thromboxane-b2 and Shock--Septic

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

Levels of thromboxane B2 (TxB2), the stable metabolite of thromboxane A2, are elevated in human and experimental septic shock. The thromboxane synthetase inhibitor dazoxiben has improved survival and decreased pulmonary hypertension in experimental endotoxemia. A randomized prospective study of 10 patients with the clinical diagnosis of sepsis and early adult respiratory distress syndrome (hypoxemia, radiologic evidence of the syndrome, and intrapulmonary shunt greater than 20%) was performed to test the efficacy of dazoxiben in ameliorating the effects of human sepsis. Five subjects received dazoxiben and five received placebo. Dazoxiben, 100 mg, or placebo was injected intravenously every 4 hours for a maximum of 72 hours. Plasma immunoreactive TxB2 (iTxB2) levels were determined by radioimmunoassay. Before dazoxiben, the plasma iTxB2 level was 752 +/- 261 pg/ml (n = 5) and was reduced within 1 hour to 333 +/- 137 pg/ml. The plasma levels of iTxB2 remained significantly decreased with subsequent doses of dazoxiben and it was 201 +/- 67 pg/ml (n = 4) 60 hours after dosing. In contrast, placebo had no significant effect on plasma iTxB2 levels (n = 5) throughout the entire period of observation. Dazoxiben did not induce any significant changes in pulmonary or systemic vascular resistance, intrapulmonary shunting, clotting studies, or extravascular lung water. One of the five subjects in the placebo group died and two of the five subjects in the dazoxiben group died. We conclude that dazoxiben was safe and effectively lowered plasma iTxB2 levels in patients with sepsis and incipient adult respiratory distress symptom, but did not significantly alter the hemodynamic and pulmonary sequelae of established sepsis.

Topics: Adult; Aged; Blood Pressure; Cardiac Output; Drug Evaluation; Female; Humans; Imidazoles; Infusions, Parenteral; Male; Middle Aged; Prospective Studies; Pulmonary Wedge Pressure; Radioimmunoassay; Random Allocation; Respiratory Distress Syndrome; Shock, Septic; Thromboxane B2; Vascular Resistance

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

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

Sepsis-associated changes of the arachidonic acid metabolism and the utility of arachidonic acid metabolites for the diagnosis of sepsis have been poorly investigated so far. Therefore, the primary objective of our study was to screen for differentially regulated arachidonic acid metabolites in septic patients using a lipopolysaccharide whole-blood model and to investigate their diagnostic potential.. Prospective, observational, single-center, clinical study.. Intensive care unit at University Hospital Leipzig.. Thirty-five patients (first cohort 25 patients, second cohort 10 patients) meeting the criteria for severe sepsis or septic shock were enrolled. Eighteen healthy volunteers (first cohort 15 subjects, second cohort 3 subjects) were enrolled as controls.. None.. Arachidonic acid and its metabolites were investigated in supernatants of nonactivated (baseline) and lipopolysaccharide-activated heparinized whole blood of healthy subjects (n=15) and septic patients (n=25) by solid phase extraction and subsequent liquid chromatography-tandem mass spectrometry. Arachidonic acid, arachidonic acid analogues, and the cyclooxygenase-associated metabolites prostaglandin E2, 11-hydroxyeicosatetraenoic acid, and thromboxane B2 were identified as differentiating metabolites between septic patients and healthy subjects. Some of these compounds, including arachidonic acid, its analogues, and the cyclooxygenase metabolites prostaglandin E2 and thromboxane B2 differed at baseline. The inducibility of arachidonic acid and the cyclooxygenase metabolites 11-hydroxyeicosatetraenoic and prostaglandin E2 were reduced by 80% to 90% in septic patients. The degree of the inducibility was associated with severity of sepsis and clinical outcome. A reduced inducibility of COX-2 but preserved inducibility of mPGES-1 on gene expression level were confirmed in an independent cohort of septic patients (n=10) by quantitative reverse-transcription polymerase chain reaction compared to healthy controls (n=3).. Arachidonic acid metabolism is markedly affected in patients with sepsis. Our data suggest that the analysis of arachidonic acid metabolites in an in vitro whole blood activation model may be a promising approach for risk estimation in septic patients that has to be further evaluated in subsequent large-scale clinical studies.

Topics: Adult; Aged; Arachidonic Acid; Chromatography, Liquid; Dinoprostone; Female; Humans; Hydroxyeicosatetraenoic Acids; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Shock, Septic; Tandem Mass Spectrometry; Thromboxane B2; Young Adult

This study addressed the possible role of cyclooxygenase (COX) and its products in the rebound response to inhaled nitric oxide (INO). Anesthetized, mechanically ventilated piglets were exposed to endotoxin alone, endotoxin combined with INO, or endotoxin with INO plus the COX inhibitor diclofenac (3 mg/kg iv) (n = 8 piglets/group). A control group of healthy pigs (n = 6) was also studied. Measurements were made of blood gases, hemodynamic parameters, lung tissue COX expression, and plasma concentrations of thromboxane B(2) (TxB(2)), PGF(2alpha), and 6-keto-PGF(1alpha). Endotoxin increased lung inducible COX (COX-2) expression and circulating prostanoids concentrations. Inhalation of NO during endotoxemia increased the constitutive COX (COX-1) expression, and the circulating TxB(2) and PGF(2alpha) increased further after INO withdrawal. The combination of COX inhibitor with INO blocked all these changes and eliminated the rebound reaction to INO withdrawal, which otherwise was seen in endotoxemic piglets given INO only. We conclude that the rebound response to INO discontinuation is related to COX products.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Inhalation; Animals; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Isoenzymes; Lung; Nitric Oxide; Osmolar Concentration; Prostaglandin-Endoperoxide Synthases; Shock, Septic; Swine; Thromboxane B2

To assess the effect of diisopropyl phenol (propofol), with and without Intralipid, on the cardiopulmonary system and on thromboxane production in endotoxic pigs.. Prospective, randomized animal study.. Animal research laboratory at a major teaching hospital.. Twenty-four pigs, divided into three groups (n = 8).. Pulmonary arterial catheters and arterial cannulas were inserted into all pigs. Each pig received a 30 ng/kg bolus of endotoxin at 1 hr, followed by a continuous infusion of endotoxin at 24 ng x kg-1 x hr-1. Diisopropyl phenol at 25, 75, and 200 microg x kg-1 x min-1 was administered to all pigs, beginning at 1, 2, and 3 hrs, respectively. The pigs were divided into three groups to receive 0.25 g x kg-1 x hr-1, 0.08 g x kg-1 x hr-1, or no Intralipid, starting at time t = 0. Heart rate and mean arterial, central venous, and pulmonary arterial pressures were recorded continuously. Core temperature, arterial blood gases, mixed venous oxygen saturation, pulmonary arterial occlusion pressure, and cardiac output were measured intermittently. Thromboxane B(2) concentrations were measured at baseline and at 60, 75, 120, 135, 180, 195, and 240 mins. Data are expressed as mean +/- sd. Groups were compared by using repeated analysis of variance, with p <.05 used for statistical significance.. All pigs completed the 4-hr study. Marked variabilities were noted for individual pigs. Following the infusion of endotoxin, compared with baseline, there was a significant increase in pulmonary vascular resistance and a decrease in Pao(2) (p <.001 and p <.008, respectively). This response was not affected by the increasing dose of diisopropyl phenol, nor were there differences between the Intralipid and control groups. Pao(2) remained significantly lower in all groups, compared with the baseline measurements (p <.001) over the 4 hrs of the experiment. Thromboxane B(2) concentrations remained elevated compared with baseline and were significantly higher (p <.05) in the high-dose Intralipid group, compared with the low-dose and the control groups, during the last hour of the experiment.. Small doses of endotoxin, when given to pigs, induce major perturbations of cardiopulmonary function. Neither Intralipid, high vs. low dose, nor diisopropyl phenol, at sedating vs. anesthetizing doses, worsened the physiologic derangement associated with the stress of low-dose endotoxemia.

Topics: Animals; Dose-Response Relationship, Drug; Fat Emulsions, Intravenous; Hemodynamics; Lung; Male; Propofol; Respiratory Distress Syndrome; Shock, Septic; Swine; Thromboxane B2; Vascular Resistance

Despite major developments in the management of septic shock, the mortality rate had progressively increased. Ibuprofen has been shown to have beneficial physiological effects when used as a treatment. However, there are conflicting results with respect to survival. This study aims to investigate the effect of ibuprofen on vital functions, various physiological parameters and survival during endotoxic shock in rabbits.. Twenty-eight New Zealand rabbits were randomly separated into four groups. The first group received only saline, the second was given 2 mg/kg intravenous endotoxin at t0, the third received 30 mg/kg ibuprofen 30 minutes after endotoxin administration, whilst the fourth group received ibuprofen 30 minutes before the endotoxin. Respiratory and heart rate, mean arterial blood pressure and rectal temperature were recorded. Complete blood counts were performed and thromboxane B2 was measured every 30 minutes for the first two hours, and then hourly over the course of the experiment. Urine samples were collected at the same time points for the measurement of prostaglandin E2.. Ibuprofen was found to improve respiratory rate, heart rate, and arterial pressure. However, it did not improve the negative effects of endotoxin on body temperature, haematocrit values, white blood cell count, and thrombocyte number. Thromboxane B2 levels in group IV were significantly lower than in the other groups, and the increase started at a later timepoint. In ibuprofen-treated animals, Prostaglandin E2 levels stayed low for at least 90 minutes, but started to rise thereafter. While the average survival in Group II animals was 192.9 +/- 46.9 minutes, those of groups III and IV were 339.1 +/- 33.5 minutes (p < 0.05) and 383.0 +/- 39.6 minutes (p = 0.01), respectively.. Ibuprofen appears to increase survival in endotoxic shock-induced animals. Therefore, it may be helpful for the prophylaxis and treatment of patients with, or who are likely to develop, septic shock.

