thromboxane-a2 has been researched along with Shock--Septic* in 60 studies
5 review(s) available for thromboxane-a2 and Shock--Septic
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Novel mediators of sepsis-associated renal failure.
Topics: Acute Kidney Injury; Animals; Bacterial Infections; Endothelins; Humans; Leukotrienes; Shock, Septic; Thromboxane A2 | 1994 |
Phospholipids and their inhibitors: a critical evaluation of their role in the treatment of sepsis.
The clinical condition sepsis and its sequelae are caused by numerous mediators that are released by various cell types. The purpose of this review is to describe the results of various studies performed with agents that either inhibited or stimulated the synthesis of, or affected the receptor-binding characteristics of a specific class of these mediators, the phospholipids.. Antagonists to platelet-activating factor and thromboxane A2 receptors, monoclonal antibodies to phospholipase A2, agents which increased levels of prostaglandins, and cyclooxygenase, lipoxygenase, and other specific pathway inhibitors, which block the production of leukotrienes and thromboxane A2, were used in the studies described to affect the physiologic correlates of sepsis animal models and human studies.. The matters discussed in this paper come from a wide variety of sources, including many broad-based clinical studies of humans with inflammatory disease. Many animal studies are discussed, along with some in vitro cell culture studies and work in molecular genetics.. This article reviews a subject that is rapidly evolving, with frequent discoveries. Thus, much of the article discusses research in basic science, particularly the use of experimental drugs in animals. Clinical studies are generally of large numbers of patients showing overt signs of sepsis.. Most cited literature was found in reputable, peer review journals, including such major basic science journals as Science, and clinical journals such as the Journal of the American Medical Association, New England Journal of Medicine, and Critical Care Medicine.. Occasionally, contradictions do occur in the results of various studies. These contradictions are discussed in this review, and may often be due to the use of different protocols and definitions of the various clinical states.. Increases of some mediators, such as platelet-activating factor, thromboxane A2, and the leukotrienes are associated with animal models of sepsis and seem to have a negative effect on the course of sepsis. Antagonists and blockers of these mediators increased survival in these studies. More research is needed to identify how these mediators of inflammation are associated with sepsis, and what the effects of blocking their actions will have on sepsis. Topics: Animals; Cyclooxygenase Inhibitors; Humans; Leukotriene Antagonists; Phospholipids; Platelet Activating Factor; Prostaglandins, Synthetic; Sepsis; Shock, Septic; Thromboxane A2 | 1992 |
Prostaglandins, cyclo-oxygenase inhibitors, and thromboxane synthetase inhibitors in the pathogenesis of multiple systems organ failure.
The role of the various cyclo-oxygenase products of arachidonic acid metabolism in the production of the pathologic, physiologic, hemodynamic, and metabolic derangements of sepsis has been reviewed and there is a wide variation in different species and with different models of sepsis. The relationship of these potential mediators cannot be definitely determined. There is much circumstantial evidence that would incriminate the various arachidonic metabolites in the production of the sepsis manifestations; however, we must keep in mind that this may only be "guilt by association." Clearly, the available evidence does suggest that there is some role played by TXA2 and PGI2 in the physiologic and hemodynamic manifestations of sepsis, but the exact role remains undetermined. Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Cyclooxygenase Inhibitors; Epoprostenol; Humans; Multiple Organ Failure; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase | 1989 |
Role of thromboxane receptor antagonists in cardiovascular disease.
A number of reports indicate the TX receptor antagonists may be useful in preventing coronary artery reocclusion following fibrinolytic therapy, reducing myocardial ischemia/reperfusion injury and consequent neutrophil accumulation, preventing thrombocardiac sudden death, and attenuating the sequelae of endotoxic shock. Limited clinical studies have been initiated, and no adverse clinical effects can be associated with specific TX receptor blockade. Further clinical studies will be required to confirm the provocative animal studies, as well as defining the role of TX as a mediator of coronary vasospasm, respiratory disorders, and renal failure and rejection episodes. Topics: Animals; Cardiovascular Diseases; Coronary Thrombosis; Humans; Myocardial Infarction; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2 | 1989 |
Role of thromboxane, prostaglandins and leukotrienes in endotoxic and septic shock.
Intravenous bolus endotoxin elicits a marked but transient increase in plasma TxB2 and 6-keto-PGF1 alpha in a large number of species. A smaller, delayed and more prolonged increase in TxB2 and 6-keto-PGF1 alpha are reported in animals with septic shock, i.e., those with fecal peritonitis or cecal ligation. Thromboxane synthetase inhibitors or antagonists attenuate endotoxin-induced acute cardiopulmonary changes, the delayed increase in serum lysosomal enzymes, fibrin/fibrinogen degradation products and the thrombocytopenia in a number of species. While these drugs increase survival of rats or mice following endotoxin they do not alter survival of rats in septic shock. These results support the hypothesis that TxA2 exerts a pathophysiologic effect in shock following bolus endotoxin. In contrast, nonsteroidal antiinflammatory drugs (NSAID) and dietary essential fatty acid deficiency increase survival of rats subjected to endotoxin shock, and survival time in models of septic shock. These results also suggest that some other cyclooxygenase product(s) is involved in septic shock due to fecal peritonitis or cecal ligation. Preliminary experimental studies indicate salutary effects of leukotriene inhibitors and antagonists in endotoxin shock and in models of acute pulmonary injury. Clinical studies have demonstrated elevated plasma TxB2 and 6-keo-PGF1 alpha concentrations in patients with septic shock, and elevated LTD4 in pulmonary edema fluid of patients with the adult respiratory distress syndrome. In view of these clinical and experimental results, clinical trials of NSAID and/or leukotriene inhibitors/antagonists should be considered. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents; Cats; Endotoxins; Fatty Acids, Essential; Hemodynamics; Humans; Leukotriene B4; Prostaglandins; Rats; Shock, Septic; SRS-A; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes | 1986 |
1 trial(s) available for thromboxane-a2 and Shock--Septic
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[Impacts of high-volume hemofiltration on hemodynamics and vascular endothelial permeability in children with septic shock].
To investigate the effects of high-volume hemofiltration (HVHF) on hemodynamics, vasoactive factors, and vascular endothelial permeability in children with septic shock by a comparative analysis.. Thirty-six children who were diagnosed with septic shock between January 2013 and September 2014 were randomly divided into control and observation groups (n=18 each). Children in the control group were treated with the standard-volume hemofiltration (SVHF), while children in the observation group were treated with HVHF. The hemodynamic indices and levels of vasoactive factors including 6-keto-prostaglandin F1α (6-keto-PGF1α), thromboxane B2 (TXB2), soluble E-selectin (sE-selectin), and endothelium-derived relaxing factor (EDRF) were determined before and after treatment. In addition, the effects of ultrafiltrate on endothelial cell permeability were assessed.. Compared with the control group, the observation group had significantly higher mean arterial pressure, significantly higher blood oxygen saturation, and a significantly lower heart rate after treatment (P<0.05). The levels of TXB2 and sE-selectin were significantly lower in the observation group than in the control group (P<0.05), while the levels of 6-keto-PGF1α and EDRF were significantly higher in the observation group than in the control group (P<0.05). Compared with the control group, the ultrafiltrate significantly attenuated the transepithelial electrical resistance in the observation group (P<0.05).. Compared with SVHF, HVHF is a more effective approach for improving the hemodynamics and levels of vasoactive factors and reducing the vascular endothelial permeability in children with septic shock. Topics: Capillary Permeability; Child; Child, Preschool; Epoprostenol; Female; Hemodynamics; Hemofiltration; Humans; Infant; Male; Shock, Septic; Thromboxane A2 | 2015 |
54 other study(ies) available for thromboxane-a2 and Shock--Septic
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Pharmacological modulation of procoagulant microparticles improves haemodynamic dysfunction during septic shock in rats.
Circulating microparticles play a pro-inflammatory and procoagulant detrimental role in the vascular dysfunction of septic shock. It was the objective of this study to investigate mechanisms by which a pharmacological modulation of microparticles could affect vascular dysfunction in a rat model of septic shock. Septic or sham rats were treated by activated protein C (aPC) and resuscitated during 4 hours. Their microparticles were harvested and inoculated to another set of healthy recipient rats. Haemodynamic parameters were monitored, circulating total procoagulant microparticles assessed by prothrombinase assay, and their cell origin characterised. Mesenteric resistance arteries, aorta and heart were harvested for western blotting analysis. We found that a) the amount and phenotype of circulating microparticles were altered in septic rats with an enhanced endothelial, leucocyte and platelet contribution; b) aPC treatment significantly reduced the generation of leucocyte microparticles and norepinephrine requirements to reach the mean arterial pressure target in septic rats; c) Microparticles from untreated septic rats, but not from aPC-treated ones, significantly reduced the healthy recipients' mean arterial pressure; d) Microparticle thromboxane content and aPC activity were significantly increased in aPC-treated septic rats. In inoculated naïve recipients, microparticles from aPC-treated septic rats prompted reduced NF-κB and cyclooxygenase-2 arterial activation, blunted the generation of pro-inflammatory iNOS and secondarily increased platelet and endothelial microparticles. In conclusion, in this septic shock model, increased circulating levels of procoagulant microparticles led to negative haemodynamic outcomes. Pharmacological treatment by aPC modified the cell origin and levels of circulating microparticles, thereby limiting vascular inflammation and favouring haemodynamic improvement. Topics: Animals; Cell-Derived Microparticles; Coagulants; Cyclooxygenase 2; Hemodynamics; Humans; Inflammation; Male; NF-kappa B; Phenotype; Protein C; Rats; Rats, Wistar; Recombinant Proteins; Shock, Septic; Thromboplastin; Thromboxane A2; Time Factors; Treatment Outcome | 2014 |
ExoU-induced vascular hyperpermeability and platelet activation in the course of experimental Pseudomonas aeruginosa pneumosepsis.
To address the question whether ExoU, a Pseudomonas aeruginosa cytotoxin with phospholipase A2 activity, can induce hemostatic abnormalities during the course of pneumosepsis, mice were instilled i.t. with the ExoU-producing PA103 P. aeruginosa or with a mutant obtained by deletion of the exoU gene. Control animals were instilled with sterile vehicle. To assess the role of ExoU in animal survival, mice were evaluated for 72 h. In all the other experiments, animals were studied at 24 h after infection. PA103-infected mice showed significantly higher mortality rate, lower blood leukocyte concentration, and higher platelet concentration and hematocrit than animals infected with the bacterial mutant, as well as evidences of increased vascular permeability and plasma leakage, which were confirmed by our finding of higher protein concentration in bronchoalveolar lavage fluids and by the Evans blue dye assay. Platelets from PA103-infected mice demonstrated features of activation, assessed by the flow cytometric detection of higher percentage of P-selectin expression and of platelet-derived microparticles as well as by the enzyme immunoassay detection of increased thromboxane A2 concentration in animal plasma. Histopathology of lung and kidney sections from PA103-infected mice exhibited evidences of thrombus formation that were not detected in sections of animals from the other groups. Our results demonstrate the ability of ExoU to induce vascular hyperpermeability, platelet activation, and thrombus formation during P. aeruginosa pneumosepsis, and we speculate that this ability may contribute to the reported poor outcome of patients with severe infection by ExoU-producing P. aeruginosa. Topics: Animals; Bacterial Proteins; Capillary Permeability; Cell-Derived Microparticles; Female; Kidney; Mice; P-Selectin; Platelet Activation; Pneumonia, Bacterial; Pseudomonas aeruginosa; Pseudomonas Infections; Shock, Septic; Thromboxane A2 | 2010 |
Circulating microparticles from patients with septic shock exert protective role in vascular function.
