal loops, we determined the sites of eicosanoid release and their contribution to the vascular effects of N-formyl-methionyl-leucyl-phenylalanine (fMLP) and platelet-activating factor (PAF) in damaged and SOD-salvaged intestine. The vascular effluent was the primary site of stimulated eicosanoid release. The vascular responses to fMLP (vasoconstriction) and PAF (vasodilation) were not altered by SOD, although vascular resistance was higher in the SOD group. SOD treatment attenuated 1) transmural fluid shifts in ex vivo perfused intestinal preparations, an index of vascular permeability, 2) fMLP-induced prostaglandin E2, 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and leukotriene B4 (LTB4) release, and 3) PAF-induced release of 6-keto-PGF1 alpha and LTB4. Stimulated thromboxane B2 release was not altered by SOD. Thus NEC can be established by a luminal insult that causes local generation of free radicals and exaggerated release of prostaglandins and leukotrienes.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Depression, Chemical; Dinoprostone; Disease Models, Animal; Enterocolitis, Pseudomembranous; Leukotriene B4; Leukotrienes; Male; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activating Factor; Prostaglandins; Rabbits; Superoxide Dismutase; Thromboxane B2

1. A cross-sectional study (protocol A) was performed in 19 rats with cirrhosis, induced by carbon tetrachloride (CCl4), and ascites and in 10 control animals to assess renal prostaglandin (PG) excretion in experimental cirrhosis. In an additional group of animals, including nine rats chronically exposed to CCl4 (CCl4 rats) and six control rats, a longitudinal study (protocol B) was performed to investigate the temporal relationship between changes in renal PG excretion, the renin--aldosterone system and renal function. 2. Urinary PG excretion was assessed by specific radioimmunoassay of PGE2, PGF2 alpha, 6-keto-PGF1 alpha and thromboxane (TX) B2 after extraction with octadecyl silica cartridges and h.p.l.c. purification. Recoveries for each prostanoid (61 +/- 8% for PGE2, 64 +/- 12% for PGF2 alpha, 65 +/- 11% for 6-keto-PGF1 alpha and 66 +/- 17% for TXB2) were determined in every sample by adding tritiated standards, and the final values were corrected according to the individual recoveries. 3. Cirrhotic rats with ascites in protocol A showed a significantly higher plasma renin and aldosterone concentrations and urinary excretion of 6-keto-PGF1 alpha and TXB2 than did control animals. Urinary excretion of PGE2 and PGF2 alpha, however, was significantly reduced in cirrhotic animals as compared with controls. 4. In CCl4 rats included in protocol B, there was a close chronological relationship between the activation of the renin-aldosterone system, as estimated by urinary aldosterone excretion, the onset of sodium retention and the increase in urinary excretion of 6-keto-PGF1 alpha and TXB2. The urinary excretion of PGE2 and PGF2 alpha in CCl4 rats was reduced throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Aldosterone; Animals; Carbon Tetrachloride; Disease Models, Animal; Kidney; Liver Cirrhosis, Experimental; Longitudinal Studies; Male; Prostaglandins; Rats; Rats, Inbred Strains; Renin; Renin-Angiotensin System; Sodium; Thromboxane B2

We conducted studies to determine the effects of parenteral therapy with indomethacin, ibuprofen, and piroxicam on key immunologic and hematologic alterations induced by thermal injury. Drugs (10-20 mg/kg) or placebo were administered intramuscularly to thermally injured guinea pigs at 3 h postburn and then daily for nine days postburn. All three drugs inhibited production of 6-keto prostaglandin F1 alpha and thromboxane B2 in wound fluid and concomitantly restored the bactericidal activity of polymorphonuclear leukocytes (PMNLs) against Pseudomonas aeruginosa to normal. Indomethacin also increased the proliferative response of splenic lymphocytes to concanavalin A; however, ibuprofen and piroxicam had no effect on this response. None of the drugs affected the extent of systemic complement consumption, thrombocytopenia, leukocytosis, or leukopenia in the injured animals. These results suggest that the PMNL bactericidal defect induced by thermal injury is preventable or reversible and that the mechanisms responsible for this defect are inhibitable by nonsteroidal anti-inflammatory drugs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Bactericidal Activity; Blood Cell Count; Burns; Complement System Proteins; Concanavalin A; Cyclooxygenase Inhibitors; Disease Models, Animal; Guinea Pigs; Ibuprofen; Indomethacin; Kinetics; Lymphocyte Activation; Neutrophils; Phagocytosis; Piroxicam; Pseudomonas aeruginosa; Spleen; Thromboxane B2

The acute phase of oxygen-induced retinopathy is associated with vasoconstriction and occlusion of the retinal vessels. Because this acute vasoobliterative phase could be due to the inhibition in retinal vessels of the production of the potent vasodilator and antithrombotic metabolite prostacyclin, animal experiments were performed to assess this possibility. Eight litters of 27 kittens (four to six days of age) were used. Control kittens were left in room air; hyperoxic kittens were placed in 80% oxygen for 48 hours; recovery kittens were returned to room air for 24 hours following hyperoxic exposure. Following treatments, the animals were killed, retinas isolated, and prostaglandin formation assessed. Retinal tissues produced 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, prostaglandin E2, and thromboxane B2 from exogenous arachidonate. A significant (approximately 33%) reduction in retinal 6-keto-prostaglandin F1 alpha (the end product of prostacyclin) was observed both in the hyperoxic and recovery litter mates when compared with controls. Both of the experimental groups also demonstrated a reduction in total retinal prostanoids that paralleled the changes observed in prostacyclin, suggesting that the biochemical effect of hyperoxia on retinal vascular arachidonic acid metabolism occurred at the level of cyclooxygenase. A decrease in the local production of prostacyclin during hyperoxia is consistent with the histologic retinal changes observed during the acute phase of oxygen-induced retinopathy.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Carbon Radioisotopes; Cats; Dinoprost; Dinoprostone; Disease Models, Animal; Epoprostenol; Humans; Infant, Newborn; Oxygen; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Prostaglandins F; Retinal Vessels; Retinopathy of Prematurity; Thromboxane B2

In a well defined endotoxin (ET) shock model we compared the influence of a selective LOX-inhibitor FLM 5011 and the COX-inhibitor Acetylsalicylic acid (ASA) on survival as well as on their effects on TXB2 and 6-oxo-PGF1 and on selected parameters characterizing the shock syndrome. Pretreatment with both substances reduced the lethality rate. Neither TXB2 nor the PGF1 concentration revealed a consistent trend after therapeutic intervention. None of the investigated mediators could be identified as the primary "shock mediator".