Topics: Animals; Blood Pressure; Body Temperature; Cyclooxygenase Inhibitors; Dinoprostone; Heart Rate; Hematocrit; Ibuprofen; Leukocyte Count; Platelet Count; Rabbits; Random Allocation; Respiration; Shock, Septic; Thromboxane B2

This study evaluated whether prostacyclin is a necessary mediator of inflammation in graded bacteremia or is sufficient alone in pathophysiologic concentrations to cause the pulmonary derangement of bacteremic shock.. Experimental.. Laboratory.. Twenty-three anesthetized adult swine. INTERVENSIONS: Swine were studied in four groups for 4 hrs: a) an anesthesia control group (n = 6); b) a septic control group (n = 6), in which 1010/mL Aeromonas hydrophila was infused intravenously at 0.2 mL.kg-1.hr-1 and increased to 4.0 mL.kg-1.hr-1 over 3 hrs; c) a prostacyclin infusion group (n = 6), which received prostacyclin infusion to match septic control plasma concentrationsclm without bacteremia; and d) an antiprostacyclin antibody group (n = 5), which received continuous Aeromonas hydrophila infusion plus antiprostacyclin antibody infusion.. Pulmonary hemodynamics, arterial blood gases, and plasma concentrations of arachidonate metabolites were measured hourly over a 4-hr period. In the septic control group and antiprostacyclin antibody group, elevated pulmonary vascular resistance index and pulmonary artery pressure with decreased Pao2, as well as lower pH, were documented after 1 and 3 hrs of graded bacteremia compared with the anesthesia control group and prostacyclin infusion group (p <.05). Thromboxane B2 concentration increased significantly in all groups during septic shock. In the antiprostacyclin antibody group, leukotriene B4 increased immediately after starting antiprostacyclin antibody infusion and reached significance at 3 hrs compared with the septic control group (p <.05). The prostacyclin infusion group had consistently lower concentrations of leukotrienes C4, D4, and E4 than all other groups.. Prostacyclin does not mediate blood gas changes, alterations of pulmonary hemodynamics, or platelet abnormalities in porcine septic shock, because antiprostacyclin antibody infusion did not change the pulmonary hypertension and hypoxemia, and infusion of prostacyclin to pathophysiologic blood concentrations did not reproduce such changes. Antiprostacyclin blockade during bacteremia significantly increased concentrations of leukotrienes C4, D4, and E4 and leukotriene B4, whereas prostacyclin infusion suppressed concentrations of leukotrienes C4, D4, and E4, suggesting that endogenous prostacyclin may blunt leukotriene release.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Antihypertensive Agents; Bacteremia; Epoprostenol; Gram-Negative Bacterial Infections; Hemodynamics; Hypertension, Pulmonary; Leukotriene B4; Lung Diseases; Matched-Pair Analysis; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; SRS-A; Swine; Thromboxane B2

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

This study evaluated whether or not prostacyclin (PGI2) was necessary or sufficient by itself in a pathophysiologic concentration to mediate the cardiovascular dysfunction of septic shock. Anesthetized adult swine received anesthesia only (ANESTHESIA CONTROL, n = 6); graded Aeromonas hydrophila, 10(10)/mL, infusion at 0.2 mL/kg/h that increased to 4.0 mL/kg/h over 3 h (SEPTIC SHOCK CONTROL, n = 6); pathophysiologic prostacyclin infusion to match septic shock control plasma levels without bacteremia (PGI2 INFUSION, n = 6), or graded Aeromonas hydrophila plus anti-prostacyclin antibody infusion (ANTI-PGI2-Ab INFUSION, n = 5). This graded porcine bacteremia model was 100% lethal after 4 h. Cardiovascular hemodynamics, arterial blood gases, and plasma levels of arachidonate metabolites were measured at baseline and hourly over a 4-h period. The results showed that PGI2 was not a necessary mediator of impaired cardiovascular hemodynamics in graded bacteremia, as anti-PGI2 antibody infusion did not improve the cardiac index, systemic vascular resistance, or peripheral oxygen balance in septic animals. Also, PGI2 was not sufficient alone to cause the cardiovascular dysfunction of sepsis, as pathophysiologic infusion of PGI2 did not reproduce such changes in normal animals. PGI2 blockade during bacteremia significantly increased LTC4D4E4, and LTB4 whereas PGI2 infusion suppressed LTC4D4E4 concentration, suggesting that endogenous PGI2 may blunt leukotriene release during septic shock. These results indicate a complex dynamic equilibrium among prostacyclin and leukotrienes in septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Aeromonas hydrophila; Animals; Antibodies; Bacteremia; Epoprostenol; Gram-Negative Bacterial Infections; Leukotriene C4; Leukotriene D4; Leukotriene E4; Shock, Septic; Swine; Thromboxane B2

The physiological inhibitor of thrombin, antithrombin III (ATIII, Kybernin P) was investigated for its antiinflammatory and anticoagulant effects in a pig model of septic shock. Pigs were infused with a dose of 0.25 microgram. kg-1. h-1 of lipopolysaccharide (LPS) over a period of 3 hours. Animals developed systemic inflammation, disseminated intravascular coagulation (DIC), organ failure and cardiovascular abnormalities, namely pulmonary hypertension and systemic hypotension. Twenty septic pigs were allocated to 2 study groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minutes) followed by a single IV bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg (120 to 150 minutes). ATIII significantly prevented the development of a DIC; the increase in fibrin monomers (placebo, 11.4+/-9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (P<0. 05). ATIII significantly prevented the increase in thromboxane (TXB2) levels, which were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum group after 6 hours (P<0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 microgram. kg-1. h-1). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (P<0.05, chi2 test) a significant reduction of pulmonary hypertension (placebo, 42.0+/-11. 1 mm Hg; ATIII, 23.6+/-7.5 mm Hg, P<0.05), but no effect on systemic hypotension, was noted in the ATIII group. It was thus concluded that modulation of the procoagulatory state by substitution of ATIII results in a late beneficial antiinflammatory effect in this model of septic shock.

Topics: Animals; Antithrombin III; Blood Coagulation; Disseminated Intravascular Coagulation; Inflammation; Male; Shock, Septic; Swine; Thromboxane B2

The effects of tyrphostin AG-556 (TYR), a tyrosine kinase inhibitor, were evaluated on shock induced by lipopolysaccharide (LPS) or group B streptococcus (GBS) in rats. Mortality and mean survival time were monitored. Plasma 6-keto prostaglandin F1alpha (6-keto PGF1alpha) was also measured at four hours after LPS injection. The effects of TYR on the production of 6-keto PGF1alpha thromboxane B2(TXB2) and nitrite (NO) from LPS or GBS stimulated in vitro peritoneal rat macrophage were also examined. Salmonella enteritidis LPS (12 mg/kg, i.v. ) (n=6) produced severe shock (100% mortality). Simultaneous treatment with TYR (n=6) significantly (p < 0.01) extended mean survival time and 33% of rats survived. Plasma 6-keto PGF1alpha concentrations were increased in LPS controls, whereas TYR (5 mg/kg) significantly (p < 0.05) decreased the production. Animals treated with GBS/D-galactosamine (n=9) also exhibited shock with 100% lethality and TYR again prolonged survival time (p < 0.05) with 55% of the animals surviving. To evaluate direct effects of TYR on mediator production induced by LPS or GBS, rat macrophages were stimulated with heat-killed GBS or LPS with or without TYR. Supernatants were collected at 24 h for determination of TXB2, 6-keto PGF1alpha and NO. All mediators measured were significantly increased (p < 0.05) with LPS or GBS. TYR inhibited (p < 0.05) the production of all mediators from macrophages induced by LPS or GBS. The decrease in eicosanoids was associated with a reduction of the content of cyclooxygenase-2 (COX-2) as determined by western blotting. Collectively, these results suggest that TYR ameliorates toxic shock induced by LPS or gram positive bacteria. This protection is associated with suppression of macrophage mediator production.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Cyclooxygenase 2; Endotoxins; Gram-Positive Bacteria; Isoenzymes; Lipopolysaccharides; Macrophages, Peritoneal; Male; Nitrites; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Long-Evans; Shock, Septic; Streptococcus; Thromboxane B2; Tyrphostins

Liposome-encapsulated hemoglobin (LEH) is an experimental oxygen-carrying resuscitation fluid. Because LEH is cleared from the circulation primarily by the reticuloendothelial system, its effect on the development of sepsis remains a major concern. Thus, the present study aimed to evaluate whether LEH modifies consequences of endotoxemia in the conscious normovolemic rat. LEH infusion at 10% of estimated blood volume (n = 10) did not affect mortality (30%, p < .05) and serum tumor necrosis factor-alpha levels (6204 +/- 414, p < .05) induced by 3.6 mg/kg Escherichia coli endotoxin administered (intravenous bolus) 22 h later. In contrast, when a shorter LEH-endotoxin time interval (<12 h, n = 10) or a higher dose of endotoxin (14.4 mg/kg, n = 20) was tested, LEH enhanced endotoxin-induced mortality (90% and 100%, respectively, p < .05) and broadened serum tumor necrosis factor-alpha response without modifying its peak levels. LEH (n = 20) did not exacerbate the endotoxin-induced tachycardia, leukopenia, and thrombocytopenia. Therefore, in this model, the effect of LEH on endotoxin-induced responses was dependent on the time interval between LEH and endotoxin administration as well as the endotoxin dose. The clinical relevance of these results should be further investigated.