Sepsis is an archetypal condition with molecular links between inflammation and coagulation. Both events can be orchestrated by the interaction between circulating and vascular cells that under activation release microparticles.. We characterized circulating microparticles from both nonseptic subjects and patients with septic shock and evaluated their contribution to vascular function.. Circulating microparticles and their cell origin were measured in blood from 36 patients with septic shock and 18 nonseptic subjects by flow cytometry. Microparticles were then injected intravenously into mice and vascular reactivity was assessed in aorta. Expression and activity of enzymes involved in nitric oxide (NO) and cyclooxygenase metabolite production were analyzed.. Circulating levels of microparticles and platelet- and endothelial-derived microparticles were increased in septic patients. Surprisingly, septic microparticles enhanced the sensitivity of contraction of mouse aorta in response to serotonin. Interestingly, septic microparticles enhanced the contraction of aorta from lipopolysaccharide-treated mice. This effect was linked neither to increased calcium entry nor to Rho kinase inhibitor-sensitive mechanisms. In addition, the effect of septic microparticles was not modified either by NO-synthase or cyclooxygenase-2 inhibitors, and was not associated with NO or O2- overproduction. The nonselective cyclooxygenase-2 inhibitor indomethacin reduced, and the specific thromboxane A2 antagonist SQ-29548 abolished, aortic contraction in mice treated with nonseptic and septic microparticles. The effect of septic microparticles was associated with increased thromboxane A2 production, and was sensitive to a selective thromboxane A2 antagonist.. We provide evidence that increased circulating microparticles are protective against vascular hyporeactivity accounting for hypotension in patients with septic shock. Topics: Adult; Aged; Animals; Case-Control Studies; Cell-Derived Microparticles; Disease Models, Animal; Endothelium, Vascular; Female; Humans; Hypotension; Male; Mice; Middle Aged; Shock, Septic; Thromboxane A2; Vasoconstriction; Vasodilation | 2008 |
Effect of a novel thromboxane A2 inhibitor on right ventricular-arterial coupling in endotoxic shock.
We investigated the effects of a dual thromboxane (TX)A2 synthase inhibitor and TXA2 receptor antagonist (BM-573) on right ventricular-arterial coupling in a porcine model of endotoxic shock. Thirty minutes before the onset of 0.5 mg/kg endotoxin infusion, six pigs (Endo group) received an infusion with a placebo solution, and six other pigs (Anta group) with BM-573. Right ventricular pressure-volume loops were obtained by the conductance catheter technique. The slope (Ees) of the end-systolic pressure-volume relationship and its volume intercept at 25 mmHg were calculated as measures of right ventricular systolic function. RV afterload was quantified by pulmonary arterial elastance (Ea), and Ees/Ea ratio represented right ventricular-arterial coupling. Mechanical efficiency was defined as the ratio of stroke work and pressure-volume area. In this model of endotoxic shock, BM-573 blunted the early phase of pulmonary hypertension, improved arterial oxygenation, and prevented a decrease in right ventricular myocardial efficiency and right ventricular dilatation. However, the drug could not prevent the loss of homeometric regulation and alterations in right ventricular-arterial coupling. In conclusion, dual TXA2 synthase inhibitor and receptor antagonists such as BM-573 have potential therapeutic applications, improving right ventricular efficiency and arterial oxygenation in endotoxic shock. Topics: Animals; Catheterization; Disease Models, Animal; Endotoxins; Female; Heart Ventricles; Male; Myocardium; Oxygen; Pancreatic Elastase; Placebos; Pressure; Pulmonary Circulation; Shock, Septic; Swine; Systole; Thromboxane A2; Time Factors | 2004 |
Effects of BM-573, a novel thromboxane A2 inhibitor, on pulmonary hemodynamics in endotoxic shock.
Thromboxane A2 is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in proinflammatory reactions. The effects of a novel dual TXA2 synthase inhibitor and TXA2 receptor antagonist (BM-573) on pulmonary hemodynamics were investigated in endotoxic shock. 30 mins before the start of a 0.5 mg/kg endotoxin infusion, 6 pigs (Endo group) received a placebo infusion and 6 other pigs (Anta group) received a BM-573 infusion. In Endo group, pulmonary artery pressure increased from 25 +/- 1.8 (T0) to 42 +/- 2.3 mmHg (T60) (p < 0.05) after endotoxin infusion while, in Anta group, it increased from 23 +/- 1.6 (T0) to 25 +/- 1.5 mmHg (T60). This difference is due to a reduction in pulmonary vascular resistance in Anta group while pulmonary arterial compliance changes in Endo group remained comparable with the evolution in Anta group. In Endo group, PaO2 decreased from 131 +/- 21 (T0) to 74 +/- 12 mmHg (T300) (p < 0.05), while in Anta group, PaO2 was 241 +/- 31 mmHg at the end of the experimental period (T300). These results demonstrate that TXA2 plays a major role in pulmonary vascular changes during endotoxin insult. Concomitant inhibition of TXA2 synthesis and of TXA2 receptors by BM-573 inhibited the pulmonary vasopressive response during the early phase of endotoxin shock as well as the deterioration in arterial oxygenation. Topics: Animals; Arachidonic Acid; Blood Pressure; Cardiac Output; Female; Heart Rate; Male; Oxygen Consumption; Partial Pressure; Platelet Aggregation; Pulmonary Artery; Pulmonary Circulation; Shock, Septic; Sulfonylurea Compounds; Swine; Thromboxane A2 | 2003 |
Mechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human platelets.
In this study, gram-positive Staphylococcus aureus lipoteichoic acid (LTA) dose-dependently (0.1-1.0 microg/ml) and time-dependently (10-60 min) inhibited platelet aggregation in human platelets stimulated by agonists. LTA also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. LTA (0.5 and 1.0 microg/ml) also significantly inhibited thromboxane A2 formation stimulated by collagen in human platelets. Moreover, LTA (0.1-1.0 microg/ml) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatrience. Rapid phosphorylation of a platelet protein of Mr. 47,000 (P47), a marker of protein kinase C activation, was triggered by PDBu (30 nM). This phosphorylation was markedly inhibited by LTA (0.5 and 1.0 microg/ml) within a 10-min incubation period. These results indicate that the antiplatelet activity of LTA may be involved in the following pathways: LTA's effects may initially be due to induction of conformational changes in the platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca+2 mobilization and phosphorylation of P47 protein. Therefore, LTA-mediated alteration of platelet function may contribute to bleeding diathesis in gram-positive septicemic and endotoxemic patients. Topics: Calcium Signaling; Cell Membrane; Collagen; Cytosol; Dose-Response Relationship, Drug; Endotoxemia; Enzyme Activation; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Hemorrhagic Disorders; Humans; L-Lactate Dehydrogenase; Lipopolysaccharides; Membrane Fluidity; Membrane Lipids; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peptides; Phorbol 12,13-Dibutyrate; Phosphatidylinositols; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Kinase C; Protein Processing, Post-Translational; Sepsis; Shock, Septic; Staphylococcus aureus; Teichoic Acids; Thromboxane A2; Thromboxane B2 | 2000 |
Platelet-activating factor and arachidonic acid metabolites mediate tumor necrosis factor and eicosanoid kinetics and cardiopulmonary dysfunction during bacteremic shock.
Platelet-activating factor (PAF) and eicosanoids are putative mediators of septic shock that are associated with release of tumor necrosis factor (TNF). The purpose of this investigation was to a) examine temporal patterns of TNF and arachidonic acid metabolite release in a porcine model of bacteremic shock and b) selectively block PAF, thromboxane A2, prostacyclin, and leukotrienes to determine the relationships among these inflammatory response mediators and the alterations in cardiorespiratory dysfunction for which they are required.. Prospective, nonrandomized, controlled trial.. Laboratory at a university medical center.. Thirty-four female Yorkshire swine.. Animals were divided into six experimental groups: five septic groups receiving an infusion of Aeromonas hydrophila at 0.2 mL/kg/hr, gradually increasing to 0.4 mL/kg/hr over 4 hrs. Each of four septic groups was pretreated with a specific mediator inhibitor (PAF receptor antagonist, n = 6; prostacyclin antibody, n = 5; leukotriene synthesis inhibitor, n = 5; and thromboxane receptor antagonist, n = 6). One septic group (n = 6) received no mediator inhibitor and served as a septic control, and one anesthesia control group (n = 6) received no intervention.. PAF receptor blockade significantly increased systemic hypotension and mixed venous oxygen saturation and decreased pulmonary artery pressure, oxygen extraction and consumption, hemoconcentration, and levels of TNF and eicosanoids. Leukotriene inhibition increased mean arterial pressure, pulmonary and systemic vascular resistance indices, and arterial and mixed venous oxygen saturation and reduced pulmonary hypertension, oxygen delivery, oxygen extraction, oxygen consumption, and all measured mediators. Thromboxane receptor blockade lowered TNF and leukotriene levels, ameliorated systemic and pulmonary vasoconstriction, and significantly increased arterial and tissue oxygenation compared with septic controls. Prostacyclin antagonism reduced prostacyclin plasma concentrations, arterial hypoxemia, and oxygen consumption during sepsis and increased circulating leukotriene B4.. Elevations in plasma TNF predictably precede peak levels of eicosanoids in this model. PAF, leukotrienes, and thromboxane A2 are necessary for pulmonary hypertension during bacteremia. Systemic hypotension and increased vascular permeability are mediated by both leukotrienes and PAF. There are complex interactions among mediators during sepsis and further studies are required to define these relationships. Topics: Aeromonas hydrophila; Animals; Arachidonic Acid; Azepines; Bridged Bicyclo Compounds, Heterocyclic; Eicosanoids; Female; Gram-Negative Bacterial Infections; Heart Diseases; Hemodynamics; Hypertension, Pulmonary; Lipoxygenase Inhibitors; Masoprocol; Oxazoles; Oxygen; Oxygen Consumption; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Swine; Thromboxane A2; Triazoles; Tumor Necrosis Factor-alpha | 1999 |
Protective effects of a thromboxane synthetase inhibitor and continuous arteriovenous hemofiltration in rat endotoxic shock.
We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) and a thromboxane synthetase inhibitor (TSI) on survival and their effect on TXA2, PGI2, TNF alpha, and IL-1beta production in rat endotoxemia. Thirty-six endotoxemic rats were randomized to one of 4 groups: (A) no TSI, sham CAVH; (B) no TSI, CAVH; (C) TSI, sham CAVH; and (D) TSI, CAVH. Either CAVH (Group B) or pretreatment with TSI (Group C) resulted in increased survival time. CAVH did not prevent the rise in TX (Group B). TNF alpha levels at 2 h after LPS infusion were higher in Group D compared to Group B (26.1 +/- 3.7 vs 13.2 +/- 4.3 ng/mL, P < 0.05) respectively. IL-1beta was detected earlier in Groups C,D when compared to Groups A,B (P < 0.02). TNF alpha and IL-1beta were not ultrafiltered. CAVH and the inhibition of TX synthesis independently improved survival in endotoxemia, however, their beneficial effects were not additive. While TSI may improve survival by blocking TXA2 production, the salutary effects of CAVH appear to be from removal of an undetermined TXA2 dependent mediator. TNF alpha and IL-1beta concentrations do not appear to influence survival times in this model. Topics: Animals; Blood Pressure; Combined Modality Therapy; Enzyme Inhibitors; Epoprostenol; Heart Rate; Hemofiltration; Imidazoles; Inflammation Mediators; Interleukin-1; Male; Rats; Rats, Sprague-Dawley; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha | 1997 |
Effects of eicosanoids on lipopolysaccharide-induced ornithine decarboxylase activity and polyamine metabolism in the mouse liver.