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Cyclooxygenase Inhibitors; Disease Models, Animal; Lauric Acids; Leukocyte Count; Lipoxygenase; Lipoxygenase Inhibitors; Male; Oximes; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

This study examines the effect of dexamethasone (Dex), a phospholipase A2 inhibitor, on the reversal of 1-kidney, 1-clip (1K,1C) hypertension and the synthesis of phospholipase A2-dependent products. Male Sprague-Dawley 1K,1C hypertensive rats [blood pressure (BP) greater than 190 mmHg] were allocated to three groups: two groups were given daily oral doses of Dex (0.142 mg/kg in water) for 72 h, whereas the third group was given water only (controls). One of the Dex-treated groups was then sham unclipped (n = 9), while the other Dex-treated group (n = 8) and the control group (n = 8) were unclipped. Dex attenuated the BP fall in the unclipped (223 +/- 8-148 +/- 9 mmHg) compared with the control unclipped (226 +/- 9-114 +/- 5 mmHg) animals (P less than 0.005). Aortic 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) was reduced in unclipped Dex-treated rats (13.4 +/- 1.2 ng/mg) compared with unclipped control rats (16.3 +/- 1.4 ng/mg; P less than 0.05) but was higher than in the sham-unclipped Dex group (11.5 +/- 1.2 ng/mg; P less than 0.05). Serum thromboxane B2 (TxB2) in the unclipped Dex-treated group was lower than in the unclipped control rats (P less than 0.05) but higher than in sham-unclipped rats (P less than 0.05). Dex significantly increased urinary prostaglandin E2 (PGE2) excretion, whereas urinary 6-keto-PGF1 alpha was unaltered. After unclipping, both urinary PGE2 and 6-keto-PGF1 alpha increased significantly, although there was no obvious difference between Dex-treated and control animals. These findings demonstrate opposite effects of Dex on renal compared with extrarenal prostanoid synthesis and support the hypothesis that attenuation of aortic 6-keto-PGF1 alpha synthesis may be responsible for the smaller fall in BP after unclipping in Dex-treated rats.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Creatinine; Dexamethasone; Dinoprostone; Disease Models, Animal; Hypertension, Renovascular; Male; Phospholipases A; Phospholipases A2; Potassium; Rats; Rats, Inbred Strains; Reference Values; Sodium; Thromboxane B2

Reperfusion of ischemic tissue is responsible for production of metabolites with deleterious local vascular effects. Thromboxane A2, a potent vasoconstrictor and platelet aggregator, has been implicated as a mediator of the "reperfusion injury." We studied the effect of an experimental thromboxane synthetase inhibitor, OKY-046, on coronary sinus thromboxane levels, ventricular irritability, myocardial contractility, infarct salvage, and histologic features of reperfusion. Sixteen sheep were randomized to OKY-046, 3 mg/kg, or saline vehicle before 3-hour occlusion and subsequent reperfusion of the left anterior descending artery. The OKY group demonstrated less ventricular irritability as measured by incidence of ventricular fibrillation and necessity for countershock to reverse tachyarrhythmias. Coronary sinus thromboxane levels were significantly lower in the OKY group compared with the control group. There is additional evidence to suggest that OKY increases infarct salvage and attenuates histologic features of microcirculatory damage.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Methacrylates; Microcirculation; Myocardial Contraction; Random Allocation; Sheep; Thromboxane B2; Thromboxane-A Synthase; Ventricular Fibrillation

In the majority of clinical cases, smoke inhalation results in a self-limited lung injury mostly confined to the airways. In this study, an animal model of inhalation injury was developed that reflected similar pathophysiology. Cardiopulmonary parameters were studied in awake, instrumented goats following spontaneous inhalation of characterized Douglas fir smoke. Peak carboxyhemoglobin levels averaged 37% during a mean exposure time of 33 minutes. All animals survived the 24-hour study period, and showed only transient abnormalities in lung fluid balance and gas exchange, with no change in lung mechanics or plasma eicosanoid (TxB2 and 6-keto-PGF1 alpha) levels. However, extravascular lung water at 24 hours was increased 33%, suggesting the presence of some airway edema and retained secretions. We feel this model fairly represents the majority of clinical smoke inhalation cases. This model is compared to other large animal inhalation injury models producing more severe lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Water; Burns, Inhalation; Carboxyhemoglobin; Disease Models, Animal; Goats; Hemodynamics; Lung; Pulmonary Gas Exchange; Thromboxane B2

One hundred NZB/W F1 female mice were studied to compare the effects of a thromboxane synthase inhibitor (TSI), a stable prostacyclin analog (iloprost) and prostaglandin E1 (PGE1) in the evolution of the nephritis. At 10 weeks of age mice were randomly assigned to cohorts of 20 to receive either no treatment, vehicle control, PGE1, iloprost or TSI. Proteinuria, mortality, systemic blood pressure, renal immune complex deposition, urinary TX B2 and 6 keto PGF1 alpha levels were measured. Mice receiving PGE1 and iloprost had a significant delay in the onset of proteinuria and reduction in mortality at 40 weeks. The TSI treatment had no apparent effect on proteinuria or mortality. The amelioration of the nephritis was not associated with an alteration in immune complex deposition in survivors at 40 weeks. Although PGE1 and iloprost lessened the age related increase in urinary TX B2, increased the urinary 6 keto PGF1 alpha levels and the ratio of 6 keto PGF1 alpha to TX B2; so did the TSI. The PGE1 treated mice did experience a marked and persistent reduction in blood pressure but this was not observed in the iloprost- or the TSI-treated mice. All drugs tested reduced the age-related increase in thromboxane B2 but only the PGE1 and iloprost had a significant effect on the evolution of the nephritis.

Topics: 6-Ketoprostaglandin F1 alpha; Age Factors; Alprostadil; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epoprostenol; Female; Iloprost; Lupus Nephritis; Mice; Mice, Inbred NZB; Mice, Inbred Strains; Nephritis; Proteinuria; Thromboxane B2; Vasodilator Agents

Two experimental models of acute non-immune inflammation have been developed to enable studies of the biochemical composition and cellular content of exudates to be undertaken. Both are based on the creation of a mild, reproducible and reversible inflammatory reaction, which is free from uncontrolled incidental factors and which causes minimal distress to the experimental animals. The polyester sponge model involves the insertion of small polyester sponge strips soaked in sterile carrageenan solution into subcutaneous neck pouches and their serial removal. The tissue-cage model is based on the initial insertion of a spherical tissue-cage subcutaneously in the neck and the subsequent stimulation with carrageenan of the granulation tissue which lines and permeates the cage. The acute inflammatory exudates have been shown to contain eicosanoids with prostaglandin E2 predominant. Polymorphonuclear leucocyte numbers increased progressively in the polyester sponge model, whereas cell numbers were maximal at 12 hours in the tissue-cage model. The relationships between eicosanoid formation at the site of inflammation and leucocyte accumulation, enzyme release, total protein content of exudates and the temperature of the lesions have been investigated.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Carrageenan; Dinoprostone; Disease Models, Animal; Exudates and Transudates; Horse Diseases; Horses; Inflammation; Leukotriene B4; Prostaglandins E; Proteins; Thromboxane B2

An equine model of acute non-immune inflammation has been developed to facilitate studies of the inflammatory process and the actions of novel anti-inflammatory drugs. Five polyester sponge strips soaked in sterile 2% carrageenin solution were placed in subcutaneous pouches prepared under local anaesthesia in the necks of conscious ponies. Serial removal of the strips and harvesting of the exudate enabled studies to be made of the cellular, biochemical and mediator aspects of the localised, acute inflammation, and the heat generated by the lesion was monitored by infra-red thermometry. Maximal concentrations of the eicosanoids 6-keto-prostaglandin F1 alpha, thromboxane B2 and leukotriene B4 occurred at 9 h, whereas leukocyte numbers, lactate dehydrogenase (LDH) and total protein concentrations were greatest at 24 h. Lesional skin temperature was increased by approximately 4 degrees C throughout the 24 h period. The novel anti-inflammatory agent BW540C, administered orally at a dose-rate of 20 mg/kg, did not affect leukocyte infiltration or the concentrations of protein, LDH and eicosanoids in exudate but serum thromboxane B2 levels were reduced. Skin temperature rises were greater in drug-treated animals. It is concluded that higher doses of BW540C will be required for a clinically useful anti-inflammatory action in horses.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carrageenan; Disease Models, Animal; Exudates and Transudates; Female; Horse Diseases; Horses; Inflammation; L-Lactate Dehydrogenase; Leukocyte Count; Leukotriene B4; Proteins; Pyrazoles; Skin Temperature; Thromboxane B2