Topics: Animals; Blood Substitutes; Drug Compounding; Drug Delivery Systems; Heart Rate; Hemoglobins; Lipopolysaccharides; Liposomes; Male; Rats; Rats, Sprague-Dawley; Shock, Septic; Thromboxane B2; Tumor Necrosis Factor-alpha

A porcine model of endotoxemic shock was used to test the hypothesis that endothelins (ET) mediate the sustained increases in portal and pulmonary vascular resistances. Anesthetized pigs (n = 18) were instrumented and pretreated with 1) saline as a control; 2) indomethacin (Idm), a cyclooxygenase (Cox) inhibitor; or 3) Idm + bosentan (Bos), a mixed ET-receptor antagonist, and then were treated with endotoxin to produce shock and followed for 240 min. Global and regional hemodynamic parameters and plasma levels of ET-1 and thromboxane B2 were measured. The results show that 1) ET is independently responsible for the sustained increase in pulmonary vascular resistance; 2) ET and Cox products combine to increase portal venous resistance; 3) ET independently reduces cardiac output and attenuates or negates global systemic arterial vasodilation (presumptively mediated by nitric oxide) and exhibits regional differences, having little if any influence on the gut arterial bed. When considered with our prior study of nitric oxide regulation of the same beds in endotoxemic shock (N. Brienza, T. Ayuse, J. P. Revelly, C. P. O'Donnell, and J. L. Robotham, J. Appl. Physiol. 78: 784-792, 1995), the similarities between the portal venous and pulmonary arterial beds suggest that these two beds reflect phenomena occurring in microvascular and/or venous beds in multiple organs. The overall results suggest that a dynamic balance exists between NO and ET regulating arterial and microvascular and/or venous vasomotor activity during the evolution of endotoxemic shock.

Topics: Analysis of Variance; Animals; Bosentan; Cyclooxygenase Inhibitors; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endotoxemia; Hemodynamics; Hypertension, Portal; Hypertension, Pulmonary; Indomethacin; Liver Circulation; Portal System; Pulmonary Artery; Pulmonary Circulation; Regional Blood Flow; Shock, Septic; Sulfonamides; Swine; Thromboxane B2; Vascular Resistance

This study was undertaken to identify those events of bacteremic shock that pathophysiologic levels of leukotriene C4 (LTC4) alone were sufficient to cause. Sixteen adult swine were studied for 4 h in three groups: ANES (n = 6) received anesthesia only; Septic (n = 6) received Aeromonas hydrophila, 10(9)/mL, intravenously, increased incrementally from .2 to 4.0 mL/kg/h; LTC4 (n = 4) received LTC4 infused intravenously, at rates that approximated LTC4 levels of Septic animals. Measurements included mean arterial pressure and arterial PO2, mmHg, pulmonary and systemic (SVRI) vascular resistance indexes, cardiac index (CI), oxygen extraction ratio, hematocrit; thromboxane B2 (TxB2), prostaglandin 6 keto F1 alpha (6 keto), leukotrienes B4 and C4D4E4, and tumor necrosis factor were measured in pg/mL by ELISA. Statistical analysis was performed by ANOVA and general linear model). Mean arterial pressure increased from 100 +/- 5 to 141 +/- 9 in the LTC4 group, but decreased in the Septic group from 90 +/- 7 at baseline to 62 +/- 6 at 3 h. In the LTC4 group, SVRI did not differ from ANES, and pulmonary vascular resistance, PO2, and CI did not change from baseline. In the LTC4 group, TxB2 and 6 keto levels decreased from 149 +/- 26 to 87 +/- 18 and 58 +/- 10 to 44 +/- 12, respectively; in the Septic group, TxB2 increased 140-fold and 6 keto increased 60-fold. Pathophysiologic LTC4 is not sufficient alone to cause the derangements in CI and SVRI, and tissue metabolism induced by graded bacteremia. Significantly increased systemic blood pressure suggests that endogenous pathophysiologic LTC4 may be involved. LTC4 does not increase plasma eicosanoids and tumor necrosis factor, but may down-regulate prostaglandin and leukotriene release.

Topics: Animals; Bacteremia; Cytokines; Eicosanoids; Enzyme-Linked Immunosorbent Assay; Female; Heart; Hemodynamics; Leukotriene B4; Leukotriene C4; Lung; Reference Values; Shock, Septic; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha

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

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

Sesamin, present in sesame seed oil (SSO), can inhibit delta-5-desaturase activity and cause accumulation of dihomo-gamma-linolenic acid (DGLA), which displaces arachidonic acid, and subsequently decrease production of dienoic eicosanoids. The effects of diets containing both SSO and Quil A, a saponin that emulsifies fats and potentiates the immune responses, were also studied. A mixture of oils having a fatty-acid composition similar to that of SSO served as a control diet. The levels of docosapentaenoic acid in mice fed Quil-A-supplemented diets and of DGLA in those fed SSO diets were markedly higher in the liver. These changes were associated with a significant reduction in the plasma prostaglandin-E(1+2) and thromboxane-B2 levels in response to an intraperitoneal injection of a lethal dose of lipopolysaccharide (LPS) endotoxin (LD50 20 mg/kg). The levels of interleukin (IL-)6 were elevated and those of IL-1beta were decreased in mice consuming Quil-A-supplemented diets. The IL-10 levels that were elevated in all mice after LPS exposure, remained higher (even at 9 h) only in those fed Quil-A-supplemented diets, but declined rapidly in others. During a 48-hour observation period following LPS injection, all control animals died, and survival was 40% in the SSO group, and 27 and 50%, respectively, in those fed Quil-A-supplemented control and SSO diets. These data suggest that SSO and Quil A when present in the diet exerted cumulative effects that resulted in a decrease in the levels of dienoic eicosanoids with a reduction in IL-1beta and a concomitant elevation in the levels of IL-10 that were associated with a marked increase in survival in mice.

Topics: Animals; Dietary Supplements; Dinoprostone; Dioxoles; Eicosanoids; Fatty Acids; Female; Interleukins; Lignans; Liver; Membranes; Mice; Mice, Inbred BALB C; Quillaja Saponins; Saponins; Sesame Oil; Shock, Septic; Survival Analysis; Thromboxane B2

The role of platelet-activating factor (PAF) as a mediator of endotoxin-induced pathophysiology has been studied in several animal models with conflicting results. We evaluated the effect of a new, potent, and specific PAF receptor antagonist, ABT-299 (Abbott Laboratories) against endotoxin (lipopolysaccharide; LPS)-induced cardiopulmonary dysfunction in a porcine model. In initial experiments, the potency of ABT-299 was confirmed in vitro by its ability to inhibit PAF-induced porcine platelet aggregation at an IC50 of .047 +/- .01 microM, and in vivo by the ability of low doses (.12 mg/kg + .03 mg/kg/h) to block the cardiopulmonary pathologic response to exogenous PAF infusion. To evaluate the effect of ABT-299 administration during endotoxemia, pigs were randomly assigned to one of three groups: controls (n = 7), LPS (n = 9), or ABT-299 + LPS (n =7). ABT-299 was given at 1.0 mg/kg from -0.5 to 0 h plus .3 mg/kg/h from 0 to 6 h. LPS was given at .5 micrograms/kg/hr from 0 to 6 h. ABT-299 reduced the early LPS-induced fall in cardiac index and stroke volume, pulmonary hypertension and vasoconstriction, bronchoconstriction, and hypoxemia. Administration of LPS resulted in 44% mortality (before 6 h), which was blocked by ABT-299. Results with this antagonist indicate that PAF contributes to endotoxin-induced cardiopulmonary dysfunction in the pig, and is associated with mortality in this model.