During endotoxic shock, arachidonic acid is released from the inflammatory cell membranes and is metabolized to form eicosanoids, which modify the deleterious effects of lipopolysaccharide (LPS) on liver function. However, it is not known which prostaglandins (PGs) or leukotrienes (LTs) are produced or how they affect the LPS-treated liver. As LPS treatment elevates hepatic ornithine decarboxylase (ODC) activity and affects the polyamine levels of the mouse liver, this study was carried out to examine the effects of eicosanoids and their inhibitors on the induction of ODC activity and polyamine levels in the LPS-treated mouse liver.. LPS in the presence or absence of other drugs was intraperitoneally administered to 6-week-old mice and the livers were then removed. The hepatic ODC activity, polyamine levels, and level of ODC mRNA were determined.. The levels of LPS-induced ODC activity, the putrescine (PUT) and N1-acetylspermidine (A-SPD) were reduced by the administration of PGE1. ODC activity was enhanced by the administration of corticosterone, AA-2414 (an antagonist of thromboxane (TX) A2) and TXB2, whereas the A-SPD level was reduced by corticosterone and AA-2414 treatment. The level of ODC mRNA changed in parallel with the change in ODC activity.. PGE1 may reduce the LPS-induced production of inflammation-accelerating cytokines and reduce the level of ODC activation. Corticosterone and AA-2414 treatment may attenuate the LPS-induced production of eicosanoids, and enhance the LPS-induced ODC activation. It is possible that the eicosanoids produced by LPS treatment inhibit ODC activation during endotoxic shock. Topics: Alprostadil; Animals; Benzoquinones; Blotting, Northern; Corticosterone; Eicosanoids; Enzyme Induction; Escherichia coli; Heptanoic Acids; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred BALB C; Ornithine Decarboxylase; Polyamines; Prostaglandin Antagonists; Putrescine; RNA, Messenger; Shock, Septic; Spermidine; Thromboxane A2 | 1997 |
Induction mechanism of small intestinal lesions caused by intravenous injection of endotoxin in rats.
The pathogenesis of intestinal damage caused by bolus intravenous injection of endotoxin (ETX; 3 mg/kg) was investigated. Administration of ETX to rats induced reddish discoloration suggestive of bleeding, increased hemoglobin amounts, and leakage of plasma protein in the intestine. However, light microscopic examination of the intestine demonstrated blood congestion of the microvessels. Plasma accumulation was partially inhibited by combined pretreatment with a histamine H1 antagonist and a serotonin (5-HT) antagonist. Neither a 5-lipoxygenase inhibitor, a soybean trypsin inhibitor, nor atropine was observed to inhibit plasma accumulation. Both the intestinal leakage of plasma and the accumulation of hemoglobin were completely inhibited by indomethacin, a selective thromboxane A synthetase inhibitor (OKY 1581), and a stable PGI2 analogue (beraprost). Intravital microscopic observation of the microvessels of the small intestinal villi demonstrated microthrombus formation within several minutes after the injection of ETX, and pretreatment with OKY 1581 attenuated the formation of microthrombus. Platelet counts decreased significantly 10 min after ETX administration, and the decrease was not inhibited by pretreatment with either OKY 1581 or beraprost. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were not prolonged. These observations thus suggest that microcirculatory disturbances by platelet thrombus, which are mediated by thromboxane A2 at least in part, play an important role in ETX-induced intestinal damage. Topics: Animals; Capillary Leak Syndrome; Cyclooxygenase Inhibitors; Endotoxins; Enzyme Inhibitors; Epoprostenol; Escherichia coli; Gastrointestinal Hemorrhage; Indomethacin; Intestine, Small; Male; Methacrylates; Microcirculation; Platelet Activation; Rats; Rats, Sprague-Dawley; Shock, Septic; Specific Pathogen-Free Organisms; Thrombosis; Thromboxane A2; Thromboxane-A Synthase | 1996 |
Modulation by dexamethasone of phospholipase A2 activities in endotoxemic guinea pigs.
One hour after lipopolysaccharide (LPS) administration (intravenous) in guinea pigs, alveolar macrophages are primed for an ex vivo increased secretion of arachidonic acid metabolites from the cyclooxygenase and the lipoxygenase pathways, with challenge by a second stimulus. At the same time, maximal levels of tumor necrosis factor-alpha (TNF-alpha) are observed in the circulation and in the bronchoalveolar lavage fluid. An extracellular form of phospholipase A2, corresponding probably to the low-molecular-mass type II enzyme, known to accumulate in inflammatory exudates, appears later in the serum of guinea pigs, to reach maximal levels 6 h after the LPS. Unlike the intracellular enzyme, extracellular phospholipase A2 is not increased by LPS in alveolar macrophages or in bronchoalveolar lavage fluids. After 24 h, at the time when neither TNF-alpha nor extracellular phospholipase A2 is present and priming of macrophages is over, maximal neutrophil infiltration is observed in the alveolar space of LPS-treated guinea pigs. Dexamethasone administered repeatedly during 3 days (subcutaneous) before the LPS challenge prevented both early events such as the macrophage priming and the TNF-alpha appearance and later events such as extracellular phospholipase A2 release and neutrophil recruitment. Topics: Animals; Anti-Inflammatory Agents; Arachidonic Acid; Bronchoalveolar Lavage Fluid; Dexamethasone; Down-Regulation; Guinea Pigs; Kinetics; Leukotriene C4; Lipopolysaccharides; Lung; Macrophage Activation; Macrophages, Alveolar; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phospholipases A; Phospholipases A2; Shock, Septic; Thromboxane A2; Tumor Necrosis Factor-alpha | 1995 |
Thromboxane-blocked swine as an experimental model of severe intravascular inflammation and septic shock.
The cardiopulmonary response elicited by intravenous bacteria or endotoxin is well characterized in swine and has two major components. The first represents the acute pulmonary and broncho-constrictive phase (0-2 h) and the second phase (3-8 h) represents increased microvascular permeability, hypotension, and enhanced leukocyte-endothelial adhesion. The pulmonary vasoconstriction and bronchoconstriction of phase 1 results in acute pulmonary hypertension and airway dysfunction, which may result in rapid mortality. Because this acute pulmonary response may not mimic the development of human septic shock, we sought to block this early phase and examine the role of tumor necrosis factor in the latter septic phase (3-8 h). Employing a thromboxane A2 (TXA2) receptor antagonist (BAY U 3405) in the presence of LD100 Escherichia coli challenge, we blocked the acute pulmonary hypertensive phase and prevented early mortality, however, TXA2 blockade did not affect the latter development of septic shock and death. This latter lethal phase, characterized by prolonged leukopenia, was blocked in a dose-dependent manner by tumor necrosis factor monoclonal antibody. We conclude that the TXA2-blocked E. coli-challenged swine may provide a novel animal model in which to investigate the pathophysiology of acute septic shock. Topics: Animals; Antibodies, Monoclonal; Bronchoconstriction; Capillary Permeability; Carbazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Escherichia coli; Inflammation; Leukocytes; Leukopenia; Lung; Platelet Aggregation Inhibitors; Pulmonary Circulation; Receptors, Thromboxane; Shock, Septic; Sulfonamides; Swine; Thromboxane A2; Tumor Necrosis Factor-alpha; Vasoconstriction | 1995 |
Efficacy of continuous arteriovenous hemofiltration in endotoxic shock.
We determined the efficacy of continuous arteriovenous hemofiltration (CAVH) in removing tumor necrosis factor (TNF), thromboxane A2, and prostacyclin, and in improving survival in endotoxemia. Twelve rats were given 10 mg/kg of E. coli 0:127:B8 lipopolysaccharide. Fifteen min later, the rats were randomized to ultrafiltered or non-ultrafiltered groups. Blood and ultrafiltrate were collected for TNF, thromboxane B2 (TxB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). After 4 hr, surviving rats were sacrificed. Five of 6 ultrafiltered and none of 6 non-ultrafiltered rats survived 4 hr. Plasma TxB2 > 1,000 pcg/ml and its rate of increase within the first 2 hr predicted death (P < 0.03). Ultrafiltration decreased the rate of rise in TxB2 (P < 0.04). Plasma TxB2 inversely correlated with TxB2 clearance by ultrafiltration. The concentration and rate of increase in TNF and 6-keto-PGF1 alpha did not predict survival. We conclude that CAVH improves short term survival in endotoxemia. Salutary effects appear to be due to thromboxane A2 removal. Topics: Animals; Epoprostenol; Escherichia coli; Hemofiltration; Lipopolysaccharides; Male; Rats; Rats, Sprague-Dawley; Shock, Septic; Survival Rate; Thromboxane A2; Tumor Necrosis Factor-alpha | 1994 |
Streptococcus pneumoniae-induced pulmonary hypertension and systemic hypotension in anesthetized sheep.
Because some patients with Streptococcus pneumoniae bacteremia may present with shock, we reasoned that this organism may produce substances that cause shock. To test this hypothesis, type III pneumococcus supernatant, suspended in 10 ml of sterile water, was infused over 1 min in 8 adult anesthetized sheep. Normal saline was used as a control and had no effect on any of the hemodynamic parameters. Infusion of supernatant resulted in a precipitous fall in cardiac output from a control value of 4.25 +/- 0.54 to 2.80 +/- 0.43 (SE) l/min, a fall in mean systemic arterial pressure from 70 +/- 4 to 49 +/- 8 mmHg, and an increase in the mean pulmonary arterial pressure from 13 +/- 2 to 23 +/- 4 mmHg within 1 min after the infusion was completed. The peak hemodynamic effects were observed at approximately 3 min and returned to normal within 10 min after the infusion was completed. The thromboxane B2 level increased from a control value of 10 +/- 5 to 156 +/- 43 pg/ml at 3 min after the infusion was completed and decreased to 63 +/- 34 pg/ml at 20 min. A second identical dose of pneumococcal supernatant, repeated within 2 h of the first dose, had no effect on hemodynamic variables. Pretreatment with indomethacin, 5 mg/kg body wt, completely blocked the hemodynamic effects of pneumococcal supernatant (n = 3 sheep). Thus, we conclude that S. pneumoniae supernatant contains substances that cause septic shock syndrome through the synthesis of arachidonic acid metabolites and that a sublethal dose of the supernatant causes rapid tachyphylaxis. Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Cardiac Output; Hypertension, Pulmonary; Hypotension; In Vitro Techniques; Muscle Contraction; Muscle, Smooth, Vascular; Pneumococcal Infections; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Sheep; Shock, Septic; Streptococcus pneumoniae; Thromboxane A2; Thromboxane B2 | 1994 |
[Septic shock and multiple organ failure in surgical intensive care. An animal experiment model on the analysis of pulmonary and intestinal dysfunction].