To define the role of arachidonate metabolites in evolving ischaemic myocardial damage 10 anaesthetised open chest dogs underwent 90 min occlusion of the left anterior descending coronary artery followed by 5 h reperfusion. Tissue extracts from ischaemic myocardium incubated in vitro were subjected to high pressure liquid chromatography for analysis of lipoxygenase products such as mono hydroxyeicosatetraenoic (HETE) acids and to radioimmunoassay for determining a cyclooxygenase product, thromboxane B2. In ischaemic myocardium the production of 12-HETE (120(35) ng.g-1, mean (SEM)) and thromboxane B2 (18.3(2.4) ng.g-1) was significantly higher than that in normal myocardium (13(2) ng.g-1, p less than 0.01, and 4.2(0.5) ng.g-1, p less than 0.001, respectively). 12-HETE production was linearly correlated with thromboxane B2 production in ischaemic myocardium (r = 0.718, p less than 0.02). The increased production of 12-HETE and thromboxane B2 was in proportion to infarct size as measured by a percentage risk area infarcted (r = 0.732, p less than 0.02, and r = 0.942, p less than 0.001, respectively). Similarly, the increase in production of these eicosanoids was related to the degree of leucocyte infiltration in ischaemic myocardium. These results indicate that altered arachidonate metabolism is strongly associated with the progression of ischaemic myocardial damage, suggesting important roles for these eicosanoids, which may be produced by blood corpuscles during the evolution of acute myocardial infarction.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Chromatography, High Pressure Liquid; Disease Models, Animal; Dogs; Hydroxyeicosatetraenoic Acids; Myocardial Infarction; Myocardium; Perfusion; Radioimmunoassay; Thromboxane B2

The development of reproducible models of acute inflammation in which inflammatory heat is easily quantified and from which inflammatory exudate is readily harvested has facilitated studies in the horse of the actions of steroids and non-steroidal anti-inflammatory drugs (NSAIDS). Blockade of the synthesis of eicosanoids and suppression of inflammatory heat by clinical dose rates of NSAIDS suggests a causal link between the two events and provides further evidence for a role of these compounds in acute equine inflammation. The tendency for enolic and carboxylic acids NSAIDS to accumulate in inflammatory exudate may account for the duration of action of these compounds in inhibiting exudate eicosanoid synthesis and the data confirm clinical experiences with these drugs. A novel NSAID which inhibits both cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, BW540C, and two anti-inflammatory steroids, betamethasone and dexamethasone, have been evaluated in the models of equine inflammation with some interesting and unexpected findings. This paper emphasises the interrelationships between the inflammatory process and the actions and fate of anti-inflammatory drugs.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Chemical Phenomena; Chemistry; Dinoprostone; Disease Models, Animal; Epoprostenol; Horse Diseases; Horses; Inflammation; Prostaglandins E; Steroids; Thromboxane B2; Tissue Distribution

Accelerated anti-glomerular basement membrane nephritis was induced in rabbits, and the immunological, clinical and histological evolution studied in relation to urinary immunoreactive thromboxane B2 (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. In control nephritic animals, urinary i-TXB2 increased 5-fold on day +1, but was normal again by day +5. The urinary i-TXB2 showed a positive correlation with creatinine clearance (CCr), proteinuria and anti-sheep immunoglobulin antibody. Urinary i-PGE2 excretion increased by 50% on day +1, but was indistinguishable later from controls. The effects of the specific thromboxane synthetase inhibitor OKY-046 on this model was studied. In non-nephritic control animals, OKY-046 did not affect the CCr, the urinary protein excretion or the number of monocytes in glomeruli but reduced the excretion of i-TXB2. Although OKY-046 markedly inhibited the i-TXB2 excretion throughout the experiment in nephritic animals, the creatinine clearances were significantly worse, the proteinuria greater, and the number of infiltrating monocytes greater at day +5; by day +10 there was no difference from controls. There was no evidence that TXB2 is involved in the induction of proteinuria, and increased PGE2 synthesis did not protect against later proteinuria and fall in creatinine clearance. Inhibition of thromboxane synthetase appears to make this model of nephritis worse, rather than better.

Topics: Acrylates; Animals; Basement Membrane; Creatinine; Depression, Chemical; Dinoprostone; Disease Models, Animal; Female; Immunoenzyme Techniques; Immunoglobulin G; Kidney Glomerulus; Methacrylates; Nephritis; Prostaglandins E; Rabbits; Thromboxane B2; Thromboxane-A Synthase

The effects of ibuprofen (I) and methylprednisolone (M) were studied in the Pseudomonas porcine model of adult respiratory distress syndrome (ARDS). Four groups of animals were anesthetized and ventilated with 0.5 FIO2, 5 cm PEEP, and 20 cc/kg tidal volume: a control group given saline alone; Pseudomonas infusion alone (P); Pseudomonas with ibuprofen (I), 12.5 mg/kg given at 20 and 120 min; and P with methylprednisolone (M), 30 mg/kg given at 20 and 120 min. We compared the alteration in pulmonary hemodynamics with the alteration in the plasma concentration of thromboxane (TxB2) and 6-keto PGF1 alpha in the treated and untreated groups. Hemodynamic parameters measured included the pulmonary (PAP) and systemic (SAP) arterial pressures, cardiac index (C1), thermal-cardiogreen extravascular lung water (EVLW), and PaO2. Albumin Flux was measured by a gamma scintigraphic method (slope index; SI). P produced a dramatic increase in PAP (P less than 0.05) with a progressive increase in EVLW and SI (P less than 0.05) and fall (P less than 0.05) in PaO2, CI, and SAP. The acute pulmonary hypertension was associated with a significant rise in TxB2 and 6-keto PGF1 alpha in the Pseudomonas group. I effectively blocked the elevation of TxB2 and caused a significant but transient improvement in PAP and rise in PaO2. Albumin flux and water leak as measured by SI and EVLW were not affected by ibuprofen. M reduced the elevation of TxB2 and 6-keto PGF1 alpha but failed to block these prostaglandins significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Capillary Permeability; Disease Models, Animal; Hemodynamics; Ibuprofen; Methylprednisolone; Pseudomonas Infections; Respiratory Distress Syndrome; Swine; Thromboxane B2

Pulmonary dysfunction is a well-recognized complication of burn wound excision. It remains unclear whether this is caused by bacteria or inflammatory mediators released during excision of the wound. We produced a 15% full-thickness burn in 18 sheep, and between days 5 and 7 completely excised the wound under general anesthesia. Pulmonary parameters of static and dynamic lung compliance (CSTAT and CDYN), PaO2/FiO2, and pulmonary artery pressure (Ppa) were measured, as well as burn lymph, venous and aortic thromboxane B2 (TxB2), chemotactic index (chemotaxis/chemikinesis), and oxygen radical activity reflected in the level of lipid peroxidation in lung tissue. We noted a transient increase in burn lymph and venous TxB2 during excision, increasing from a preburn value of 200 and 220 +/- 50 pg/ml to 950 +/- 210 and 980 +/- 280 pg/ml, respectively. In 13 of 18 sheep, chemotactic activity and lung tissue lipid peroxidation, measured as malondialdehyde (MDA) content, were not increased. In this group only a very transient decrease in CDYN, PaO2/FiO2, and a 3 mm Hg increase in mean Ppa was seen with excision, with these parameters returning rapidly to baseline. Five of the 13 sheep had wound biopsy specimens that were greater than 10(6) organisms/gm tissue. In the remaining five sheep, plasma chemotactic index was also significantly increased with excision, as was lung MDA content, while decreases in CDYN, CSTAT, and PaO2/FiO2 and an increase in Ppa were more protracted. Three of these five sheep had wound biopsy specimens greater than 10(6) organisms/gm. We conclude that a release of thromboxane occurs during excision, which corresponds in time to transient lung dysfunction. If there is also a release of chemotactic factors, a more protracted pulmonary response occurs with evidence of O2 radical-induced lung changes.