Topics: Animals; Blood Pressure; Cardiac Output; Dose-Response Relationship, Drug; Lipopolysaccharides; Lung; Peroxidase; Platelet Activating Factor; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Prodrugs; Pyridinium Compounds; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Shock, Septic; Stroke Volume; Swine; Thiazoles; Thromboxane B2; Vascular Resistance

We studied whether dibutyryl cyclic adenosine monophosphate (DbcAMP), which freely penetrates into the cells, improves systemic vasoconstriction caused by endotoxin in dogs. Thirteen anesthetized dogs were randomized into three groups. The endotoxin (ETX) group (n = 5) received only Escherichia coli endotoxin (3 mg.kg-1, intravenously). The ETX + DbcAMP group (n =5) received DbcAMP (6 mg.kg-1, intravenously) 30 min before the administration of endotoxin. The DbcAMP group received the same dose of DbcAMP 30 min after administration of saline. In the ETX group, systemic blood pressure and cardiac index significantly decreased, and systemic vascular resistance significantly increased, while in the ETX + DbcAMP group, increases in systemic and pulmonary vascular resistances after the administration of endotoxin were attenuated. DbcAMP did not cause hemodynamic changes in normal dogs. Plasma concentrations in thromboxane B2 in the ETX group were higher than in the ETX + DbcAMP group. Also, the change in plasma cyclic AMP concentrations showed a good logarithmic correlation with the change in plasma thromboxane B2 concentrations after the administration of endotoxin (r = .908, log (delta T x B2) = -.002* (delta cAMP) + 3.786). We conclude that DbcAMP improves systemic vasoconstriction caused by endotoxin in dogs. The beneficial mechanism of DbcAMP on systemic vasoconstriction after the administration of endotoxin may be partially due to inhibition of thromboxane B2.

Topics: Animals; Blood Pressure; Bucladesine; Cardiac Output; Cyclic AMP; Dogs; Dose-Response Relationship, Drug; Escherichia coli Infections; Hemodynamics; Lethal Dose 50; Lipopolysaccharides; Shock, Septic; Thromboxane B2; Time Factors; Vascular Resistance; Vasoconstriction

The effect of CV-3988, a platelet activating factor antagonist, in the treatment of endotoxic shock was evaluated from the changes in plasma 6-keto-PGF1 alpha and thromboxane B2 concentrations. The animals consisted of 10 beagle dogs anesthetized with pentobarbital sodium and divided into a treatment group (n = 5) and a control group (n = 5). Endotoxic shock was experimentally induced in both groups by intravenous administration of endotoxin (lipopolysaccharide, 3 mg/kg). The treatment group was intravenously given 10 mg/kg of CV-3988 for 10 min from immediately after endotoxin. Mean aortic pressure, cardiac output and urine volume were remarkably decreased after the administration of endotoxin to both groups. These parameters were higher after the administration of CV-3988, in the treatment group than in the control group. Furthermore, the increase in plasma 6-keto-PGF1 alpha and thromboxane B2 concentrations was significantly inhibited. These results suggest the effectiveness of CV-3988 in the treatment of endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dog Diseases; Dogs; Hemodynamics; Phospholipid Ethers; Platelet Activating Factor; Shock, Septic; Thromboxane B2

G 619 is 3-carbamyl-(3'-picolyl)-4-methoxy-1-benzamide. The compound is structurally related to picotamide, a previously reported dual thromboxane synthase inhibitor/thromboxane A2 receptor antagonist, which displays inhibitory activity on tumor necrosis factor-alpha. The aim of the present work was to study the effect of G 619 on tumor necrosis factor-alpha synthesis both in vivo and in vitro. Salmonella enteritidis lipopolysaccharide was used to induce tumor necrosis factor-alpha production. Septic shock was produced in male rats by a single intravenous (i.v.) injection of 20 mg/kg (LD90) of Salmonella enteritidis lipopolysaccharide. Rats were pretreated with G 619 (50 mg/kg, i.v.) or vehicle (1 ml/kg, i.v.) 1 h before endotoxin challenge. Salmonella enteritidis lipopolysaccharide administration dramatically reduced survival rate (0%, 72 h after endotoxin administration), reduced mean arterial blood pressure, increased plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha and enhanced serum levels of tumor necrosis factor. Furthermore, endotoxic shock produced characteristic gastric damage, consisting of haemorrhagic infiltrates. Pretreatment with G 619 in vivo significantly protected against Salmonella enteritidis lipopolysaccharide-induced lethality (80% survival rate and 60% survival rate 24 h and 72 h after Salmonella enteritidis lipopolysaccharide injection, respectively), reduced hypotension, decreased plasma thromboxane B2 and serum tumor necrosis factor-alpha levels and enhanced blood levels of 6-keto-prostaglandin F1 alpha. In rat peritoneal macrophages, G 619 in vitro (25, 50 and 100 microM) significantly blunted (P < 0.001) Salmonella enteritidis lipopolysaccharide-stimulated production of tumor necrosis factor-alpha, whereas it increased 6-keto-prostaglandin F1 alpha and cyclic AMP levels. The present data indicate that G 619 may be useful during disease states characterized by elevated tumor necrosis factor-alpha levels.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Benzamides; Cyclic AMP; Gastric Mucosa; Lipopolysaccharides; Macrophages, Peritoneal; Male; Picolines; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Salmonella enteritidis; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase; Tumor Necrosis Factor-alpha

Rat neonatal mortality to endotoxin and age-related changes in adherent splenic cell mediator production in vitro were investigated. Neonatal rat pups, 24, 48, 96, and 216 h old or maternal adult rats were administered doses of Salmonella enteritidis endotoxin, (.024 mg to 7.5 mg/kg) and survival was monitored for 72 h. Mortality demonstrated high sensitivity (p < .05) of neonates to endotoxin (particularly 24 h old neonates). Endotoxin administration .6 mg/kg intracardiac) produced a 100% lethality in 24 h neonates (p < .05) versus 23% or less lethality in the 48 to 216 h old age group. Endotoxin administration (.4 mg/kg subcutaneous) also produced 100% lethality in 24 h old neonates compared with reduced mortality versus older age groups. Endotoxin in vitro stimulated (p < .05) adherent splenic cell thromboxane (TX)B2, interleukin-6, and nitrite production in most groups. Splenic cell nitrite production was higher (p > .05) in the 24 h old neonates, but lower in 48 h and 96 h old groups compared with maternal adults. Splenic cell TXB2 production was higher (p < .05) in the 24 h and 216 h old neonates relative to maternal adults. In conclusion, 24 h old rat pups are more susceptible to endotoxic shock than older age groups and adults, and exhibit altered production of the cellular mediators nitric oxide and TXB2.

Topics: Aging; Animals; Animals, Newborn; Cell Adhesion; Endotoxins; Interleukin-6; Nitric Oxide; Rats; Rats, Sprague-Dawley; Shock, Septic; Spleen; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Diet; Dinoprostone; Infusions, Parenteral; Macrophages; Male; Nucleic Acids; Nucleosides; Nucleotides; Rats; Rats, Wistar; Shock, Septic; Thromboxane B2; Tumor Necrosis Factor-alpha

The parasympathetic nervous system actively participates in the regulation of pathophysiologic responses in circulatory shock. To determine the effects of cholinergic blockade in endotoxic shock in newborn piglets, 16 chronically instrumented newborn piglets were infused with 10 mg/kg of endotoxin over 10 min. Eight animals were injected intravenously with 10 mg/kg of anisodamine, an anticholinergic drug, 10 min before endotoxin and then with escalating doses of 2, 5, 10, and 20 mg/kg every 10 min, beginning 60 min after endotoxin. The other eight animals were given saline as a control. Endotoxin infusion caused elevations in mean pulmonary artery pressure and vascular resistance index and an initial increase in systemic artery pressure followed by hypotension. Heart rate was stable for 45 min and then increased. Cardiac index fell from a baseline of 173 +/- 20 (mean +/- S.E.) to 136 +/- 23 mL.min-1.kg-1 60 min after endotoxin. Pretreatment with anisodamine increased heart rate from 163 +/- 15 to 289 +/- 10 beats.min-1 and cardiac index from 195 +/- 15 to 238 +/- 14 mL.min-1.kg-1 before endotoxin infusion. These variables remained at higher levels than in the control group until 60 min after endotoxin infusion; thereafter, the two groups were similar. The changes in pulmonary and systemic artery pressures were not significantly altered by anisodamine. After 60 min, additional doses of anisodamine caused no significant hemodynamic responses, and the differences between the two groups were not significant. Arterial plasma thromboxane B2 levels rose immediately and tumor necrosis factor-alpha levels increased 60 min after endotoxin infusion; no significant differences were noted between groups at any time.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analysis of Variance; Animals; Animals, Newborn; Blood Pressure; Carbon Dioxide; Cardiac Output; Diarrhea; Digestive System; Dose-Response Relationship, Drug; Endotoxins; Female; Heart Rate; Hemodynamics; Oxygen; Parasympatholytics; Partial Pressure; Pulmonary Artery; Shock, Septic; Solanaceous Alkaloids; Stroke Volume; Swine; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha; Vascular Resistance; Vomiting