The study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Critical Care; Epoprostenol; Escherichia coli Infections; Hemodynamics; Interleukin-6; Intestinal Mucosa; Intestines; Ion Channels; Ischemia; Lung; Microscopy, Electron; Multiple Organ Failure; Platelet Activating Factor; Postoperative Complications; Potassium; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; Swine; Thromboxane A2; Tumor Necrosis Factor-alpha | 1993 |
Hemodynamic variables and plasma levels of PGI2, TXA2 and IL-6 in a porcine model of recurrent endotoxemia.
The pulmonary and systemic hemodynamic effects of recurrent endotoxemia were studied in pigs over a 48-hr period. Six pigs of the test group were given 0.5 micrograms/kg of an E. coli endotoxin (WO111: B4) over 60 min at the beginning and in the middle (22 hr) of the experiment. Three pigs given the same amount of physiological saline solution served as controls. The hemodynamic response to the first LPS injection was characterized by severe pulmonary hypertension, a significant increase in systemic vascular resistance, and a marked decrease in cardiac output. Circulating TxB2 levels were higher than those of 6-keto-PGF1 alpha levels, so that the first response to LPS is influenced by the vasoconstrictive actions of TxA2. With the second LPS application, the pulmonary response was attenuated, although a significant increase of pulmonary artery pressure and pulmonary vascular resistance occurred. Once again systemic vascular resistance rose and cardiac output decreased, but this time plasma levels of 6-keto-PGF1 alpha were greater than those of TxB2. Toward the end of the experiment, we noted the progressive onset of a hyperdynamic and hypotensive state. Systemic vascular resistant index decreased to 50% of the baseline value. IL-6, a cytokine of systemic importance during the course of septic shock, markedly and significantly peaked after each LPS injection. Circulating plasma levels in response to recurrent endotoxemia are described. Topics: Animals; Disease Models, Animal; Endotoxins; Epoprostenol; Escherichia coli Infections; Hemodynamics; Interleukin-6; Shock, Septic; Swine; Thromboxane A2 | 1991 |
Relationship between PAF-acether and thromboxane A2 biosynthesis in endotoxin-induced intestinal damage in the rat.
PAF-receptor antagonists are known to inhibit gastrointestinal damage induced by endotoxin. In the present study, the interaction between the biosynthesis of PAF and thromboxane (TX) A2, as putative mediators of the acute intestinal damage induced by endotoxin, has been investigated in the anaesthetised rat. Bolus intravenous administration of lipopolysaccharide from E. coli (5-50 mg/kg) induced dose-related jejunal damage, assessed using both macroscopic and histological techniques. This damage was accompanied by significant increases in the jejunal formation of PAF determined by bioassay, and of TXB2, determined by radioimmunoassay. Pretreatment with the structurally-unrelated thromboxane synthase inhibitors, 1-benzyl imidazole (10-50 mg/kg) or OKY 1581 (25 mg/kg) substantially reduced both jejunal damage and TXB2 formation, but did not inhibit PAF formation. Likewise, pretreatment with indomethacin (5 mg/kg) or BW 755C (50 mg/kg) reduced jejunal damage and TXB2 formation but did not affect PAF formation. Pretreatment (2h) with dexamethasone (4 mg/kg) reduced jejunal damage and the formation of both TXB2 and PAF. Intravenous infusion of PAF (100 ng/kg/min for 10 min) induced jejunal damage and significantly increased the formation of TXB2, whereas non-specific jejunal damage induced by oral administration of ethanol did not augment PAF formation. The present findings that inhibition of jejunal thromboxane formation is associated with a substantial reduction in jejunal damage, with no corresponding inhibition in PAF formation, therefore suggests a complex interaction or sequential release of these tissue destructive mediators underlying the intestinal damage induced by endotoxin. Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Escherichia coli; Ethanol; Imidazoles; Indomethacin; Jejunum; Lipopolysaccharides; Male; Methacrylates; Platelet Activating Factor; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase | 1989 |
Effect of dietary linolenic acid on endotoxin-induced thromboxane and prostacyclin production by equine peritoneal macrophages.
In laboratory animals, the incorporation of alpha linolenic acid or other n-3 series fatty acids into the diet results in marked changes in cell membrane composition as well as arachidonic acid metabolism. The purpose of the present study was to determine whether endotoxin-induced thromboxane A2 (TxA2) and/or prostacyclin (PGI2) production by equine peritoneal macrophages was altered by feeding horses a diet containing 8% linseed oil as a source of alpha linolenic acid for 8 weeks. Peritoneal macrophages were cultured in vitro in the presence of endotoxin (LPS) (0.5-500 ng/ml) or calcium ionophore for 6 and 24 hours. After horses were fed the alpha linolenic acid-enriched diet, their peritoneal macrophage production of TxA2 was reduced in response to 0.5 ng/ml and 5 ng/ml LPS. compared to that before the diet (P less than .05). The production of PGI2 during 6 hour incubation with 5 ng/ml and 50 ng/ml LPS and during 24 hour incubation with 5 ng/ml LPS were reduced, compared to that before the diet (P less than .05). Peritoneal macrophage production of PGI2 during 24 hour incubation with nothing, LPS (0.5 ng/ml, 5 ng/ml and 500 ng/ml), and calcium ionophore was greater than during 6 hour incubation, after horses were fed the ALA-rich diet (P less than .05). Results suggest that linseed oil supplementation may be an aid in prophylaxis of endotoxemia in horses. Topics: Animals; Epoprostenol; Escherichia coli Infections; Female; Horses; Linolenic Acids; Macrophages; Male; Peritoneal Cavity; Shock, Septic; Thromboxane A2 | 1989 |
Protective effects of ONO 3708, a new thromboxane A2 receptor antagonist, during experimental endotoxin shock.
The effects of ONO 3708, a new thromboxane A2 (TXA2) receptor antagonist, on platelet aggregation in human plasma, the survival rate of rats subjected to lethal endotoxin shock, and the pathophysiological consequences of endotoxin shock in anesthetized dogs were investigated. ONO 3708 inhibited dose dependently human platelet aggregation induced by 2.5 microM of STA2, analogue of TXA2. Treatment with ONO 3708, 1 mg/100 g i.v., significantly improved the survival rate of rats in endotoxin shock from 38 to 72% at 24 hr and from 27 to 61% at 48 hr. ONO 3708 significantly attenuated endotoxin-induced thrombocytopenia, but not leukopenia. In anesthetized dogs, endotoxin-induced pulmonary hypertension was completely prevented, and increased airway pressure was significantly attenuated by ONO 3708. These results suggest that ONO 3708, the antagonist of TXA2 receptor, has beneficial effects during endotoxin shock, at least in part by inhibiting platelet aggregation. Topics: Animals; Dose-Response Relationship, Drug; Endotoxins; Escherichia coli; Humans; Male; Platelet Aggregation; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2 | 1989 |
[The effects of ONO 3708, a new thromboxane receptor antagonist, on cardiovascular response during the early phases of endotoxin shock in anesthetized dogs].
The effects of ONO 3708, a new thromboxane A2 receptor antagonist, on cardiovascular and airway responses, at an early phase during endotoxin shock were investigated in anesthetized dogs. The i.v. infusion (1mg.kg-1) of E.coli endotoxin caused an increase in mean pulmonary artery pressure (MPAP) from 9.9 +/- 1.0 to 19.1 +/- 2.3 mmHg at 5 min, and at 15 min after infusion, elevated MPAP returned toward the control level. Pretreatment with ONO 3708 abolished these effects of endotoxin on pulmonary artery pressure at an early phase. The change in airway pressure reached a maximum of 14.4 +/- 1.7 cmH2O from 10.0 +/- 1.9 at 5 min, followed by a gradual decline toward a baseline value at 30 min in the control group. ONO 3708 significantly attenuated increase in airway pressure induced by E. coli endotoxin. But pretreatment with ONO 3708 could not prevent decrease in systemic arterial pressure and cardiac output induced by endotoxin. These results suggest that role of thromboxane A2 on the cardiovascular response during endotoxin shock is played only on pulmonary vascular changes, and ONO 3708 has a beneficial effect at least during the early phase of endotoxin shock. Topics: Animals; Dogs; Hemodynamics; Shock, Septic; Thromboxane A2; Time Factors | 1989 |
Cardiopulmonary function as related to thromboxane A2 synthesis in experimental septic shock.
The aim of the present study was to explore the possible involvement of thromboxane A2(TxA2) in the development of cardiopulmonary dysfunction in experimental septic shock. Sepsis was induced in anesthetized cats by intravenous (i.v.) infusion of live Escherichia coli. One series (No. = 12) was pretreated with a specific TxA2 synthetase inhibitor, dazmegrel; another (No. = 8) served as a septic control series. In both series a systemic arterial hypotension developed after 2 hr; no differences in cardiac function were detected. After 2 hr bacteremia cardiac preload was increased by a rapid infusion of dextran. This showed that cardiac function was significantly more preserved in dazmegrel-pretreated cats compared with septic controls. Pretreatment with dazmegrel totally prevented the pulmonary vascular response to bacterial infusion. The pulmonary compliance decreased to 40% in controls but to only 75% in the dazmegrel series, and airway resistance increased to 300% and 140%, respectively. The ventilation-perfusion ratio was less impaired in the pretreated series. Pretreatment with dazmegrel abolished the increase in thromboxane B2 (TxB2), the stable metabolite of TxA2, seen in the untreated series. The rise in 6-keto-prostaglandin F1a (6-keto-PGF1a), the stable metabolite of prostaglandin I2PGI2, was evident in both series. We concluded that TxA2 is important for the impaired cardiac performance in septic shock. Furthermore, TxA2 is involved, but not as the only factor, in the development of pulmonary dysfunction. Topics: Airway Resistance; Animals; Cats; Escherichia coli; Heart; Hemodynamics; Imidazoles; Lung; Lung Compliance; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Ventilation-Perfusion Ratio | 1988 |
Systemic and regional hemodynamic effects of cyclo-oxygenase and thromboxane synthetase inhibition in normal and hyperdynamic endotoxemic rabbits.
We tested the hypothesis that prostaglandins (PGs) and thromboxane (Tx) A2 are important mediators of the hemodynamic derangements occurring in a rabbit model of hyperdynamic endotoxicosis. Rabbits were injected with either normal saline (NS) or Escherichia coli lipopolysaccharide (LPS; 1-3 micrograms/kg) and studied 6 hr later. Cardiac index (CI) and regional blood flow were determined using thermodilution and radioactive microspheres, respectively. Systemic and regional hemodynamics were determined before and 40 min after administering indomethacin (cyclo-oxygenase inhibitor; 5 mg/kg), UK38485 (Tx synthetase inhibitor; 10 mg/kg), or NS. LPS increased CI (P = .0024) and decreased mean arterial pressure (P = .0031) and systemic vascular resistance index (P = .0001). LPS increased flow to the heart and small intestine and decreased flow to the hepatic artery and pancreas. The systemic and regional hemodynamic effects of indomethacin were similar in NS- and LPS-treated rabbits. UK38485 decreased perfusion of skeletal muscle and diaphragm in both endotoxemic and control animals. This agent increased splenic perfusion only in NS-treated rabbits. Plasma levels of 6-keto PGF1 alpha (PGI2 metabolite) were typically undetectable in both NS- and LPS-treated rabbits. These data do not support the hypothesis that PG's or TxA2 are major determinants of the hemodynamic perturbations that occur in this endotoxicosis model. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase Inhibitors; Disease Models, Animal; Endotoxins; Escherichia coli; Hemodynamics; Imidazoles; Indomethacin; Lipopolysaccharides; Male; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase | 1988 |
Selective thromboxane synthetase inhibition by picotamide and effects on endotoxin-induced lethality.