Topics: 6-Ketoprostaglandin F1 alpha; Anesthesia; Animals; Burns; Chemotactic Factors; Disease Models, Animal; Lung; Lung Compliance; Lymph; Malondialdehyde; Oxygen; Prostaglandins; Pulmonary Wedge Pressure; Sheep; Thromboxane B2; Vascular Resistance

The effects of ibuprofen (I) were studied in the Pseudomonas (P) porcine ARDS model. Pigs, 14-26 kg (5 in each group), were anesthetized and ventilated with 0.5 FiO2 and 5 cm H2O PEEP. A control (C) group received saline only, a second group was given P, 1 X 10(8) org/ml at 0.3 cc/20 kg/min, and a third group was given P followed by 12.5 mg I at 20 and 120 min. Pulmonary arterial (PAP), wedge (PWP) and systemic arterial pressures, cardiac output (CO), and thermal-cardiogreen extravascular lung water (EVLW), thromboxane (TxB2), 6-keto-PGF1 alpha, PaO2, PaCO2 were determined every 30 min. Albumin flux was measured with scintigraphic determination of lung:heart radioactivity ratios versus time, called slope index (SI). At 3 hr, P produced marked (P less than 0.05) increases in PAP (18 +/- 7 to 37 +/- 2 mm Hg), TxB2 (471 +/- 513 to 9216 +/- 3615 pg/ml), 6-keto-PGF1 alpha, EVLW (6.4 +/- 1.4 to 14.6 +/- 5.7 mg/kg), and SI (0.4 +/- 0.2 to 1.7 +/- 0.5 X 10(-3) U/min) with decreases in PaO2 (214 +/- 47 to 101 +/- 41 torr), CO and SAP. Ibuprofen caused a rapid clearing of TxB2 and 6-keto-PGF1 alpha associated with a transient decrease in PAP; PaO2 was considerably improved compared to P; however, CO, SAP, EVLW, and SI were unaffected. Prostaglandin blockage temporarily ameliorated the pulmonary hypertension and markedly improved oxygenation in this porcine septic ARDS model, but failed to alter increased permeability, confirming other studies that the increased pulmonary shunt in ARDS is not only dependent upon capillary leak.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Carbon Dioxide; Cardiac Output; Disease Models, Animal; Ibuprofen; Oxygen; Pseudomonas Infections; Pulmonary Artery; Pulmonary Wedge Pressure; Radioimmunoassay; Respiratory Distress Syndrome; Swine; Thromboxane B2

A rabbit model of group B Streptococcal (GBS) shock was used to study the effects of prostaglandin synthetase inhibition on the hemodynamic and hematologic response to GBS shock. The infusion of heat-killed GBS in groups I and II produced significant decreases in mean arterial pressure, neutrophil counts, and platelet counts (p less than 0.05), and significant rises in concentrations of thromboxane B2 and 6-Keto-PGF1 alpha, the stable metabolites of thromboxane A2 and prostacyclin (p less than 0.05). Administration of indomethacin (4 mg/kg) after GBS infusion (group II) was associated with a significant rise in mean arterial pressure and a significant decline in thromboxane B2 and 6-Keto-PGF1 alpha concentrations (p less than 0.05) but had no effect on GBS-induced hematologic alterations. Indomethacin administration before GBS infusion (group III) prevented alterations in mean arterial pressure and was associated with a decrease in thromboxane B2 and 6-Keto-PGF1 alpha concentrations. Indomethacin in group III did not prevent neutropenia and thrombocytopenia and may have exacerbated neutropenia. Alteration of experimental GBS shock with prostaglandin synthetase inhibition produces disparate hemodynamic and hematologic response.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bicarbonates; Blood Gas Analysis; Blood Platelets; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Humans; Indomethacin; Infant; Leukocyte Count; Neutrophils; Platelet Count; Rabbits; Shock, Septic; Streptococcal Infections; Streptococcus agalactiae; Thromboxane B2

The essential fatty acid deficient (EFAD) chicken was evaluated as a model for cystic fibrosis (CF). Three semipurified diets--(I) 1% hydrogenated coconut oil (HCO), (II) 10% soybean oil + 1% HCO, and (III) 11% HCO--were fed to chickens from hatching to 5, 8, or 11 wk. Groups I and III exhibited poor weight gain and abnormal serum fatty acid patterns characteristic of EFAD. Production of prostaglandin F2 alpha, thromboxane B2, 6-keto-prostaglandin F1 alpha, and prostaglandin E in lung was significantly reduced at 5, 8, and 11 wk in both EFAD groups. Histopathologic examination revealed increased peribronchiolitis in group I compared with II. Incidence of pulmonary lesions in group III was intermediate. These data support the theory that essential fatty acids are necessary to maintain proper lung function. In this respect, the chicken is a good model for studying the relationship between EFAD and pulmonary disease in CF patients.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chickens; Cystic Fibrosis; Dinoprost; Disease Models, Animal; Fatty Acids; Fatty Acids, Essential; Lung; Prostaglandins E; Prostaglandins F; Thromboxane B2

In a 12-day treatment schedule, 5 ponies were given orally a paste formulation of phenylbutazone (PBZ) and 5 matched ponies were given equivalent doses of a placebo paste. On day 12, a mild, nonimmune inflammatory reaction was induced subcutaneously in the neck of each pony by inserting sterile, polyester sponge strips soaked in a 2% carrageenan solution. Exudate was collected at 4, 8, 12, and 24 hours by serial removal of sponges. There were no significant (P less than 0.05) differences in exudate protein concentration and leukocyte numbers between the treatment groups, but the group given PBZ had significantly reduced exudate concentrations of eicosanoids 6-keto-prostaglandin F 1 alpha (the stable metabolite of prostacyclin) at 4, 8, and 12 hours; thromboxane B2 at 8, 12, and 24 hours; and bicyclic prostaglandin E2 at 8 hours. The maximal depression of eicosanoid synthesis occurred at times of peak exudate concentrations of PBZ (8 and 12 hours). Phenylbutazone was cleared more slowly from exudate than from plasma. Changes in surface skin temperature were measured by infrared thermometry. Lesional temperatures were recorded 1 cm below the base of the incision line, and mean increases were significantly (P less than 0.05) less in PBZ-treated than in placebo-treated ponies between 4 and 24 hours. The importance of the findings for the clinical efficacy of this dosage schedule is considered.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Body Temperature; Dinoprostone; Disease Models, Animal; Exudates and Transudates; Female; Horse Diseases; Horses; Inflammation; Leukocyte Count; Male; Phenylbutazone; Prostaglandins E; Thromboxane B2

We studied the effect of cod-liver oil on the development and progression of coronary artery disease in swine subjected to coronary balloon abrasion and fed an atherogenic diet for eight months. Sections from serial 3-mm segments of the coronary arteries were analyzed morphometrically in 7 pigs given a cod-liver-oil supplement and 11 control animals not given the supplement. Significantly less disease was seen in the sections from the animals fed cod-liver oil. The mean lesion area per vessel, mean luminal encroachment per vessel, and mean maximal luminal encroachment per vessel were reduced in animals fed cod-liver oil, as compared with controls, (P = 0.05, P = 0.016, and P = 0.011, respectively). Both groups of animals had severe hyperlipidemia throughout the study. Differences in the extent of coronary atherosclerosis were not related to differences in plasma lipid levels. Platelet arachidonate was markedly reduced, platelet eicosapentaenoic acid was increased, and serum thromboxane was decreased in the oil-fed group as compared with the control group. We conclude that in our animal mode, dietary cod-liver oil retarded the development of coronary artery disease, possibly through changes in prostaglandin metabolism.