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

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

We sought to determine whether a standardized "priming" event, namely a small dose of LPS, would alter physiological responses to a subsequent larger "challenge" dose of endotoxin. Accordingly, four groups of pigs (N = 5-6) were studied. One group received neither priming nor challenge doses of LPS. A second group were not primed but were infused with a challenge dose (250 micrograms/kg) of LPS. A third group were pretreated 18 h before being studied with a priming dose of LPS (20 micrograms/kg), but were not infused with a second dose of LPS. A fourth group received both priming and challenge doses of LPS. Priming with LPS exacerbated endotoxin-induced arterial hypoxemia, and decreased animal-to-animal variability in the degree of hypoxemia induced by a challenge dose of endotoxin. Priming blunted the early phase (30 min) and exacerbated the delayed phase (120-210 min) of LPS-induced pulmonary hypertension. Priming blunted LPS-induced release of prostacyclin and thromboxane A2. The use of a priming dose of LPS increases the severity and reproducibility of LPS-induced acute lung injury in swine.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bronchoalveolar Lavage Fluid; Cardiac Output; Drug Administration Schedule; Endotoxins; Hypoxia; Lipopolysaccharides; Male; Oxygen; Partial Pressure; Premedication; Pulmonary Fibrosis; Shock, Septic; Swine; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha; Vascular Resistance

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

The therapeutic effect of ulinastatin (25,000 U/kg, i.v.) on endotoxin-induced shock was compared with that of methylprednisolone (30 mg/kg, i.v.) in 17 anesthetized dogs. Both of these drugs had almost the same tendency to improve the hemodynamics, arachidonate cascade metabolites and pulmonary surface activity. There was little difference between the effectiveness of ulinastatin and that of methylprednisolone. It was newly confirmed that the release of 6-keto-PGF1 alpha, thromboxane B2 and leukotriene B4, arachidonate cascade metabolites and chemical mediators associated with endotoxin-induced shock, were significantly (p < 0.01 and p < 0.05) decreased by ulinastatin in the same way as methylprednisolone. These results suggest that ulinastatin is as useful as methylprednisolone for the treatment of endotoxin-induced shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Glycoproteins; Hemodynamics; Leukotriene B4; Lung; Methylprednisolone; Shock, Septic; Thromboxane B2; Trypsin Inhibitors

1. We continuously recorded systemic and renal haemodynamic changes, and arterial, renal venous and urinary concentrations of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2, and determined their relationship to renal function in an ovine model of progressive hyperdynamic sepsis. 2. Nine chronically instrumented unanaesthetized sheep were given a continuous intravenous infusion of Escherichia coli endotoxin (20 ng min-1 kg-1) for 3 days. 3. Within the first 12 h of infusion, endotoxin induced a major hypotensive septic syndrome, including a persistent 30% reduction in mean arterial pressure, a 50% decrease in systemic vascular resistance and a 50% increase in mean pulmonary artery pressure, associated with severe lactacidaemia. 4. Renal blood flow decreased by 40%, and creatinine clearance, urine flow, and fractional sodium excretion decreased by more than 75%, of baseline values. After 12 h of endotoxin infusion, cardiac output increased two-fold and renal blood flow recovered to baseline values, whereas creatinine clearance remained depressed. Four sheep died between 13 and 22 h of endotoxaemia; these animals (allocated to group 1) presented a significantly and persistently more reduced renal blood flow (-23%) and creatinine clearance (-77%) after 4 h than the remaining five sheep (allocated to group 2), which survived more than 36 h (-16% and -21%, respectively), whereas systemic and pulmonary haemodynamic and gas exchange data remained similar in both groups. 5. The more pronounced decreases in renal blood flow, creatinine clearance and urine flow in group 1 were associated with higher plasma renin activity and plasma 6-keto-prostaglandin F1 alpha concentrations and a lower fractional urinary excretion of 6-keto-prostaglandin F1 alpha than in group 2, whereas plasma thromboxane B2 concentrations were similarly increased in both groups. Plasma prostaglandin E2 concentrations and urinary excretion were not notably affected by endotoxin infusion in either group. 6. Our results are not in favour of a significant renal production of any of these three prostanoids during endotoxaemia. In both groups, values of creatinine clearance were linearly correlated with simultaneous mean arterial pressure values after starting endotoxin infusion (group 1: creatinine clearance = 1.99 x mean arterial pressure--105, r = 0.95; group 2: creatinine clearance = 2.06 x mean arterial pressure--104, r = 0.80).(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Endotoxins; Escherichia coli; Hemodynamics; Kidney; Kinetics; Lactates; Lactic Acid; Pulmonary Gas Exchange; Renal Artery; Renal Circulation; Renin; Sheep; Shock, Septic; Thromboxane B2

The therapeutic effect of dibutyryl cyclic AMP (DBcAMP) in endotoxic shock was evaluated, using 11 dogs with experimentally-induced endotoxic shock (5 in DBcAMP group and 6 in control group) under general anesthesia. The DBcAMP group was treated by single intravenous injection of DBcAMP (10 mg/kg) at 15 min before inoculation with endotoxin (3 mg/kg). After the inoculation of endotoxin, this group was given drip infusion of DBcAMP at a rate of 0.1 mg/kg/min over 180 min. Hemodynamic parameters and chemical mediators were measured until 360 min after endotoxin inoculation. The cardiac output and urinary volume, which were decreased in the control group, were significantly inhibited to decrease in the DBcAMP group (p < 0.01). The increases in 6-keto-PGF1 alpha and thromboxane B2, chemical mediators released in endotoxic shock, were significantly inhibited (P < 0.05 and p < 0.01, respectively). These results suggested that DBcAMP is useful for the treatment of endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Bucladesine; Cardiac Output; Dogs; Endotoxins; Escherichia coli; Heart Rate; Hemodynamics; Injections, Intravenous; Shock, Septic; Thromboxane B2; Time Factors; Urine; Vascular Resistance

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

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

This study examined the differential effects of endotoxin on renal and splanchnic vascular (SV + SI) eicosanoid synthesis. Dogs were anesthetized and subjected to a challenge of 1 mg/kg (i.v.) bolus of B-lipopolysaccharide endotoxin followed by a 3 h infusion of endotoxin at 0.5 mg/kg/h. The kidney and SV + SI were cannulated and perfused in vitro with Krebs buffer. The venous effluent from the kidney and SV + SI were assayed for 6-keto-PGF1a (PGI2), PGE2, Leukotriene B4 (LTB4), LTC4, and thromboxane B2 (TXB2) by enzyme immunoassay. Endotoxin treatment markedly increased splanchnic PGI2 release (splanchnic vasodilator) two fold and decreased release of all other measured eicosanoids. Endotoxin treatment markedly increased renal PGE2 (renal vasodilator) but did not significantly increase PGI2. These data showed that endotoxin treatment stimulated both the splanchnic vascular bed and kidney to increase synthesis and release of their major endogenous vasodilator eicosanoids.

Topics: Animals; Chemotherapy, Cancer, Regional Perfusion; Dinoprostone; Dogs; Eicosanoids; Endotoxins; Epoprostenol; Immunoenzyme Techniques; In Vitro Techniques; Kidney; Leukotriene B4; Lipopolysaccharides; Male; Mesentery; Renal Circulation; Shock, Septic; Splanchnic Circulation; SRS-A; Thromboxane B2

Newborn endotoxic shock syndrome is associated with high morbidity and mortality, yet presents with different clinical manifestations than in older patients. To determine the influence of age on hemodynamic and metabolic responses to endotoxin, we developed a chronically instrumented endotoxic shock model using eight 1-3-day-old and seven 2-3-week-old piglets. Three days after surgery, 10 mg/kg of endotoxin was infused intravenously over 10 min in the younger group, and 5-10 mg/kg was given to the older animals. Two older piglets died immediately after infusion of 5 mg/kg of endotoxin, and five of the seven died within 4 hr, while all eight younger animals lived longer than 4 hr. Pulmonary artery pressure increased significantly after endotoxin in both groups, and there were no differences between groups. Systemic artery pressure and cardiac index fell by 44 +/- 10% and 70 +/- 15%, respectively, 5 min after endotoxin infusion in the older group, while these values did not change significantly in the younger group. Endotoxin infusion also caused greater elevation in pulmonary vascular resistance index in the older animals. In the later phase, which began 30 min after endotoxin, both groups displayed systemic hypotension and pulmonary hypertension, and the groups did not differ from one another in this regard. With progression of endotoxic shock, more severe metabolic acidosis developed in the older animals than in the younger animals. Plasma thromboxane B2 levels in the older group were about double those in younger piglets. Plasma 6-keto-PGF1 alpha and TNF alpha levels in both groups were similar and were significantly increased in the later phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Aging; Animals; Animals, Newborn; Blood Pressure; Endotoxins; Escherichia coli; Female; Hemodynamics; Kinetics; Oxygen; Pulmonary Artery; Shock, Septic; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha; Vascular Resistance

Previous studies in adult animals have indicated that plasma angiotensin converting enzyme (ACE) activity is inhibited by endotoxin. Reduced ACE activity may decrease plasma angiotensin II (AII) levels, contributing to the refractory hypotension we have previously reported in neonatal septic shock. In this study, hemodynamic function, plasma renin activity (PRA), AII, prostacyclin (PGI2), and thromboxane B2 (TxB2) levels were measured in 17-20-day-old dogs before and 1, 2, and 3 hr after endotoxin administration (1 mg/kg, Escherichia coli lipopolysaccharide-B). PRA and AII levels rose significantly 60 min post-endotoxin, returning to baseline values by 180 min; PGI2 and thromboxane B2 levels rose post-endotoxin and remained elevated. Indomethacin or captopril was given by oral gavage 30-35 min before endotoxin. Captopril significantly blunted the rise in PRA and AII, while indomethacin blocked the rise in PGI2 and TxB2. Mean arterial blood pressure and cardiac output fell 60 min after endotoxin challenge without pharmacologic intervention and remained depressed. Our data suggest that renin and AII responses to endotoxin challenge remain intact in the neonatal subject. Maintenance of hemodynamics in indomethacin-pretreated dogs may be due to unopposed stimulation of the peripheral vasculature by AII. Thromboxane B2 in maintenance of vasomotor tone may be minimal in the young.