The efficacy of N,N'-bis-(3-picolyl)-methoxyisophthalamide (picotamide) as an in vitro thromboxane synthetase inhibitor and its effect on endotoxin (LPS)-induced lethality in rats were assessed. Picotamide at 0.5 and 1.0 mM concentrations significantly (P less than 0.05) inhibited basal and LPS-stimulated synthesis of TxA2 measured by its stable immunoreactive (i) metabolite TxB2 in rat peritoneal macrophages. This compound did not inhibit synthesis of i6-keto-PGF1 alpha, the stable metabolite of PGI2, and produced significant shunting to i6-keto-PGF1 alpha. For lethality studies rats were pretreated, by gavage with picotamide, at either 75, 150, 300, or 600 mg/kg 2 hr prior to iv S. enteritidis (LPS, 20 mg/kg). Both 150 and 300 mg/kg doses of picotamide significantly (P less than 0.05) improved survival in endotoxin shock at 48 hr. These studies demonstrate that picotamide is a selective thromboxane synthetase inhibitor, and that it may be useful during disease states characterized by increased TxA2 synthesis. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Lipopolysaccharides; Macrophages; Male; Peritoneal Cavity; Phthalic Acids; Rats; Salmonella enteritidis; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase | 1988 |
[Experimental study on the pathophysiology of endotoxin shock as analysed by alterations in thromboxane B2 and 6-keto-PGF1 alpha levels].
To evaluate the pathophysiological role of thromboxane A2 (TXA2) in endotoxin shock, plasma concentrations of TXA2 and PGI2 following E. coli endotoxin (ET) administration were measured in dogs and rats by radioimmunoassay of their stable metabolites TXB2 and 6-keto-PGF1 alpha, respectively. Also, the effects of TXA2 synthetase inhibitor (OKY046) on eicosanoid levels, haemodynamics and survival were assessed. The following results were obtained: 1) Survival rates of the rats given 50 mg/kg of ET were 31% at 12 hrs and 17% at 24 hrs. Pretreatment with OKY046 markedly improved the survival rates. 2) Plasma concentrations of TXB2 were rapidly elevated in untreated control dogs and rats following ET administration, whereas plasma 6-keto-PGF1 alpha levels were gradually elevated. TXB2/6-keto-PGF1 alpha ratio showed an early elevation at 15 minutes after ET administration. The ratio became lower than base line, thereafter. 3) In contrast to the controls, animals pretreated with OKY046 did not exhibit significant elevations in plasma TXB2 levels. On the other hand, plasma levels of 6-keto-PGF1 alpha were not altered by OKY046 treatment. 4) In the control dogs given ET, the early elevations in pulmonary artery pressure (PAP) and reduction in lung compliance correlated with the early elevation in plasma TXB2/6-keto-PGF1 alpha ratio. 5) In OKY046-treated dogs, the early elevation in TXB2/6-keto-PGF1 alpha ratio was not seen and PAP increase and lung compliance reduction were prevented. The results suggest that TXA2 plays an important pathophysiological role in the development of endotoxin shock. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Endotoxins; Escherichia coli; Methacrylates; Rats; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase | 1988 |
Cardiopulmonary changes with intermittent endotoxin administration in sheep.
Chronic sepsis was induced by administering endotoxin (lipopolysaccharide--LPS) at 12-hr intervals to sheep. The animals (n = 7) responded to the first dose of LPS with increased pulmonary arterial pressure (PAP), systemic vascular resistance, plasma and lymph thromboxane B2 (TxB2) concentrations, and lung lymph flow rate concurrent with a reduction in the cardiac index (CI). Subsequent doses of LPS produced an elevation of PAP and TxB2 which was progressively attenuated and eventually disappeared. With LPS the lung lymph flow was markedly elevated and CI increased. This latter was transient and associated with a reduction in systemic vascular resistance. Concomitant with the cardiopulmonary changes prekallikrein levels were not diminished, but there was a statistically significant reduction in C1-esterase inhibitor. The administration of LPS was discontinued after 5 days and the cardiopulmonary variables rapidly returned to baseline levels. Chronic endotoxemia appears to be associated with an elevated pulmonary microvascular permeability and a tendency toward a hyperdynamic circulation but with an appreciable degree of refractoriness associated with regional hemodynamics and eicosanoid biosynthesis. Topics: Animals; Cardiac Output; Chronic Disease; Complement C1 Inactivator Proteins; Disease Models, Animal; Drug Administration Schedule; Endotoxins; Escherichia coli; Heart Rate; Hemodynamics; Hypertension, Pulmonary; Lipopolysaccharides; Lung; Lymph; Prekallikrein; Sheep; Shock, Septic; Thromboxane A2; Time Factors; Vascular Resistance | 1988 |
[The role of thromboxane A2 in shock. II. Bacteremic shock].
Topics: Animals; Disease Models, Animal; Dogs; Escherichia coli; Hemodynamics; Shock, Septic; Thromboxane A2 | 1987 |
The role of prostanoids in the feline intestinal vascular and central haemodynamic responses to i.v. infusion of live E. coli.
Bacterial infusion in the cat, causing experimental septic shock, induces an early vascular response mainly characterized by pulmonary hypertension and intestinal vasoconstriction. Prostanoids are held to be important mediators of the pulmonary vascular reaction. This study was performed to explore the involvement of prostanoids in the central haemodynamics and the small intestinal vascular reactions in experimental septic shock. Aortic blood pressure was continuously monitored, as were aortic blood flow, the pressure in a. pulmonalis and the small intestinal venous outflow. All cats (n = 24) were given live E. coli (10(10) ml-1) as a continuous intravenous infusion. One series was pretreated with indomethacin, another with UK-38,485, a specific thromboxane A2 synthetase inhibitor, and a third series served as untreated control. The pulmonary hypertensive response was clearly attenuated in the two pretreated series, in fact abolished in the one given UK-38,485. The early intestinal vasoconstriction was eliminated in the two pretreated series. Later during bacteraemia, when untreated and indomethacin-pretreated cats showed intestinal vasoconstriction, UK-38-485-pretreated animals kept intestinal blood flow within the preseptic range. These data suggest that in the cat, thromboxane A2 is the prostanoid mediating the vascular reactions, not only in the lung but also in the small intestine. Topics: Animals; Cats; Escherichia coli; Hemodynamics; Imidazoles; Indomethacin; Intestines; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction | 1987 |
Endotoxin-induced hemodynamic and prostaglandin changes in ponies: effects of flunixin meglumine, dexamethasone, and prednisolone.
Shock was induced in four groups of anesthetized ponies with an intravenous injection of Escherichia coli endotoxin [125 micrograms/kg]. Five minutes after endotoxin injection, the ponies were given no treatment (group A), flunixin meglumine (FM:1.1 mg/kg) (group B), dexamethasone (2 mg/kg) (group C), or prednisolone (10 mg/kg) (group D). Additionally, FM was given every 3 hours, and the steroids were given at 3, 9, and 24 hours following endotoxin. Hemodynamic measurements were made during the 4-hour anesthetic period. Blood samples were collected for the analysis of prostaglandins, blood chemicals, and enzymes until death. Microspheres labeled with one of four radionuclides were used to determine regional blood flow at 0, 0.1, 1, and 2 hours after endotoxin was given. Plasma levels of both thromboxane and prostaglandin I2 increased from less than 1 ng/ml to between 3 and 5 ng/ml following the injection of endotoxin. The elevated thromboxane corresponded with high pulmonary arterial pressure [between 35 and 55 mm Hg] and low mean systemic arterial pressure (between 40 and 65 mm Hg) during the first 5-10 minutes following endotoxin. Increased concentrations of prostaglandin I2 were temporally related to systemic arterial hypotension, which occurred 1-2 hours following endotoxin in all groups except group B. The rise of prostaglandin I2 and hypotension were not observed in the flunixin meglumine-treated ponies. Dexamethasone was less effective, and prednisolone was ineffective in preventing the synthesis of prostaglandin I2 and the accompanying hemodynamic changes that occurred during the first 2 hours following endotoxin. This is probably due to the fact that steroids require a longer period of time before prostaglandin synthesis is reduced. Although not statistically significant, increased survival trends were observed in ponies treated with flunixin meglumine. Topics: Animals; Clonixin; Dexamethasone; Endotoxins; Epoprostenol; Escherichia coli; Female; Hemodynamics; Horses; Male; Nicotinic Acids; Prednisolone; Shock, Septic; Thromboxane A2 | 1987 |
Profiles of endogenous prostaglandin F2 alpha, thromboxane A2 and prostacyclin with regard to cardiovascular and organ functions in early septic shock in man.
15 out of 68 patients with severe sepsis were examined in an early stage of shock and analyzed for objective hemodynamic and functional shock criteria. These data were correlated to endogenous plasma concentrations of the vasoactive arachidonate derivatives: prostaglandin F2 alpha (PGF2 alpha), thromboxane A2 (TXA2) and prostacyclin (PGI2). Marked differences in invasively measured data of cardiac, pulmonary and renal functions divided clinically otherwise comparable patients into group I and II. Group I was characterized by a hypodynamic response as compared to group II which was hyperdynamic. In spite of similar levels of PGF2 alpha (570 +/- 80 vs. 560 +/- 103 pg/ml) in both groups indicating a comparable state of arachidonate turnover, opposing profiles with regard to the TXA2/PGI2 ratio as measured from their stable degradation products were found (TXB2 [I]: a 740 +/- 184; TXB2 [II]: 280 +/- 75; 6-k-PGF1 alpha [I]: 260 +/- 117; 6-k-PGF1 alpha [II]: 940 +/- 190 pg/ml). It is concluded that early sepsis in man leads to variable profiles of endogenously released prostaglandins and thromboxane in which the predominance of PGI2 over TXA2 is associated with better cardiovascular performance and organ functions, and vice versa. Topics: Adolescent; Adult; Aged; Creatinine; Dinoprost; Epoprostenol; Female; Hemodynamics; Humans; Kidney; Lung; Male; Middle Aged; Multiple Organ Failure; Prostaglandins F; Retrospective Studies; Shock, Septic; Thromboxane A2 | 1987 |
Thromboxane A2 mediates hemodynamic and respiratory dysfunction in graded bacteremia.
Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis. Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aeromonas; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Cardiac Output; Epoprostenol; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Hypoxia; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Sepsis; Shock, Septic; Swine; Thromboxane A2; Thromboxane B2 | 1986 |
Prostacyclin and thromboxane A2 in septic shock: species differences.