Topics: Animals; Arachidonic Acids; Blood Platelets; Cod Liver Oil; Coronary Disease; Coronary Vessels; Diet, Atherogenic; Disease Models, Animal; Fish Oils; Hyperlipidemias; Lipids; Male; Swine; Thromboxane B2

The action of AD6 as an anti-thrombotic agent was studied in a model of coronary artery thrombosis and on platelet aggregation in the dog. AD6 (10-100 microM) in vitro inhibited aggregation induced by ADP, epinephrine, collagen and PAF (platelet aggregating factor) used at their threshold concentration for maximal aggregation. Arterial thrombosis was induced in a coronary vessel by critically reducing (about 70%) the vessel lumen. Thrombus formation was estimated by measuring coronary flow in the stenosed vessel. Using this procedure on the left descending coronary artery (LAD), we obtained reproducible blood flow changes in 18 dogs. AD6 was given i.v. at three different doses. At 0.25 mg/kg two out of four dogs showed decreased thrombus formation at the stenosis site. Seven out of eleven dogs treated with 0.5 mg/kg and two out of three treated with 1.5 mg/kg showed decreased thrombus formation. Major decreases in coronary resistance, evaluated by measuring blood flow in the unstenosed left circumflex artery (LCX), were evident only after the highest dose. We conclude that AD6 has an inhibitory action on dog platelet aggregation and reduces thrombus formation in a stenosed coronary vessel.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine Diphosphate; Animals; Chromonar; Collagen; Coronary Disease; Coumarins; Disease Models, Animal; Dogs; Epinephrine; Male; Platelet Activating Factor; Platelet Aggregation; Regional Blood Flow; Thromboxane B2

Septic shock is associated with increased metabolism of arachidonic acid to thromboxane A2 (TxA2) and prostacyclin (PGI2). The effects of ibuprofen, methylprednisolone-sodium succinate, and gentamicin alone, or in combination on survival time and, TxA2 and PGI2 production in rats in a LD100 fecal peritonitis shock model were assessed. Plasma levels of TxA2 and PGI2 were measured by radioimmunoassay of their stable metabolites immunoreactive (i) TxB2 and i6-keto-PGF1 alpha, respectively. Drugs were given 30 min before induction of fecal peritonitis. Survival times in hours were as follows: fecal peritonitis = 10.5 +/- 0.4 (n = 50); ibuprofen (15 mg/kg) = 16.1 +/- 0.8 (n = 8); methylprednisolone-sodium succinate (40 mg/kg) = 17.1 +/- 0.7 (n = 22); methylprednisolone-sodium succinate (80 mg/kg) = 46.1 +/- 10.4 (n = 25) with 8% long-term survivors (survival greater than 7 days); gentamicin (4 mg/kg) = 23.8 +/- 4.4 (n = 16); methylprednisolone-sodium succinate (40 mg/kg) + ibuprofen = 20.3 +/- 1.8 (n = 6); gentamicin + methylprednisolone-sodium succinate = 31.0 +/- 1.6 (n = 11); gentamicin + ibuprofen = 28.5 + 2.3 (n = 12); gentamicin + methylprednisolone-sodium succinate (40 mg/kg) + ibuprofen = 46.9 +/- 5.4 (n = 8). Treatment with the combination of gentamicin + ibuprofen + methylprednisolone-sodium succinate (80 mg/kg) resulted in a mean survival time of 116 +/- 13.9 h with 26% long-term survivors. Methylprednisolone-sodium succinate (40 mg/kg) reduced (P less than 0.05) plasma iTxB2 from 995 +/- 78 (n = 16) to 714 +/- 48 (n = 18) pg/ml and i6-keto-PGF1 alpha from 4,090 +/- 334 (n = 12) to 2,009 +/- 119 (n = 17) pg/ml, 4 h post-FP. Methylprednisolone-sodium succinate (80 mg/kg) produced no further decrease in either iTxB2 or i6-keto-PGF1 alpha. Ibuprofen reduced the fecal peritonitis-induced iTxB2 and i6-keto-PGF1 alpha synthesis to nondetectable levels (less than 200 pg/ml). The latter results demonstrate that methylprednisolone-sodium succinate is less effective than ibuprofen in inhibiting arachidonic acid metabolism and suggest other salutary actions. These composite observations provide evidence that conjoint therapy with steroidal and nonsteroidal anti-inflammatory agents, and antibiotics in septic shock may be beneficial.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Drug Therapy, Combination; Female; Gentamicins; Ibuprofen; Indomethacin; Methylprednisolone; Peritonitis; Rats; Shock, Septic; Thromboxane B2

The effects of lipoxygenase enzyme inhibitor nafazatrom on infarct size, haemodynamics, and prostanoid release was studied in a canine occlusion-reperfusion model of ischaemic myocardial injury. Treatment was with 10 mg/kg nafazatrom i.d., starting before coronary occlusion, 2 h and 6 h thereafter, and was repeated in 6 h intervals. The left anterior descending (LAD) coronary artery was occluded for 6 h and reperfused for 42 h. Infarct size and anatomic area dependent on the occluded LAD were determined post mortem by the tetrazolium staining technique. Nafazatrom significantly reduced the extent of irreversible myocardial ischaemic damage whether it was expressed as g/100 g left ventricle (24 +/- 4 vs. 46 +/- 6 in controls; p less than 0.01; mean +/- SEM) or as percentage of LAD risk region for infarcting (38 +/- 8 vs. 65 +/- 7% in controls; p less than 0.05). Nafazatrom did not affect peripheral haemodynamics but during drug vehicle treatment and LAD occlusion systemic blood pressure, left ventricular pressure and dP/dtmax decreased while filling pressure, heart rate, and the S-T segments of the ECG increased. The incidence of ventricular fibrillation was 8% during drug treatment and coronary ligature vs. 25% in controls (n.s.). During reperfusion, nafazatrom reduced the incidence of ventricular premature contractions and tachycardia. Ex vivo platelet aggregation in response to collagen was not inhibited by nafazatrom. Prostanoid release (thromboxane B2 and 6-keto-prostaglandin F1 alpha as breakdown products of thromboxane A2 and prostacyclin, respectively) remained unaltered in vehicle controls but nafazatrom treatment elevated prostacyclin release significantly at 4 and 5 h during LAD occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Coronary Circulation; Disease Models, Animal; Dogs; Electrocardiography; Female; Male; Myocardial Infarction; Perfusion; Platelet Aggregation; Pyrazoles; Pyrazolones; Thromboxane B2

Ablation of greater than 70% of renal mass in the rat results in hypertension, proteinuria, and glomerular sclerosis of the remnant kidney. Rats with a remnant kidney have increased excretion of thromboxane in the urine when compared with normal rats. Chronic oral administration of OKY 1581, an inhibitor of thromboxane synthesis, in rats with a remnant kidney increases renal blood flow and glomerular filtration rate (GFR), decreases protein and thromboxane excretion in the urine, lowers blood pressure and cardiac index, and improves renal histology. The degree of hypertrophy of the remnant kidney was unaffected by administration of OKY 1581. Calculated values for single nephron plasma flow and GFR were significantly greater in rats with remnant kidneys given OKY 1581 than in rats given saline. Acute i.v. administration of OKY 1581 increased renal plasma flow and GFR in rats with a remnant kidney but not in normal rats or rats with a remnant kidney previously treated with acetylsalicyclic acid. OKY 1581 markedly inhibited platelet aggregation. We suggest that in this model of renal disease platelet aggregation and intraglomerular thrombosis play a key role in the development of glomerulosclerosis. Inhibition of platelet aggregation prevents development of glomerulosclerosis, hypertension, and cardiac hypertrophy. We suggest that hyperperfusion and hyperfiltration per se occurring in remnant glomeruli are not directly responsible for the development of glomerulosclerosis.