Topics: Angiotensin II; Animals; Animals, Newborn; Captopril; Dogs; Epoprostenol; Escherichia coli; Hemodynamics; Indomethacin; Lipopolysaccharides; Renin; Shock, Septic; Thromboxane B2

This study was undertaken to evaluate the effect of a cyclooxygenase inhibitor, ibuprofen, at various time intervals in a live Escherichia coli model of canine septic shock. Group I (control) animals (n = 5) received a LD100 dose of 10(9) live E. coli per kilogram were given no further treatment. Group II animals (n = 5) received a 10 mg/kg bolus of ibuprofen 10 min prior to bacterial infusion. Group III animals (n = 5) received ibuprofen 15 min after the bacterial infusion. Statistical analysis revealed the following: Group II animals had significantly higher MABP and significantly lower levels of serum fluorescent products (superoxide radical activity), plasma thromboxane B2, prostaglandin E2, and endotoxin levels compared to Group I animals (P less than 0.05). Plasma levels of tumor necrosis factor (TNF) and interleukin-6 (IL-6) were significantly elevated (P less than 0.05) from baseline in all animals (Groups I, II, and III), but ibuprofen treatment failed to either increase or decrease these levels. This study demonstrates that ibuprofen treatment can significantly reverse the deleterious hemodynamic and metabolic effects commonly seen in live E. coli septic shock without depressing the endogenous production of TNF or IL-6. These data support the hypothesis that sepsis initiates a cascade of mediators with the cytokines TNF and IL-6 being proximal events which in turn stimulate the next level, with ibuprofen probably exerting its inhibitory effect distal to this point in the cascade.

Topics: Animals; Blood Pressure; Cardiac Output; Cytokines; Dinoprostone; Dogs; Endotoxins; Escherichia coli Infections; Ibuprofen; Interleukin-6; Lipid Peroxidation; Shock, Septic; Superoxides; Thromboxane B2; Tumor Necrosis Factor-alpha

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

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

G619, a 4-OH-isophthalic acid derivative, was studied for its capacity to inhibit platelet aggregation. G619 dose-dependently inhibited U46619, collagen, ADP, PAF, thrombin and epinephrine-induced platelet aggregation in vitro. The IC50 values for inhibition of U46619-induced human and rabbit platelet aggregation were 39 and 43 microM, respectively. G619, at 100 microM, inhibited high concentration collagen (10 micrograms/ml)-induced aggregation of rabbit platelets pretreated with indomethacin and increased the level of cAMP in washed rabbit platelets by 30% (p less than 0.01 vs basal). However, G619, did not inhibit fibrinogen binding to GPIIb/IIIa receptor, phosphodiesterase, U46619-induced contractile responses on canine saphenous vein or rabbit aorta, calcium-induced vasoconstriction and thrombin or PAF-induced elevation of [Ca++]i in platelets in vitro. In vivo, the U46619-induced maximal thrombocytopenia in rats was reduced from 40% (vehicle) to 22% and 18% by 10 and 30 mg/kg of G619 i.v., respectively. G619 (30 mg/kg) had no effect on the U46619-induced vasopressor response or sudden death in rats, and had no effect on TxB2 formation. Our results indicate that G619 is a broad-spectrum platelet aggregation inhibitor and may have its effect on a common mechanism for platelet aggregation besides an effect on the thromboxane A2 receptor.

Topics: Adenosine Diphosphate; Animals; Benzamides; Calcium; Collagen; Dogs; Epinephrine; Fibrinogen; Humans; Male; Phenylacetates; Picolines; Platelet Activating Factor; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Membrane Glycoproteins; Prostaglandin Endoperoxides, Synthetic; Rabbits; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Shock, Septic; Sulfonamides; Thrombin; Thromboxane B2; Vasoconstriction

Continuous lipopolysaccharide (LPS) infusion in pigs induced death in approximately half of the animals and a prolonged state of shock (up to 3 hours of experimental observation period, i.e., two hours after discontinuation of LPS infusion) in the surviving animals. Lethal-induced shock was marked by huge release of Tumor Necrosis Factor (TNF) into the blood, whereas eicosanoid and Platelet Activating Factor (PAF) levels remained unchanged. In pigs surviving LPS-infusion but still remaining in a state of shock, transient increases in PAF and thromboxane levels were observed, whereas prostacyclin and leukotrienes values remained above normal levels up to the end of the observation period. It is concluded that different types of mediators play a role in LPS-induced lethal shock as compared to non-lethal prolonged state of shock.

Topics: Animals; Blood Pressure; Diterpenes; Eicosanoids; Endotoxins; Escherichia coli; Ginkgolides; Indomethacin; Lactones; Platelet Activating Factor; Shock, Septic; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha

Tumor necrosis factor (TNF) is implicated in the pathophysiology of gram-negative sepsis. This study examined physiologic and biochemical effects of pretreatment with an anti-TNF alpha monoclonal antibody immediately before the onset of sepsis. Three groups of anesthetized ventilated pigs were studied for 300 minutes. Groups 1 (n = 12) and 2 (n = 6) received a 1-hour infusion of live Pseudomonas aeruginosa. Group 2 was pretreated with anti-TNF alpha monoclonal antibody (15 mg/kg). Group 3 (n = 8) received intravenous sterile saline. Group 1 exhibited a significant rise in plasma TNF activity, which was abolished in group 2. Cardiac index was reduced in both groups 1 and 2 in the first hour but recovered in group 2 (3.3 +/- 0.4 l/min per square meter at 300 minutes in group 2 vs 1.3 +/- 0.2 L/min per square meter in group 1). Metabolic acidosis was attenuated (arterial pH, 7.39 +/- 0.01 in group 2 vs 7.16 +/- 0.03 at 300 minutes in group 1). Increased extravascular lung water was also attenuated (5.9 +/- 0.7 in group 2 vs 13.2 +/- 1.5 mL/kg at 300 minutes in group 1). However, pulmonary hypertension and hypoxemia, which are known cyclooxygenase effects, were not affected. In the early phase of the study, plasma thromboxane B2 levels were elevated in both groups 1 and 2. We conclude that anti-TNF alpha monoclonal antibody offered significant protection against the effects of sepsis, but that other mediators may be responsible for the early changes seen in this model.

Topics: Animals; Antibodies, Monoclonal; Bacteremia; Extravascular Lung Water; Hemodynamics; Lung; Pseudomonas Infections; Shock, Septic; Swine; Thromboxane B2; Tumor Necrosis Factor-alpha

The time course of thromboxane B2 (TxB2), 6-keto-PGF1 alpha (stable metabolite of prostacyclin), tumor necrosis factor-alpha (TNF alpha), platelet activating factor (PAF), and interleukin-6 (IL-6) formation after three lipopolysaccharide (LPS) infusions was studied in pigs over an 18-hr, period. The Escherichia coli endotoxin W0111:B4 was injected i.v. into 10 of the test group pigs at a dose of 0.5 micrograms/kg over 30 min at 0, 5 and 10 hr of the experiment. Three pigs injected with physiological saline served as controls. At defined time points before and after each LPS administration venous blood was withdrawn (0, 15, 30, 45, 60, 120, 180 min) and plasma levels of TxB2, 6-keto-PGF 1 alpha, PAF, TNF alpha and IL-6 were determined. Pulmonary artery pressure (PAP) and cardiac output (CO) were measured every 15 min. TxB2 and PAF peaked significantly between 30 and 45 min, TNF alpha and 6-keto-PGF 1 alpha between 30 and 60 min, and IL-6 between 120 and 180 min after each LPS injection. The mediators PAF, TNF alpha and TxB2 showed a decreasing three-peak profile whereas 6-keto-PGF1 alpha exhibited an increasing one. IL-6 plasma concentrations increased after each LPS injection. The peak after the third LPS administration, however, was surprisingly low compared to the previous two. The first LPS infusion in our test group led to a significant, sustained rise in mean PAP. After recurrent LPS injections the peak in PAP was not as marked as after the first infusion, indicating the development of a tolerance towards LPS. Initially, CO showed hypodynamic values, whereas the end stage of the experiment was characterized by hyperdynamic CO levels. In conclusion, we believe this porcine model of septic shock to be one of the first large animal models to describe in detail the time-course of various important inflammatory mediators.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Inflammation; Interleukin-6; Lipopolysaccharides; Platelet Activating Factor; Pulmonary Wedge Pressure; Shock, Septic; Swine; Thromboxane B2; Time Factors; Tumor Necrosis Factor-alpha