Prostacyclin and thromboxane A2 have been implicated as mediators of septic shock. Correlations between the human prostanoid response to sepsis and experimental paradigms are poorly understood. The purpose of this study was to compare changes in plasma levels of prostaglandin 6-keto-F1 alpha (PGI) and thromboxane B2 (TxB) during septic shock in Sprague-Dawley rats, domestic pigs, mongrel dogs, and man. Severe sepsis followed by septic shock (systolic BP less than 90 mmHg) was induced in rats by inoculation of 1.0 X 10(9) Aeromonas hydrophila, in pigs by graded IV infusion of 1.0 X 10(9)/ml A. hydrophila; and in dogs by an IV bolus injection of 5.0 X 10(9)/ml Escherichia coli. Plasma PGI and TxB (pg/ml) were measured by radioimmunoassay in control, septic, and septic shock experimental blood samples, and in normal controls, severly septic, and septic shock (systolic BP less than 90 mmHg) S.I.C.U. patients. Control, septic, and septic shock TxB levels in the dog and the pig were significantly greater than in the rat and man. PGI levels in the dog were significantly greater than in other species. TxB increased significantly in murine sepsis and PGI increased significantly in sepsis and septic shock. TxB increased during porcine sepsis and septic shock. In man, both PGI and TxB were significantly increased in severe sepsis, compared to normal controls, but only PGI was significantly higher in septic shock versus normotensive sepsis. Patterns of change in TxB/PGI ratios were similar for all species studied. Changes in PGI in the porcine septic experiments most closely paralleled those observed clinically. Topics: Animals; Dogs; Epoprostenol; Female; Humans; Male; Rats; Rats, Inbred Strains; Shock, Septic; Species Specificity; Swine; Thromboxane A2 | 1986 |
[The role of thromboxane A2 in shock. I. Endotoxic shock].
Topics: Animals; Blood Pressure; Dogs; Methacrylates; Respiratory System; Shock, Septic; Thromboxane A2 | 1986 |
AH23848: a thromboxane receptor-blocking drug that can clarify the pathophysiologic role of thromboxane A2.
Despite numerous suggestions in the literature that thromboxane A2 is involved in a variety of occlusive vascular diseases, no definitive evidence is available. Arguments have been presented to support the view that such evidence can only come from clinical studies with a highly specific thromboxane receptor-blocking drug. We have now identified such a drug, AH23848, in our laboratories. Preliminary experiments with AH23848, ([1 alpha (Z), 2 beta,5 alpha]-(+/-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholin yl)-3-oxocyclopentyl]-4-heptenoic acid), show that it is a potent, specific thromboxane receptor-blocking drug that is orally active and has a long duration of action. It should be a valuable tool in elucidating any physiologic or pathologic role of thromboxane A2. Topics: Angina Pectoris; Animals; Biphenyl Compounds; Collagen; Dogs; Dose-Response Relationship, Drug; Guinea Pigs; Humans; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Platelet Aggregation; Rats; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase; Vasoconstriction | 1985 |
Prostanoid production by lipopolysaccharide-stimulated Kupffer cells.
Although some data suggest that macrophages in the reticuloendothelial system (RES) are important sources of thromboxane A2 (TxA2) and prostacyclin (PGI2) during endotoxic shock, we are unaware of data documenting the ability of hepatic macrophages (Kupffer cells) to release either TxA2 or PGI2 when exposed to lipopolysaccharide (endotoxin, LPS). In this study, Kupffer cells were examined for their ability to release prostaglandin E2 (PGE2), TxA2, and PGI2 following stimulation with 0, 1.0, 50.0, and 100.0 micrograms/ml of Escherichia coli LPS. Kupffer cells were obtained from rat livers by enzymatic digestion with 0.05% collagenase followed by enrichment of the macrophage population on the basis of differences in density and adherence among the various cell populations isolated. Based on several criteria (phagocytosis of opsonized sheep erythrocytes, positive staining for esterase and peroxidase, failure to replicate), 95% of adherent cells were Kupffer cells. After 4 days of incubation, cells were stimulated with various doses of LPS for 4 and 8 hr. Prostanoid concentrations in culture supernatants were determined by radioimmunoassay. Increasing doses of LPS significantly (P less than 0.001) increased the concentration of immunoreactive PGE2 (iPGE2) and iTxB2 (the stable metabolite of TxA2). The concentration of i6-keto-PFG1 alpha (stable metabolite of PGI2) increased following stimulation with 1.0 microgram/ml of LPS, but declined as the dose of LPS was increased. The results provide evidence that endotoxin-activated Kupffer cells, like other macrophage populations, release several metabolites of arachidonic acid. Kupffer cell-derived prostanoids, particularly TxA2, may be important mediators of some of the pathophysiologic manifestations of acute endotoxemia. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Escherichia coli; Kupffer Cells; Male; Polysaccharides, Bacterial; Prostaglandins E; Radioimmunoassay; Rats; Rats, Inbred Strains; Shock, Septic; Stimulation, Chemical; Thromboxane A2; Thromboxane B2; Thromboxanes | 1985 |
[Effect of PSK on prostaglandin metabolism (I)].
The effect of PSK (Krestin) on the metabolism of prostaglandins was investigated. The effect of PSK on the thromboxane A2 (TXA2) level, which stimulates tumor proliferation and platelet aggregation, was examined using platelets. PSK suppressed platelet aggregation and the production of malondialdehyde (MDA) and TXB2 which is a stable metabolite of TXA2. The effect of PSK on the production of prostacyclin (PGI2), which is an anti-tumor PG, was then examined using rat arterial rings. It was found that PGI2 production was stimulated by PSK. The in vivo inhibition of platelet activation by PSK was then examined using two thrombosis models in which platelet aggregation was mainly involved. PSK exerted its anti-platelet effect by regulation of PG production. It was concluded that not only an immune regulating effect but also PG regulation are involved in the pharmacological action of PSK. Topics: Animals; Epoprostenol; Humans; In Vitro Techniques; Male; Malondialdehyde; Mice; Platelet Aggregation; Prostaglandins; Proteoglycans; Pulmonary Embolism; Rabbits; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane A2; Thromboxane B2 | 1985 |
[Arachidonic acid metabolites and shock].
The pathogenesis of shock is discussed on the basis of important results from world literature under the special point of view of the significance of eicosanoids. It results from a lower mortality of shock animals with a diet poor in polyunsaturated fatty acids and a specifically increased release of arachidonic acid as prostaglandin precursor in shock animals. Of particular importance is an increased formation of thromboxane B2 (TXB2). It this formation is specifically inhibited, the survival rate increases, the decrease of blood pressure is reduced, also the increase of the plasma-cathepsin-D-activity and of the myocardial depressant factor and the increased formation of microthrombi in renal glomeruli of shock animals. Also in patients who survived the shock the TXB2-values were only 1/10 of the values in decreased shock patients. Another therapeutic way is the infusion of prostacyclin which leads to a specific increase of the arterial blood supply of the liver and the superior mesenteric artery and also increases the ATP and creatine phosphate level. The importance of the findings of animal experiments for the pathogenesis and therapy in patients is discussed. Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cathepsin D; Dogs; Fatty Acids, Unsaturated; Humans; Lipoxygenase; Prognosis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Shock; Shock, Hemorrhagic; Shock, Septic; Thromboxane A2; Thromboxane B2 | 1985 |
The role of prostacyclin and thromboxane in sepsis and septic shock.
Prostacyclin, or prostaglandin I2 (PGI2), and thromboxane A2 (TXA2) are potent, endogenously produced, vasoactive substances that have been implicated as mediators in the pathophysiologic nature of septic shock. We investigated the contribution and production of PGI2 and TXA2 in sepsis and septic shock, using an intact rabbit model and an in vitro rabbit isolated cardiac perfusion model. Continuous hemodynamic monitoring of both experimental models, along with serial radioimmunoassays of the metabolites of PGI2 and TXA2, indicated that myocardial depression is a common finding in subjects with septic shock and that septic shock causes a suppression of PGI2 production while augmenting TXA2 production. In addition, PGI2 and TXA2 were mediators of some cardiovascular changes in septic shock but were themselves not the toxic factor(s) responsible for the associated myocardial depression. Topics: Animals; Bacterial Infections; Disease Models, Animal; Epoprostenol; Heart; Hemodynamics; Humans; Hypotension; Myocardial Contraction; Rabbits; Shock, Septic; Thromboxane A2; Thromboxanes | 1984 |
Endotoxic shock in the piglet: beneficial effects of prostaglandin synthesis inhibition.
In anesthetized piglets the intravenous injection of a lethal dose of endotoxin, 0.5 mg/kg, resulted in a progressively evolving deterioration of the cardiovascular system (hypotension, decrease in cardiac output), in an increase in pulmonary vascular resistance and in the death of all animals within 210 min following endotoxin administration. Endotoxin induced a significant increase in immunoreactive (i) i-6-oxo-PGF1 alpha, i-TXB2, and i-15-oxo-13,14-dihydro-PGF2 alpha levels in peripheral plasma. Pretreatment with the PG-synthesis inhibitor, flurbiprofen, abolished the profound rise in PG-levels, whereas cardiovascular performance was more sustained. The results suggest the involvement of several prostanoids during the evolution of endotoxic shock in the piglet. Topics: Animals; Dinoprost; Epoprostenol; Female; Flurbiprofen; Hemodynamics; Propionates; Prostaglandin Antagonists; Prostaglandins; Prostaglandins F; Shock, Septic; Swine; Thromboxane A2; Vascular Resistance | 1984 |
Inhibition of prostaglandin synthesis restores normal hemodynamics in canine hyperdynamic sepsis.
This study investigates the role of prostaglandins (PG) in hyperdynamic sepsis. Thirteen chronically instrumented dogs were rendered septic by implanting in the peritoneal cavity a fibrin clot containing viable Escherichia coli. One day later, cardiac output (CO) increased from 2.80 +/- 0.22 to 3.72 +/- 0.32 l/min (p = 0.011); heart rate (HR) increased from 122 +/- 8 to 147 +/- 6 beats/min (p = 0.005); mean pulmonary artery pressure (PAP) increased from 15 +/- 1 to 19 +/- 1 mmHg (p = 0.003); mean systemic arterial pressure (MAP) decreased from 120 +/- 5 to 107 +/- 7 mmHg; and systemic vascular resistance (SVR) decreased from 44.1 +/- 2.6 to 29.3 +/- 1.9 mmHg/l/min (p less than 0.001). Sixty minutes after intravenous injection of indomethacin (2 mg/kg) or ibuprofen (25 mg/kg), CO decreased to 2.60 +/- 0.21 l/min (p less than 0.001); HR decreased to 118 +/- 5 beats/min (p less than 0.001); PAP decreased to 17 +/- 1 mmHg (p = 0.021); and SVR increased to 43.7 mmHg/l/min (p less than 0.001). In seven control dogs, laparotomy alone did not significantly affect any of these parameters. Infusion of indomethacin caused a slight increase in MAP (106 +/- 4 to 116 +/- 4 mmHg, p = 0.035) but otherwise did not alter hemodynamics. It is concluded that administration of indomethacin or ibuprofen restores normal hemodynamics in a canine model of high-output sepsis, probably by inhibiting PG synthesis. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Dogs; Escherichia coli Infections; Female; Hemodynamics; Ibuprofen; Indomethacin; Male; Oxygen Consumption; Peritonitis; Prostaglandin Antagonists; Prostaglandins; Sepsis; Shock, Septic; Thromboxane A2 | 1984 |
Treatment of experimental canine endotoxin shock with ibuprofen, a cyclooxygenase inhibitor.