Topics: Acrylates; Animals; Blood Pressure; Disease Models, Animal; Female; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Heart; Kidney; Kidney Diseases; Methacrylates; Nephrectomy; Oxidoreductases; Platelet Aggregation; Rats; Thromboxane B2; Thromboxane-A Synthase

In chronic P. aeruginosa infection, lung tissue damage is induced by either the microorganism or the inflammatory response. We investigated, in an animal model, whether a non-steroidal anti-inflammatory drug, ibuprofen, reduced lung inflammation produced by P. aeruginosa. Lung lavages, pulmonary clearance of P. aeruginosa and lung pathology were studied in CD-1 mice injected with sodium ibuprofenate. A single dose of the drug, injected immediately after 30 min exposure to the P. aeruginosa aerosol, decreased the recruitment of granulocytes into airways in a dose-dependent manner. Pretreatment with 2 doses of the drug 18 and 6 h before the P. aeruginosa challenge was even more effective. The kinetics of changes in prostaglandin E2, 6-keto-prostaglandin F1 alpha and thromboxane B2 concentrations in lung lavage fluids after P. aeruginosa aerosol were also modified by ibuprofen. Moreover, ibuprofen treatment did not impair lung clearance of the challenge microorganisms, and the animals had less inflammation of the lungs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Disease Models, Animal; Ibuprofen; Inflammation; Kinetics; Lung; Male; Mice; Neutrophils; Pneumonia; Prostaglandins E; Pseudomonas Infections; Therapeutic Irrigation; Thromboxane B2

Perinatal cerebral infarction is a not uncommon finding in newborn babies surviving intensive care. Asphyxia, with its attendant hypotension, is the most common cause of this problem and may result in neuropathological changes in the periventricular white matter. Previous studies have demonstrated uncoupling of cerebral blood flow and metabolism in the periventricular white matter regions of newborn beagle pups exposed to hemorrhagic hypotension. This work examines the effects of hypotension on serum and regional cerebral prostaglandin levels in the newborn beagle pup. The animals were anesthetized, tracheostomized, and paralyzed. Pups were randomly assigned to two groups: one was subjected to hemorrhagic hypotension and the other received no insult. Hypotension was induced by slow venous hemorrhage calculated to maintain a mean arterial blood pressure at 20 to 30 mm Hg. Serum prostaglandin determinations were made immediately before and 15 minutes after random assignment to hypotension or control groups. In addition, regional cerebral prostaglandin determinations were performed 15 minutes after randomization. Analysis of the serum prostaglandin data revealed that there were no significant differences in the values for thromboxane B2 or 6-keto-prostaglandin (PG) F1 alpha, which are the stable breakdown products of thromboxane A2 and prostacyclin, respectively. Prostaglandin E2 levels increased in response to hemorrhagic hypotension insult. Regional cerebral prostaglandin determinations demonstrated decreases in thromboxane B2 and 6-keto-PGF1 alpha in both gray and white matter. Although gray matter PGE2 was increased in pups exposed to hemorrhagic hypotension, this increase was not found in the periventricular white matter of injured pups. This regional difference in PGE2 synthesis in response to insult may explain the periventricular white matter neuropathological changes attributed to it.

Topics: Animals; Animals, Newborn; Cerebral Hemorrhage; Cerebral Infarction; Cerebrovascular Circulation; Disease Models, Animal; Dogs; Hypotension; Prostaglandins; Prostaglandins E; Thromboxane A2; Thromboxane B2

Topics: Animals; Anti-Inflammatory Agents; Dinoprostone; Disease Models, Animal; Inflammation; Leukocyte Count; Leukotriene B4; Propionates; Prostaglandins E; Rats; Thromboxane B2

Acute respiratory failure in humans often follows extrathoracic sepsis. The purpose of this study was to determine the effect of repeated episodes of intra-abdominal sepsis over several weeks on the structure and function of rat lung. Intermittent peritonitis and a bacteremia of Escherichia coli and Bacteroides fragilis were produced by weekly intra-abdominal implants of gelatin capsules containing these organisms (3.0 +/- 1.0 X 10(7) and 5.0 +/- 1.0 X 10(7) colony-forming units/ml, respectively; mean +/- SEM). After 4 weeks alveolar walls were thickened and cellular with focal areas of alveolar space consolidation: circulating polymorphonuclear leukocytes were increased (12.2 +/- 1.2 to 19.9 +/- 2.0 X 10(3)/mm3; p less than 0.05), as were plasma levels of 6-keto-PGF1 alpha (0.56 +/- 0.08 to 1.02 +/- 0.18 ng/ml; p less than 0.01). After 8 weeks the capillary bed was dilated and the alveolar walls and ducts appeared less cellular but showed fibrosis: The WBC count had increased to 25.5 +/- 1.0 X 10(3) (p less than 0.01). After 4 or 8 weeks of intermittent sepsis there was no increase in the pulmonary artery pressure or vascular resistance or any change in arterial oxygen tension, plasma thromboxane beta 2 level, or platelet count. We conclude that repeated bouts of sepsis and bacteremia in the rat cause progressive injury to lung alveoli without evidence of altered blood gas tensions or pulmonary hemodynamics.

Topics: 6-Ketoprostaglandin F1 alpha; Abdomen; Abscess; Animals; Bacterial Infections; Bacteroides fragilis; Bacteroides Infections; Blood Cell Count; Capsules; Disease Models, Animal; Escherichia coli Infections; Hematocrit; Hemodynamics; Lung; Male; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; Thromboxane B2

The presence of cyclooxygenase products of arachidonic acid metabolism in carrageenin-induced inflammatory exudate was investigated in ponies using two models. In the first model, an inflammatory response was stimulated by injecting carrageenin into subcutaneously implanted polypropylene tissue cages and exudates were collected at five predetermined times between 3 and 48 h. In the second model, exudates were harvested at 6, 12 and 24 h from carrageenin-impregnated polyester sponges which had also been inserted beneath the skin. Prostaglandin (PG) E2, thromboxane (TX) B2 and the stable breakdown-product of prostacyclin (PGI2), 6-keto-PGF1 alpha, in exudates were measured by radio-immunoassay (RIA); PGE2-like and PGF2 alpha-like activities were bioassayed following an acid-lipid extraction technique which provided a recovery rate of 78%. Agreement between RIA and bioassay was within acceptable limits. In Model 1, using RIA, mean PGE2 concentration reached 197 ng X ml-1 at 12 h decreasing to less than 12 ng X ml-1 at 24 h. Mean TXB2 and 6-keto-PGF1 alpha levels were highest at 48 h (22.3 and 34.2 ng X ml-1, respectively) after considerable fluctuations and with wide standard errors prior to this time. In the sponge model, however, PGE2 levels were surprisingly low for each group (mean 12.8 ng X ml-1 at 12 h) and TXB2 and 6-keto-PGF1 alpha were similarly lower (means of 3.3 and 8.1 ng X ml-1 respectively at 12 h). Mean total leucocyte counts and total protein concentrations were increased in both models after carrageenin stimulus. PGF2 alpha was not detected in measurable quantities in any exudate.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Biological Assay; Carrageenan; Dinoprostone; Disease Models, Animal; Exudates and Transudates; Female; Horses; Inflammation; Leukocyte Count; Male; Prostaglandins E; Radioimmunoassay; Thromboxane B2; Thromboxanes