Intravenous lipopolysaccharide (LPS) decreases superior mesenteric arterial blood flow and increases ileal mucosal permeability in pigs. We tested the hypothesis that these phenomena can be ameliorated by pretreatment and posttreatment with ibuprofen. Pentobarbital-anesthetized immature swine were mechanically ventilated (fraction of inspired oxygen, 0.5) and infused with Ringer's lactate (RL) solution (0.8 mL/kg per minute). Animals in group RL (n = 10) received no other interventions. Animals in group RL + LPS (n = 15) were infused with LPS (50 micrograms/kg) from a time range equal to 0 through 60 minutes. Animals in group RL + LPS + ibuprofen (n = 10) were similarly infused with LPS, but in addition, they received ibuprofen (10 mg/kg at -30 minutes and 10 mg/kg per hour from -30 through 210 minutes). Intestinal permeability was assessed by measuring plasma-to-lumen clearances of two hydrophilic probes (chromium 51-labeled edetic acid monohydrate [EDTA] and urea) and by expressing the results as a clearance ratio (CEDTA/CUREA). Survival was 100%, 67%, and 100% in groups RL, RL + LPS, and RL + LPS + ibuprofen, respectively. Among survivors only, CEDTA/CUREA increased significantly over time in both endotoxic groups, but not in nonendotoxic controls. Treatment with ibuprofen transiently blocked LPS-induced mesenteric hypoperfusion. These data indicate that mediators other than cyclooxygenase-derived metabolites of arachidonic acid are responsible for the adverse effect of LPS on mesenteric permeability to hydrophilic solutes in this porcine model.

Topics: Animals; Hemodynamics; Hydrogen-Ion Concentration; Ibuprofen; Ileum; Intestinal Mucosa; Lipopolysaccharides; Male; Oxygen; Permeability; Shock, Septic; Swine; Thromboxane B2

The release of eicosanoids during endotoxin shock was investigated in anesthetized pigs receiving 5 micrograms/kg Escherichia coli lipopolysaccharide (LPS) over 60 min into the superior mesenteric artery. TXB2, 6-keto PGF1 alpha and LTB4 concentrations in blood obtained from the superior mesenteric vein (SMV), right ventricle (RV) and aorta, during LPS infusion and an additional period of 2 h, were assessed along with hemodynamic variables, blood gases and pH and laboratory parameters. Half of the animals died within 30 min after termination of LPS infusion (non-survivors, n = 8), while the other half survived the experimental period of 3 h, though in a shock state (survivors, n = 9). The non-surviving pigs demonstrated progressively reduced cardiac output, hypotension and hypoperfusion in all organs. The surviving pigs demonstrated also a reduced cardiac output, which however was compensated by an elevated systemic vascular resistance resulting in a maintenance of arterial blood pressure. After exhausting this compensation the flow to non-vital organs increased and consequently arterial blood pressure was reduced resulting in hypoperfusion. In survivors a marked, though, transient increase was measured in concentrations of TXB2 and 6-keto PGF1 alpha level. A significant increase was measured in plasma concentration of LTB4 in SMV without any elevation in RV and aorta. LTB4 production started when prostanoid release had decreased. In contrast to survivors, no changes could be observed in eicosanoid release for non-survivors. A correlation was observed between systemic vascular resistance and TXB2 to 6-keto PGF1 alpha ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Cerebrovascular Circulation; Endotoxins; Escherichia coli; Female; Hemodynamics; Leukotriene B4; Reference Values; Regional Blood Flow; Shock, Septic; Swine; Thromboxane B2; Time Factors; Vascular Resistance

To evaluate the effects of ibuprofen on gram-negative septic shock, immature piglets were subjected to fecal-Escherichia coli peritonitis. Group I (n = 5) received a 12.5 mg/kg bolus of ibuprofen in 0.9% benzyl alcohol, followed by a continuous infusion of 6.25 mg/kg/h. Group II (n = 5) received the vehicle, benzyl alcohol, and Group III (n = 5) received lactated Ringer's solution. Mean survival times among the three groups were not significantly different. Ibuprofen-treated animals had a mean survival time (+/- S.E.M.) of 17.1 +/- 2 h vs. 19.2 +/- 2.4 h in the benzyl alcohol group and 15.7 +/- 2.7 h in the animals receiving lactated Ringer's solution. Thromboxane B2 levels were not significantly different in the treatment vs. non-treatment groups while 6-keto-PGF1a levels were significantly lower in the ibuprofen-treated animals. Neutropenia and thrombocytopenia were not prevented by treatment with ibuprofen.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Escherichia coli Infections; Ibuprofen; Leukocyte Count; Peritonitis; Platelet Count; Pulmonary Circulation; Shock, Septic; Swine; Thromboxane B2; Vascular Resistance

The effect of vitamin D3 analogues on endotoxin shock in mice was investigated. Male ICR mice were orally administered vitamin D3 analogues or vehicle, accompanied by an intraperitoneal injection of endotoxin (E. Coli lipopolysaccharide, LPS, 20 mg/kg). Endotoxin caused a decrease in survival rate in a time-dependent manner. Increases in plasma immunoreactive (i) eicosanoid and hepatic malondialdehyde (MDA) levels were also observed. Administration of 1 alpha-hydroxyvitamin D3 (1 alpha-OH-D3) improved the survival rate 24 to 48 h after endotoxin treatment. The effects were markedly observed at a dose of 20 ng/kg. In addition, 1 alpha-OH-D3 restored the plasma iTXB2 and hepatic MDA levels 8 h after endotoxin injection. However, it did not affect plasma iPGE2, i6-keto-PGF1 alpha and blood iLTB4 levels. At a dose of 20 ng/kg, both 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) and 1,24(R)-dihydroxyvitamin D3 (1,24(R)-(OH)2D3) restored the survival rate, the plasma iTXB2 and hepatic MDA levels. These results suggest that vitamin D3 analogues may inhibit endotoxemia through regulation of the formation of TXA2 and free radicals.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcitriol; Cholecalciferol; Dihydroxycholecalciferols; Dinoprostone; Endotoxins; Leukotriene B4; Liver; Male; Malondialdehyde; Mice; Mice, Inbred ICR; Radioimmunoassay; Shock, Septic; Thromboxane B2

Platelet-activating (PAF) is a putative mediator in endotoxemia and sepsis. Administration of a PAF receptor antagonist prior to endotoxin improves survival in rats and attenuates the hypotension of endotoxemia. Both PAF and endotoxin stimulate eicosanoid production. We hypothesized that a PAF receptor antagonist, BN 52021, would alter the hemodynamic events, improve the survival and attenuate the eicosanoid release associated with endotoxemia in a resuscitated, but lethal, canine model. Male dogs were randomzied to two groups (n = 10 each). Group I received only E. coli endotoxin, 1 mg/kg IV, at time 0, while group II received BN 52021, 5 mg/kg IV, 30 min before and again 240 min after endotoxin treatment. During the 4-h study period, hemodynamics were measured and blood samples were taken at 0, 2, 60, 120, and 240 min. Survival was determined at 24, 48, and 72 h. All group I animals died before 24 h; all group II lived longer than 72 h (P less than 0.05). In group I, plasma TXB2 values increased from a baseline value of 0.26 +/- .04 ng/ml to 4.38 +/- 1.56 ng/ml at 120 min and then decreased to 2.64 +/- .96 ng/ml by 240 min. For group II, respective plasma TXB2 values were 0.35 +/- 0.13 ng/ml at baseline, 0.58 +/- 0.14 ng/ml at 120 min, and 0.39 +/- .09 ng/ml at 240 min. At the 120-min and 240-min time points, the groups differed at P less than 0.05. Heart rate tended to be less in group II, but MAP was unaffected. In group I, pH values were more acidotic than those observed in group II.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprostone; Diterpenes; Dogs; Endotoxins; Escherichia coli; Ginkgolides; Hemodynamics; Hydrogen-Ion Concentration; Lactones; Male; Platelet Membrane Glycoproteins; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Shock, Septic; Thromboxane B2

We compared the time course of plasma and pulmonary lymph levels of thromboxane B2 (TxB2) and 6-keto-prostaglandin (PG)F1 alpha during the development of either the hyperdynamic phase of sepsis or of the multiple organ failure syndrome (MOFS) associated with sepsis in 26 chronically instrumented awake sheep with intravascular catheters and a chronic pulmonary lymph fistula. Using a continuous i.v. infusion of Escherichia coli endotoxin administered at a rate of 20 ng.kg-1.min-1 (group E20, n = 9) resulted in hyperdynamic septic shock with more than 75% of animals surviving after 72 h of continuous endotoxin administration. Infusing endotoxin at a higher dosage (40 ng.kg-1.min-1; group E40, n = 9) resulted in the development of respiratory failure and MOFS with death occurring within 55 hr of endotoxemia. Eight similarly instrumented sheep served as controls. Administration of endotoxin produced within 4 hr in both endotoxin groups a significant increase in arterial plasma concentration of TxB2, which was not significantly different between both endotoxin groups. Thereafter, plasma TxB2 concentrations progressively decreased in the E20 group to reach at 36 hr values significantly lower than those measured in control sheep not given endotoxin. In the E40 group, plasma TxB2 concentrations returned to baseline values during the development of a MOFS. The time course of TxB2 concentrations in pulmonary lymph in both endotoxin groups was similar to that measured in each group in plasma. 6-Keto-PGF1 alpha concentrations in arterial plasma and pulmonary lymph were significantly higher than in controls during the first 20 hr following the start of endotoxin infusion in both endotoxin groups and were not different between these groups. Thereafter, plasma and pulmonary lymph 6-keto-PGF1 alpha concentrations progressively returned to baseline values in the E20 group and remained at these levels up to the end of the study period (72 hr). In the E40 group, plasma 6-keto-PGF1 alpha concentrations also decreased to baseline values during the second day of endotoxemia but then significantly increased in sheep that survived more than 36 hr and developed a hypodynamic septic state. During the first 24 hr of endotoxemia, the plasma TxB2/6-keto-PGF1 alpha ratio was similar in controls and in both endotoxin groups. During the second study day, TxB2/6-keto-PGF1 alpha ratio progressively decreased in both endotoxin groups to reach and maintain values significantly lower than tho