The arachidonic acid derivative thromboxane A2, a very potent platelet aggregator, is increased in endotoxin shock. Ibuprofen blocks the formation of thromboxane A2 and has antiplatelet and antileukocyte aggregability properties. The effects of ibuprofen on pulmonary platelet trapping, platelet and leukocyte counts, platelet aggregability, hematocrit, and blood pressure were evaluated in endotoxin-shocked dogs. The initial decrease in blood pressure and in leukocyte and platelet counts seen in endotoxin shock was not altered by ibuprofen treatment. At 2 h the ibuprofen-treated dogs had less hypotension compared to endotoxin control. Platelet counts were also higher in the ibuprofen-treated dogs at 2 h. Significant recovery of leukocytes was seen only when pretreatment was used. Pulmonary platelet trapping was significantly lower in the ibuprofen-treated dogs compared to endotoxin controls and not significantly different from the sham dogs when ibuprofen was given before endotoxin injection. This study demonstrates the efficacy of ibuprofen not only in reducing pulmonary platelet trapping but also in obviating the late hypotension in experimental endotoxin shock. Topics: Animals; Blood Pressure; Dogs; Female; Hematocrit; Hypotension; Ibuprofen; Leukocyte Count; Lung; Male; Platelet Aggregation; Platelet Count; Shock, Septic; Thromboxane A2; Time Factors | 1984 |
Role of prostaglandins, histamine, and serotonin in the pathophysiology induced by Pasteurella hemolytica endotoxin in sheep.
Pasteurella hemolytica endotoxin (12 micrograms/kg) was infused intravenously into ewes over 500 min. Blood was sampled for 60 min before the infusion and at intervals during the infusion and for 1500 min postinfusion. The control values for plasma TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin were 283 +/- 53 pg/ml (mean +/- standard error of mean), 281 +/- 14 pg/ml, 199 +/- 27 pg/ml, and 56.8 +/- 2.0 ng/ml, respectively. The plasma concentrations of TxB2, 6-keto-PGF1 alpha, PGF2 alpha, and serotonin significantly increased to a maximum at 50 min of infusion to 359%, 344%, 313%, and 201% of the control, respectively. PGF2 alpha and TxB2 returned to control levels at 300 min during infusion and 6-keto-PGF1 alpha at 60 min postinfusion and serotonin at 100 min of infusion. Serotonin concentration decreased significantly at 450 min of infusion to 73% of control and returned to control level at 1500 min postinfusion. No significant changes were found in the plasma levels of PGE, histamine, and ACE activity. We conclude that release of TxA2, PGI2, PGF2 alpha, and serotonin may contribute to pathophysiology induced by P. hemolytica endotoxin in sheep. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Endotoxins; Female; Histamine; Pasteurella; Prostaglandins; Prostaglandins F; Serotonin; Sheep; Shock, Septic; Thromboxane A2; Thromboxane B2; Time Factors | 1984 |
Gentamicin and indomethacin in the treatment of septic shock: effects on prostacyclin and thromboxane A2 production.
We investigated the effects of the thromboxane synthetase inhibitor 7-(1-imidazolyl)heptanoic acid (7-IHA) and the fatty acid cyclooxygenase inhibitors indomethacin or ibuprofen in the treatment of fecal peritonitis in the rat. The effects of gentamicin alone and in combination with reduction of arachidonic acid metabolism by either treatment with indomethacin or essential fatty acid deficiency was also investigated. 7-IHA (60 mg/kg), administered i.p. 30 min before i.p. instillation of a fecal suspension, significantly reduced the plasma levels of immunoreactive (i) TxB2 from 1066 +/- 194 pg/ml (N = 14) to nondetectable (less than 200 pg/ml; N = 9) (P less than .01) at 1 hr and from 1695 +/- 218 (N = 16) to 508 +/- 56 pg/ml (N = 6) (P less than .01) at 4 hr after instillation of feces. In contrast, the levels of i6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of prostacyclin, were significantly elevated by 7-IHA pretreatment from vehicle-treated septic control levels of 3777 +/- 414 (N = 16) to 5185 +/- 467 pg/ml (N = 9) (P less than .05) at 1 hr. Plasma i6-keto-PGF1 alpha at 4 hr in 7-IHA-treated rats (5503 +/- 665 pg/ml) (N = 6) was not different from vehicle-treated controls. Survival associated with fecal peritonitis was not altered by 7-IHA pretreatment. Indomethacin (10 mg/kg) or ibuprofen (5 mg/kg) administered i.p. 30 min before the fecal suspension significantly decreased both iTxB2 and i6-keto-PGF1 alpha, plasma levels when measured at 4 hr and prolonged survival time (P less than .05). Fibrinogen/fibrin degradation products were elevated (P less than .01) during fecal peritonitis and were reduced by indomethacin (P less than .01) or 7-IHA (P less than .05). Gentamicin significantly increased mean survival time from 8.6 +/- 0.2 (N = 50) to 23.8 +/- 2.6 hr (N = 16) (P less than .01). Gentamicin in combination with indomethacin or essential fatty acid deficiency further improved mean survival time and resulted in long-term survivals (greater than 48 hr) of 35 (N = 17) and 30% (N = 7), respectively (P less than .01 compared with gentamicin). Gentamicin pretreatment did not significantly alter plasma iTxB2 levels, but decreased i6-keto-PGF1 alpha from 9465 +/- 792 (N = 7) to 3096 +/- 1,174 pg/ml (N = 5; P less than .01) at 6 hr after induction of fecal peritonitis. These studies raise the possibility that inhibition of fatty acid cyclooxygenase may be a useful adjunct to antibiotic therapy in the treatment of septic shock. Topics: Animals; Epoprostenol; Fatty Acids, Essential; Female; Fibrin Fibrinogen Degradation Products; Gentamicins; Ibuprofen; Imidazoles; Indomethacin; Macrophages; Male; Peritonitis; Prostaglandins; Prostaglandins F; Rats; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes | 1983 |
Protective effects of thromboxane A2 synthetase inhibitors on endotoxin shock.
To elucidate the role of thromboxane A2 in the development of endotoxin shock following administration of endotoxin, the effects of three thromboxane A2 synthetase inhibitors, (E)-3-(4-(1-imidazolyl)phenyl)-2-propenoic acid hydrochloride monohydrate (OKY-046), sodium (E)-3-(4-(3-pyridylmethyl)phenyl)-2-methylacrylate (OKY-1581) and imidazole were examined. Intravenous administration of E. Coli endotoxin (3 mg/kg) produced shock and all rats died within ten hours. Pretreatment with thromboxane A2 synthetase inhibitors markedly improved the survival rates. The untreated endotoxin shock group showed marked increase in thromboxane B2 levels in the venous blood, while no such changes were seen in the pretreated groups. There were no statistically significant differences in 6-keto prostaglandin F1 alpha levels in the venous blood. In the untreated shock group, microthrombi were observed in 64% of the glomeruli in the kidneys two hours after endotoxin injection. In the groups pretreated with OKY-046, OKY-1581 and imidazole, microthrombi were seen only in 22, 19 and 24%, respectively. Thus, thromboxane A2 plays an important role in the development of endotoxin shock and thromboxane A2 synthetase inhibitors, in particular OKY-046 and -1581, are prophylactic. Topics: Animals; Fibrinogen; Glucuronidase; Kidney; Male; Methacrylates; Oxidoreductases; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thrombosis; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes | 1983 |
Thromboxane A2 and hemodynamic-biochemical parameters in canine endotoxin shock.
Prostaglandins participate in the pathophysiology of endotoxin shock; however, their exact role has not yet been clear. In this study, we investigated the role of the proaggregatory vasoconstrictor, thromboxane A2 (TXA2), an arachidonic acid metabolite, during canine endotoxin shock. The central venous plasma levels of thromboxane B2 (TXB2), the stable metabolite of TXA2, was measured by radioimmunoassay. We also investigated the therapeutic effect of reduced glutathione (GSH), a potential cell-stabilizing sulfhydryl compound, in canine endotoxin shock. Sixty minutes after the intravenous administration of E. coli endotoxin (1 mg/kg), the plasma TXB2 levels were significantly increased from 68.8 +/- 49.0 pg/ml to 318.3 +/- 117.2 pg/ml (N = 5) in the control group and from 67.9 +/- 68,4 pg/ml to 222.6 +/- 133.2 pg/ml (N = 5) in the GSH (300 mg/kg/hr) group. The levels in the GSH group were somewhat lower than in the control group for 60 to 180 minutes after the injection of endotoxin. Thromboxane A2 value appear not to relate to early thrombocytopenia and pulmonary hypertension but to relate to the change of late coagulopathy and of pulmonary vascular resistance. The administration of GSH suppressed the lactic acidemia significantly, however there was a much more decrease in the mean arterial pressure in the GSH group than in the control group. In addition, there was a tendency to inhibit the increase of the serum beta-glucuronidase activity in the GSH group. Topics: Animals; Blood Pressure; Dogs; Glucuronidase; Glutathione; Heart Rate; Lactates; Lactic Acid; Radioimmunoassay; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes; Vascular Resistance | 1983 |
Plasma thromboxane concentrations are raised in patients dying with septic shock.
Central venous plasma concentrations of thromboxane B2 (TXB2) the stable metabolite of the vasoconstrictor platelet aggregator thromboxane A2, were measured in 12 patients with septic shock. In 8 patients dying with septic shock the concentration of plasma TXB2 (912 +/- 250 pg/ml) was ten times higher than that in 4 survivors of septic shock (92 +/- 25 pg/ml) and 6 controls (91 +/- 18 pg/ml). Prothrombin time and partial thromboplastin time were significantly prolonged in nonsurvivors compared with survivors. Similarly, the alveolar-arterial oxygen gradient was significantly raised in nonsurvivors (233 +/- 39 mm Hg) compared with survivors (112 +/- 47 mm Hg). This study demonstrates that the metabolism of arachidonic acid to thromboxanes is increased in patients dying of septic shock and this raises the possibility that thromboxanes may be involved in the disseminated intravascular coagulation and respiratory distress syndrome associated with severe sepsis. Topics: Arachidonic Acids; Hemodynamics; Humans; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes | 1982 |
Association of prostacyclin production with resistance of C3H/HeJ mice to endotoxin shock.