The process of renal inflammation was examined using the partial renal vein constricted rabbit kidney ( RVC ) as a model. Forty eight hours of partial renal vein constriction in the rabbit was associated with an increase in prostaglandin (PG) and thromboxane (Tx) production. The ex vivo perfused RVC kidney showed an enhanced time-dependent increase in PG and Tx production in response to bradykinin stimulation when compared with the unaltered contralateral ( CLK ) or normal kidney. At 6 hrs of perfusion bradykinin stimulation released 2950 +/- 350 ng PGE2, 61 +/- 15 ng TxB2 from the RVC , and 225 +/- 85 ng PGE2 and undetectable TxB2 from the CLK . Histological examination of the RVC cortex showed an increase in fibroblast-like cells, a modest increase in the interstitial space and an appearance of macrophages and lymphocytes not seen in the normal or CLK . Endotoxin has been reported to stimulate macrophages in culture to produce PGE2 and TxB2. Endotoxin (100 ng) stimulation of the perfused RVC kidney caused an immediate, followed by a chronically increasing, release of PGs and Tx. Two hours after endotoxin injection 50 ml of effluent from the RVC contained 1450 +/- 107 ng PGE2 and 15.0 +/- 4.5 ng TxB2. Other animals of renal inflammation (e.g., the hydronephrotic kidney, chronic glomerulonephritis) also show the histological appearance of macrophages. In addition, hydronephrotic kidneys undergo fibroblast proliferation and changes in arachidonic acid metabolism similar to that we observed in the RVC . This work suggests that the inflammatory process (mononuclear cell infiltration, fibroblast-like cell proliferation, and accompanying changes in arachidonate metabolism is common among different forms of renal injury.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Bradykinin; Constriction; Dinoprostone; Disease Models, Animal; Endotoxins; Kidney; Microscopy, Electron; Nephritis; Prostaglandins E; Rabbits; Renal Veins; Thromboxane B2

Unilateral ureteral obstruction in rabbits leads to an influx of macrophages into the kidney, a proliferation of interstitial cells, and an increase in arachidonic acid metabolism. The role of the macrophage in the metabolic changes of hydronephrosis was investigated by using endotoxin and nitrogen mustard. The in vivo administration of endotoxin, a macrophage agonist, 1 hour before perfusion of the hydronephrotic kidney markedly enhanced (fourfold to tenfold) the peptide-stimulated arachidonic acid metabolism of the perfused kidney. Nitrogen mustard made animals leukopenic and prevented the influx of macrophages into the hydronephrotic kidney. The peptide-stimulated arachidonic acid metabolism of these kidneys was suppressed, and no enhancement was seen with in vivo endotoxin administration. The macrophage thus appears to be an essential determinant of the enhanced arachidonic acid metabolism seen in experimental hydronephrosis. An inhibitory effect of prostaglandin E2 on macrophage function in this model of renal inflammation was also demonstrated. Hydronephrotic animals were given aspirin during the period of unilateral ureteral obstruction to prevent in vivo prostaglandin E2 production. In the perfused hydronephrotic kidney, the peptide-stimulated arachidonic acid metabolism, which appears to be a marker of macrophage function in this model, was enhanced by aspirin treatment.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Aspirin; Bradykinin; Chromatography, Thin Layer; Dinoprostone; Disease Models, Animal; Endotoxins; Hydronephrosis; Kidney Cortex; Macrophages; Male; Mechlorethamine; Microsomes; Prostaglandins E; Rabbits; Thromboxane B2; Time Factors

The effect of platelet depletion on the unanesthetized sheep's pulmonary response to endotoxemia was studied in eight unanesthetized sheep. Platelets were depleted with rabbit anti-sheep platelet antibodies (APA). Bolus injections of APA alone caused marked pulmonary hypertension (PPA increased from 21 +/- 2 to 62 +/- 5 cm H2O +/- SE) and alterations in lung mechanics (dynamic compliance of the lung [Cdyn] decreased to 38.5 +/- 4.6% and resistance to air flow across the lung [RL] increased to 705 +/- 162% +/- SE of control), which were attenuated by pretreatment with meclofenamate. It was possible to deplete platelets before endotoxemia through a slow continuous infusion of APA without altering base-line values of the measured variables. Platelet depletion did not significantly attenuate the alterations in pulmonary hemodynamics, lung mechanics, lung fluid and solute exchange, or the normal increase in lung lymph concentrations of thromboxane B2 or 6-keto-PGF1 alpha observed following endotoxemia in the sheep. We conclude that normal circulating platelet counts are not required for the full expression of the sheep's response to endotoxemia.

Topics: Animals; Blood Cell Count; Blood Platelets; Disease Models, Animal; Endotoxins; Hemodynamics; Lung; Prostaglandins F; Respiration; Respiratory Distress Syndrome; Sheep; Thromboxane B2

The action of pentoxifylline on some of the consequences of acute myocardial ischaemia was studied in cats in vivo. Occlusion of the left anterior descending coronary artery (LAD) for 5 h resulted in a significant elevation in the ST-segment of the ECG, a reduction in free platelet count in right atrial blood and a loss of creatine phosphokinase (CK) and cathepsin D activities in homogenates of the severely ischaemic myocardium as compared to non-ischaemic myocardium. Intravenous infusions of pentoxifylline (0.30 mg kg-1 min-1 for 1 h and 0.15 mg kg-1 min-1 for the remainder of the 5 h observation period, starting 0.5 h after LAD occlusion) significantly reduced the loss of enzymes from the ischaemic myocardium, prevented any further increase in the ST-segment and restored the platelet count to its control level. There were no significant changes in plasma immunoreactive 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) and thromboxane B2 (TXB2), although a tendency for a reduction in TXB2 levels was observed. Pentoxifylline seems to affect, beneficially, the myocardium in this animal model of acute myocardial ischaemia. The reason for this cardioprotective action remains to be elucidated. It is, however, noteworthy that the overall profile of action of pentoxifylline resembles that of PGI2 administration in this model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cathepsin D; Cathepsins; Cats; Coronary Disease; Creatine Kinase; Disease Models, Animal; Electrocardiography; Female; Hemodynamics; Infusions, Parenteral; Male; Myocardium; Pentoxifylline; Platelet Count; Theobromine; Thromboxane B2

Blockade of the arachidonic acid cascade has been shown to improve survival and hemodynamic alterations in animal models of sepsis and acute respiratory failure (ARF). The effects of intravenous ibuprofen, a cyclooxygenase inhibitor, were observed in 20-30 kg pigs with ARF induced by a continuous LD100 infusion of live Pseudomonas aeruginosa (2 X 10(8)/20 kg/min). Cardiopulmonary parameters were monitored in animals intubated, paralyzed, and ventilated at a 250-ml tidal volume and 0.5 FiO2. Pigs were randomly assigned to three groups: Group I received 2 bolus infusions of ibuprofen (12.5 mg/kg) at 20 and 210 min after baseline; Group II had Ps. aeruginosa (2 X 10(8) CFU/20 kg/min) only; Group III received Ps. aeruginosa and 12.5 mg/kg of ibuprofen at 20 and 210 min of ARF. Ibuprofen alone caused no significant changes in cardiorespiratory parameters. With Ps. aeruginosa infusion, significant pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, and systemic hypotension occurred. In the septic animals treated with ibuprofen, oxygenation was improved by a significant decrease in shunt, pulmonary edema, and pulmonary hypertension.