Persistence of inflammatory cells in the microcirculation due to altered proportions of arachidonate metabolites could contribute to death from endotoxin (ET) shock. We tested this hypothesis by observing ET-induced cellular accumulations in capillaries of genetically resistant C3H/HeJ and sensitive C3HeB/FeJ mice after challenge with 1,000 micrograms of Salmonella typhi ET, a dose lethal only for the sensitive strain. These data were correlated with prostaglandin production by lung tissue. Six hours after challenge with ET, lung capillaries of sensitive animals were occluded with amorphous material and occasional polymorphonuclear leukocytes (PMNL). This inflammation, along with reduction in alveolar volume, was not observed in resistant mice. At this time only 10 PMNL/high-power field were seen with light microscopy in capillaries of resistant mice compared to 60 PMNL/high-power field in sensitive animals. Lung parenchymal tissue was excised from resistant and sensitive (C3H/HeN) mice six hours postchallenge with 800 micrograms of endotoxin and release in vitro of thromboxane A2 (TXA2) or prostacyclin (PGI2) over a 30-minute period was determined by radioimmunoassay. TXA2 and PGI2 released by lung fragments taken six hours after challenge with ET did not differ from normal levels of these substances in C3H/HeN mice. TXA2 release was normal at six hours in C3H/HeJ mice, but PGI2 was significantly increased (from 2.95 ng/mg to 5.73 ng/mg, P less than 0.005). The ratio of PGI2/TXA2 in resistant mice was 24.3 as compared to 10.3 in sensitive mice. Since PGI2 can reduce leukocyte adhesion, an increase in the ratio of this substance to TXA2 may be associated with resolution of PMNL from the pulmonary microcirculation of ET-resistant mice. Topics: Animals; Endotoxins; Epoprostenol; Lung; Mice; Mice, Inbred C3H; Mice, Inbred Strains; Neutrophils; Prostaglandins; Shock, Septic; Thromboxane A2 | 1982 |
Thromboxane and prostacyclin production during septic shock.
We investigated a rat fecal peritonitis model of acute intraabdominal sepsis in order to evaluate the potential role of arachidonic acid metabolites in septic shock. Immunoreactive TxB2, the stable metabolite of thromboxane A2, and i6-keto-PGF1 alpha, the stable metabolite of prostacyclin, were measured by radioimmunoassay. Plasma levels of iTxB2 rapidly increased from nondetectable (ND less than 200 pg/ml) to 1,052 +/- 208 pg/ml, one hour after feces injection. iTxB2 then increased to 1,681 +/- 248 pg/ml at four hours and remained unchanged through six hours. Plasma i6-keto-PGF1 alpha increased from ND to 3,848 +/- 489 pg/ml a one hour. Four hours after feces, i6-keto-PGF1 alpha levels rose to 7, 450 +/- 933 pg/ml then continued to rise to 9,465 +/- 792 pg/ml at six hours. Either essential fatty acid deficiency (arachidonic acid depletion) or indomethacin treatment (cyclo-oxygenase inhibition) significantly decreased (P less than 0.01) the elevation of plasma iTxB2 and i6-keto-PGF1 alpha associated with fecal peritonitis. Thrombocytopenia occurred within six hours after injection of feces and was significantly improved (P less than 0.05) by indomethacin. Elevated fibrin degradation products at six hours (18 +/- 3 micrograms/ml) were significantly reduced in essential fatty acid-deficient (7 +/- 2 micrograms/ml; P less than 0.05) and indomethacin-treated (4 +/- 0.7 micrograms/ml; P less than 0.01) rats. Survival time (8.6 +/- 0.2 hours) was significantly enhanced by essential fatty acid-deficiency (10.2 +/- 0.4 hours; P less than 0.01) or indomethacin treatment (13.3 +/- 0.6 hours; P less than 0.01). These studies show that fecal peritonitis is associated with increased synthesis of thromboxane A2 and prostacyclin and suggest that these arachidonic acid metabolites may play a role in the pathophysiology of septic shock. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Fatty Acids, Essential; Female; Fibrin Fibrinogen Degradation Products; Indomethacin; Peritonitis; Prostaglandins; Rats; Rats, Inbred Strains; Shock, Septic; Thrombocytopenia; Thromboxane A2; Thromboxanes; Time Factors | 1982 |
[Experimental investigation on the pathogenesis of endotoxin shock--the change of plasma serotonin, histamine, thromboxane B2 and 6-keto PGF1 alpha levels and modulation by indomethacin (author's transl)].
Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Histamine; Indomethacin; Serotonin; Shock, Septic; Thromboxane A2; Thromboxanes | 1982 |
Thromboxane, prostaglandin I2 (epoprostenol), and the hemodynamic changes in equine endotoxin shock.
This study had 2 objectives: (i) to correlate plasma thromboxane and prostaglandin I2 (epoprostenol) concentrations with hemodynamic changes occurring in equine endotoxin shock, and (ii) to determine the effects of flunixin meglumine on plasma concentrations of these prostaglandins relative to hemodynamic changes. Shock was induced in 2 groups, each of 4 anesthetized ponies, and in a 3rd group of 2 ponies. Group A ponies were given endotoxin only (and were not treated), and group B ponies were given endotoxin and then treated with flunixin meglumine. Group C ponies were treated with flunixin meglumine 5 minutes before they were fiven endotoxin. Arterial, pulmonary arterial, and central venous pressures were measured and blood samples were collected at 0, 0.1, 0.25, 0.5, 1, 1, 3, and 4 hours after ponies were given the endotoxin. The plasma thromboxane and prostaglandin I2 concentrations were increased in equine endotoxic shock. Increased thromboxane concentration was associated with the high pulmonary arterial and central venous pressures and low arterial blood pressure in the minutes immediately after the ponies were given endotoxin. The increased prostaglandin I2 concentration was associated with systemic hypotension at 1 to 2 hours after endotoxin. Treatment of ponies with flunixin meglumine after endotoxin was given (group B) prevented the prostaglandin I2 rise and the associated hypotension. Treatment with fluixin meglumine before endotoxin was given prevented the increase of the plasma thromboxane and prostaglandin I2 values, along with the associated hemodynamic changes. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clonixin; Epoprostenol; Escherichia coli; Female; Hemodynamics; Horse Diseases; Horses; Male; Primates; Prostaglandin Antagonists; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes | 1982 |
Implications for thromboxane A2 in the pathogenesis of endotoxic shock.
During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock. Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Ibuprofen; Indomethacin; Male; Muridae; Prostaglandins E; Prostaglandins F; Shock, Septic; Thromboxane A2; Thromboxanes | 1981 |
Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep.
Prostaglandins F2 alpha, E2, and I2 (as 6-keto-PGF1 alpha) and TxA2 (as TxB2) were measured by radioimmunoassay in plasma and lymph from 12 conscious sheep with chronic lung lymph fistulas given Escherichia coli endotoxin (2-10 micrograms/kg) and followed for 24 h. Endotoxin produced a two-phase pulmonary injury. Phase 1 was characterized by transient severe pulmonary hypertension and increased lymph flow rate (QL). Plasma and lymph PGF2 alpha concentrations increased from base-line values of 0.13 +/- 0.08 and 0.30 +/- 0.10 ng/ml to 0.96 +/- 0.37 and 2.8 +/- 0.80 ng/ml, respectively. Values for TxB2 increased from 0.7 +/- 0.1 to 5.5 +/- 1.1 ng/ml in lymph and to 3.2 +/- 0.6 in plasma. Plasma PGI2 increased from 0.48 +/- 0.29 to 4.97 +/- 1.21 ng/ml and lymph PGI2 from 1.80 +/- 0.73 to 14.19 +/- 2.79 ng/ml. Phase 2 was characterized by moderately elevated pulmonary vascular pressures and a maintained high flow rate of protein-rich lymph. Lung lymph and plasma PGF2 alpha concentrations returned to base line. Lymph PGI2 decreased significantly to 5.23 +/- 2.47 ng/ml, whereas plasma PGI2 decreased to 2.70 +/- 1.07 ng/ml. We conclude that prostaglandins, particularly PGF2 alpha and prostacyclin, are released from the lung after endotoxemia and appear in lung lymph as sensitive indicators of pulmonary microvascular injury. Prostanoid production appears to temporally correspond with changes in the pulmonary microcirculation. Topics: Animals; Capillary Permeability; Epoprostenol; Lung; Lymph; Prostaglandins; Prostaglandins F; Sheep; Shock, Septic; Thromboxane A2 | 1981 |
Sensitization of essential fatty acid-deficient rats to endotoxin by arachidonate pretreatment: role of thromboxane A2.
Topics: Animals; Arachidonic Acids; Endotoxins; Fatty Acids, Essential; Fibrin Fibrinogen Degradation Products; Platelet Count; Rats; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes | 1981 |
Platelet thromboxane production during endotoxin shock.
Circulating thromboxane (TX) is elevated following endotoxin, and platelets become hyperaggregable. Thromboxane synthesis was therefore studied in platelets during endotoxemia. Rabbit blood and platelets were taken at 0, 60 and 120 min after start of E. coli endotoxin infusion (1.10 microgram/kg min, i.v.). Blood incubation with arachidonic acid (AA, 10(-4) M) generated TXA2, which was measured using a superfused rabbit aorta bioassay. Washed platelets were stimulated with 1-14C AA (0.1 microCi) to generate radiolabeled TXB2, which was isolated by TLC and quantitated by scintillation spectrometry. Control (0 time) platelet count was 488 +/- 10(3)/mm3. In the test group, platelet counts fell to 65% of control at 60 min and to 52% at 120 min, while TXA2 generation was 95% (60 min) and 94% (120 min) of control. In contrast a serial dilution of untreated platelets yielded a progressive decline in thromboxane generation. In endotoxemic platelets, the conversion of 1-14C AA to TXB2 (percent/10(9) platelets) was increased at 120 min (0 min, 34.7; 120 min, 40.0: P less than 0.05). Endotoxemic platelets generated greater amounts of thromboxane than did normal platelets, and this condition may account for platelet hyperaggregability in shock. Topics: Animals; Blood Platelets; Male; Platelet Count; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes; Time Factors | 1981 |
Elevated thromboxane levels in the rat during endotoxic shock: protective effects of imidazole, 13-azaprostanoic acid, or essential fatty acid deficiency.
The potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A(2), in endotoxic shock was investigated in rats. Plasma thromboxane A(2) was determined by radioimmunoassay of its stable metabolite thromboxane B(2). After intravenous administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma thromboxane B(2) levels increased from nondetectable levels (<375 pg/ml) in normal control rats to 2,054+/-524 pg/ml (n = 8), within 30 min to 2,071+/-429 at 60 min, and decreased to 1,119+/-319 pg/ml, at 120 min. Plasma levels of prostaglandin E also increased from 146+/-33 pg/ml in normal controls (n = 5) to 2,161+/-606 pg/ml 30 min after endotoxin (n = 5). In contrast to shocked controls, rats pretreated with imidazole, a thromboxane synthetase inhibitor, or essential fatty acid-deficient rats, which are deficient in arachidonate and its metabolites, did not exhibit significant elevations in plasma levels of thromboxane B(2). Imidazole did not however inhibit endotoxin-induced elevations in plasma prostaglandin E. Essential fatty acid deficiency significantly reduced mortality to lethal endotoxic shock. This refractoriness could be duplicated in normal rats pretreated with the fatty acid cyclo-oxygenase inhibitor, indomethacin (10 mg/kg), intravenously 30 min before endotoxin injection. Imidazole (30 mg/kg) administered intraperitoneally 1 h before or intravenously 30 min before endotoxin, also significantly (P < 0.01) reduced mortality from lethal endotoxin shock to 40% compared to a control mortality of 95% at 24 h. Likewise pretreatment with 13-azaprostanoic acid (30 mg/kg), a thromboxane antagonist, reduced mortality from endotoxic shock at 24 h from 100% in control rats to only 50% (P < 0.01). The results suggest that endotoxin induces increased synthesis of thromboxane A(2) that may contribute to the pathogenesis of endotoxic shock. Topics: Animals; Fatty Acids, Essential; Imidazoles; Prostanoic Acids; Rats; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes | 1980 |