Topics: Acute Disease; Animals; Disease Models, Animal; Hemodynamics; Ibuprofen; Lung; Male; Pseudomonas Infections; Respiratory Insufficiency; Swine; Thromboxane B2

Topics: Animals; Arteriosclerosis; Blood Platelets; Diet, Atherogenic; Dietary Fats; Disease Models, Animal; Epoprostenol; Fatty Acids; Liver; Phospholipids; Prostaglandins; Rabbits; Rats; Thrombosis; Thromboxane B2; Thromboxanes

The tail bleeding time (BT) in rats definitely varies according to the method applied. Of the various variables that may influence BT, we have evaluated the position (horizontal or vertical) of the tail, the environment (air or saline), the temperature (4 degrees, 23 degrees or 37 degrees C) and the type of anaesthesia. Transection of the tail tip cannot be used to screen drugs active on platelet function since it is sensitive to coagulation defects. Template BT in contrast is not modified by heparin and is sensitive to defects of platelet number and function ("storage pool disease", dipyridamole-like drugs, exogenous prostacyclin). In contrast the test fails to detect aspirin-induced platelet dysfunction. The evidence reported indicates that thromboxane A2-prostacyclin balance is not a factor regulating BT. Aspirin treatment however may be a precipitating factor when associated with other abnormalities of platelet function. Template BT is a valid screening test for platelet disorders and for antiplatelet drugs.

Topics: Anesthetics; Animals; Aspirin; Bleeding Time; Blood Coagulation; Blood Platelet Disorders; Dipyridamole; Disease Models, Animal; Epoprostenol; Heparin; Indomethacin; Rats; Tail; Thromboxane B2

The compound 4'-(imidazol-1-yl) acetophenone was demonstrated to be a selective thromboxane (Tx) synthetase inhibitor in spontaneously hypertensive rats (SHR). Serum TxB2 concentrations (from clotted blood) were suppressed by 89.1% (p less than 0.001) and 41.2% (p less than 0.01) at 3 and 24 hours, respectively, following a single subcutaneous injection of 100 mg/kg of 4'-(Imidazol-1-yl) acetophenone suspended in olive oil. In contrast, plasma 6-keto-PGF1 alpha levels were not significantly altered at 3 hours following injection - a time when suppression of TXB2 was maximal. From 4 to 10 weeks of age, SHR were treated with daily injections of either 4'-(Imidazol-1-yl) acetophenone (100 mg/kg) in olive oil or olive oil alone. By 8 weeks of age systolic blood pressures in the treated group were 140.6 +/- 3.2 vs 156.6 +/- 4.5 mmHg in the control group (p less than 0.01). At ten weeks of age the separation was even more pronounced: 155.3 +/- 3.7 vs. 184.8 +/- 4.6 mmHg for treated vs. control animals (p less than 0.001). This data supports the hypothesis that thromboxanes may be involved in the development of SHR hypertension; however, alternative mechanisms are discussed.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Disease Models, Animal; Hypertension; Imidazoles; Kinetics; Rats; Thromboxane B2; Thromboxanes

Essential fatty acid deficient (EFAD) rats are significantly more resistant to the lethal effects of S. enteritidis endotoxin (20 mg/kg, IV) than normal control rats. Compared to endotoxin-treated normal rats, EFAD rats also manifested less severe alterations of hepatic and lysosomal integrity and became less hypoglycemic. Administration of the ethyl ester of the essential fatty acid, arachidonic acid (100 mp, IP) two days prior to challenge with S. enteritidis endotoxin (20 mg/kg) in EFAD rats restored their sensitivity to endotoxin, as denoted by a 100% mortality compared to a 24% mortality (P less than 0.01) in EFAD rats. Treatment of EFAD rats with the fatty acid docosahexaenoic acid, a non-prostaglandin and thromboxane precursor, (100 mg, IP) produced significantly less (less than 0.01) mortality than ethyl-arachidonate-treated groups (ie, 40% vs 100%). The arachidonate metabolite, thromboxane B2 (TxB2), increased from nondetectable plasma levels (less than 200 pg/ml) to 2285 +/- 449 pg/ml (N = 10) at 30 min and remained elevated for 180 minutes after endotoxin administration in nondeficient rats. However, plasma TxB2 was not detectable in endotoxin-treated EFAD rats and was only slightly elevated in groups supplemented with docosahexaenoic acid (273 +/- 104 pg/ml, N = 6) after 30 minutes. In ethyl arachidonate (100 mg, IP) supplemented EFAD rats, plasma TxB2 rose to 873 +/- 204 pg/ml (N = 8), 30 min after endotoxin. Pretreatment of the ethyl-arachidonate-supplemented EFAD group with a specific thromboxane synthetase inhibitor, 7-(1-imidazolyl)-heptanoic acid (30 mg/kg, IV), significantly reduced mortality 100% to 50% (P less than 0.05) from endotoxic shock. These observations suggest a deleterious role for arachidonic acid and its conversion to TxA2 in the pathogenesis of endotoxic shock.

Topics: Acid Phosphatase; Animals; Arachidonic Acid; Arachidonic Acids; Blood Glucose; Disease Models, Animal; Fatty Acids, Essential; Female; Fibrin Fibrinogen Degradation Products; Male; Muridae; Pregnancy; Shock, Septic; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Coronary Disease; Coronary Vessels; Disease Models, Animal; Dogs; Heart; Prostaglandins F; Thromboxane B2; Thromboxanes

Microsomes of albino rabbit ciliary body--iris were prepared 6 hr, 24 hr, 3 days, 7 days, and 28 days after intravitreal injection of 10 micrograms of Shigella endotoxin. The microsomal preparations were incubated for 15 min with [1-14C]arachidonic acid. Prostaglandin and thromboxane products (cyclo-oxygenase products) were identified by thin-layer chromatography and quantified by scintillation counting. Synthesis of prostaglandin F2 alpha (PGF2, PGD2, 6-keto-PGF1 alpha (a stable metabolite of PGI2) and thromboxane B2 (TXB2) (a stable metabolite of TXA2) was increased 24 hr, 3 days, and 7 days after endotoxin injection. The greatest increase was in TXB2 synthesis. Cyclo-oxygenase product synthesis returned to normal levels by 28 days. Ciliary body--iris microsomes prepared 15 min after paracentesis synthesized increased amounts of all cyclo-oxygenase products assayed, most notably TXB2 and PGE2. Ciliary body--iris microsomes from albino rabbit treated with topical 1% nitrogen mustard or pigmented rabbits treated with subcutaneous alpha-melanocyte--stimulating hormone (20 micrograms/kg) synthesized normal amounts of cyclo-oxygenase products.

Topics: Animals; Ciliary Body; Disease Models, Animal; Iris; Microsomes; Prostaglandins; Prostaglandins D; Prostaglandins E; Prostaglandins F; Rabbits; Thromboxane B2; Thromboxanes; Uveal Diseases

A model system has been developed which employs the central artery of the rabbit ear, and allows for the study of 1) ultra-structural changes in the arterial endothelium and 2) formation and release of prostacyclin and thromboxane from the arteries in situ. Use of the model should be helpful in evaluating the initial events in atherosclerosis. Both prostacyclin and thromboxane (detected by radioimmunoassay) were formed by arteries in situ in response to infusion of sodium arachidonate.

Topics: Animals; Arachidonic Acids; Arteriosclerosis; Disease Models, Animal; Ear; Endothelium; Epoprostenol; Male; Rabbits; Thromboxane B2

Topics: Animals; Aspirin; Butylated Hydroxytoluene; Carrageenan; Disease Models, Animal; Imidazoles; Inflammation; Pleural Effusion; Pleurisy; Prostaglandin Endoperoxides; Prostaglandins; Prostaglandins E; Prostaglandins F; Rats; Thromboxane B2; Thromboxanes