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Escherichia coli; Female; Hemodynamics; Kinetics; Lung; Lymph; Male; Multiple Organ Failure; Sheep; Shock, Septic; Thromboxane B2

30 rabbits received an infusion of lipopolysaccharide B (75 micrograms/kg.h) over 4 hours (groups E, EI, EA; n = 10 each). Saline was given to a control group (C; n = 8). In group EI, prostacyclin (PGI2; 500 ng/kg.min) was given simultaneously to endotoxin. Into group EA animals, aspirin (20 mg/kg) was injected before the endotoxin infusion was started. PGI2 and aspirin both improved survival of animals (6/10 each vs. 2/10 in group E). The drop of platelet counts was significantly reduced by PGI2, while leukocyte depletion was similar in all endotoxin groups. PGI2 preserved the functional capacity of platelets as indicated by collagen stimulated aggregation and thromboxane formation. PGI2 but not aspirin significantly reduced renal fibrin deposition.

Topics: Animals; Aspirin; Blood Coagulation; Blood Platelets; Blood Pressure; Carbon Dioxide; Epoprostenol; Fibrin; Fibrinogen; Lactates; Lactic Acid; Leukocyte Count; Oxygen; Partial Thromboplastin Time; Platelet Aggregation; Platelet Count; Prothrombin Time; Rabbits; Shock, Septic; Survival Analysis; Thromboxane B2

Exogenous platelet activating factor (PAF) causes hypotension, plasma extravasation, metabolic acidosis, and death. These effects are similar to those of endotoxin as well as the eicosanoids. A specific PAF receptor antagonist, BN52021, was used to determine its effects on the hemodynamic events, the eicosanoid production, and on survival in severe rat endotoxemia. Endotoxin alone significantly produced hypotension, prostaglandins (TxB2, PGE2) release, and death. In contrast pretreatment with BN52021, a specific PAF receptor antagonist, significantly altered the hypotension, significantly attenuated the eicosanoid release, and improved the survival rate (p less than 0.01). These findings suggest that PAF receptor activation is an early event in endotoxemia. Eicosanoid release in endotoxemia could be related to PAF synthesis and PAF receptor activation. These findings support the hypothesis that there may be an intimate relationship between PAF and the eicosanoids and that in endotoxemia some of the effects of PAF may be mediated via the cyclo-oxygenase pathway.

Topics: Animals; Dinoprostone; Diterpenes; Endotoxins; Escherichia coli; Ginkgolides; Lactones; Male; Plant Extracts; Platelet Activating Factor; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

Hypotension, respiratory failure and ARDS-like pulmonary morphological changes were induced by given continuous intravenous infusion of E. coli endotoxin (1-1.5 micrograms.kg/h) in goats. During endotoxin infusion, plasma TXB2 level rose markedly with peak at 0.5 h and then lowered, while 6-keto-PGF1 alpha elevated progressively with its highest level before death, and correlated with blood pressure and survival times negatively. So we suggested that prostacyclin may be one of the factors responsible for hypotension and death in late period of endotoxin induced shock and lung injury.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Escherichia coli; Goats; Lung; Respiratory Distress Syndrome; Shock, Septic; Thromboxane B2

The effect of sodium 4-[alpha-hydroxy-5-(imidazolyl)-2-methylbenzyl]-3,5-dimethyl benzoate dihydrate (Y-20811), a selective thromboxane (TX) synthetase inhibitor, on endotoxin shock was investigated in comparison with aspirin. The drugs were orally administered to rabbits at 24 and 1 hour before injection of endotoxin (5 mg/kg, i.v.). Y-20811 (1 mg/kg) promoted the recovery of decreased platelet counts, and inhibited hypotension induced by endotoxin. It also inhibited the increase in plasma TXB2 and 6-keto PGF1 alpha. Aspirin at 30 mg/kg, inhibited hypotension and the increase in both plasma TXB2 and 6-keto PGF1 alpha levels, but it failed to inhibit the decrease in platelet counts. In the control group, all rabbits died within 180 min after endotoxin injection, while Y-20811 completely protected animals against death at a dose of 0.3 mg/kg. Aspirin also protected animals against death at a dose of 30 mg/kg, which was, however, about one hundredth potent of Y-20811. These results indicate that Y-20811 is useful in treating endotoxin shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Pressure; Imidazoles; Male; Rabbits; Shock, Septic; Survival Rate; Thromboxane B2; Thromboxane-A Synthase

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

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

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Creatinine; Dinoprost; Epoprostenol; Hemodynamics; Kidney; Male; Prostaglandins; Renal Circulation; Shock, Septic; Swine; Thromboxane B2

The effect of two chemically dissimilar cyclooxygenase inhibitors was studied in pentobarbital-anesthetized endotoxic pigs. Animals in groups II-IV were infused with Escherichia coli lipopolysaccharide (LPS, 150 micrograms/kg) and resuscitated with normal saline (1.2 ml.kg-1.min-1). Animals in group I (n = 4) were resuscitated as above but were not infused with LPS. Animals in group II (n = 7) served as endotoxic controls. Pigs in groups III (n = 6) and IV (n = 5) were pre- and posttreated with ibuprofen (10 mg/kg bolus then 10 mg.kg-1.h-1 and meclofenamate (5 mg/kg then 5 mg.kg-1.h-1, respectively. Ileal intramucosal hydrogen ion concentration [( H+]) was estimated tonometrically. In group I, cardiac index (CI), mean arterial pressure (MAP), superior mesenteric arterial perfusion (QSMA), and mesenteric O2 delivery (DO2) increased significantly, but other variables were unchanged. After infusion of LPS in group II, MAP and systemic vascular resistance index were markedly diminished but CI was well preserved. In this group, QSMA, systemic DO2, and mesenteric DO2 decreased, whereas systemic O2 uptake (VO2) and gut [H+] increased; mesenteric VO2 was unchanged. Compared with pigs in group II, pigs treated with ibuprofen or meclofenamate manifested improved systemic and mesenteric DO2. In groups III and IV, QSMA remained normal, increased systemic VO2 was not observed, and gut intramucosal acidosis was ameliorated. Increased intramucosal [H+] in group II suggests that QSMA was inadequate. The salutary effects of ibuprofen and meclofenamate suggest that inadequate mesenteric perfusion was mediated, at least in part, by cyclooxygenase-derived metabolites or arachidonic acid.

Topics: 6-Ketoprostaglandin F1 alpha; Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Endotoxins; Hemodynamics; Hydrogen-Ion Concentration; Ibuprofen; Lipopolysaccharides; Male; Meclofenamic Acid; Mesentery; ortho-Aminobenzoates; Oxygen; Shock, Septic; Swine; Thromboxane B2

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

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

In a study using rats, we investigated whether liver damage induced by endotoxemia in obstructive jaundice is associated with thromboxane (TX) in order to acertain whether its vasoconstrictive and platelet aggregating properties play a role in reducing liver blood flow. The rats were divided into the following 5 groups; a control group, an endotoxin (Et) group, a bile duct ligation (BDL) group, a bile duct ligation and endotoxin (BDL + Et) group and an OKY046 (Thromboxane synthetase inhibitor) treated bile duct ligation + endotoxin (OKY-BDL + Et) group. The blood TXB2 levels in the Et, BDL and BDL + Et groups were higher than those in the control group. The liver TXB2 levels in the Et and BDL + Et groups were also higher than those in the control group. Liver phospholipids and liver blood flow decreased in the BDL + Et group, whereas in the OKY-BDL + Et group they returned close to the control group levels by decreasing the TXB2 levels in both the liver and blood to normal. These results suggest that the high level of TX in the blood and liver tissue may further aggrevate the liver during endotoxemia in obstructive jaundice by inhibiting liver blood flow.

Topics: Animals; Cholestasis, Extrahepatic; Escherichia coli Infections; Liver; Liver Circulation; Liver Cirrhosis, Biliary; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

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

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

Endotoxin given intraperitoneally to rats induced leucopenia and pulmonary oedema over 28 hr. The output of cyclo-oxygenase products PGE2, PGF2 alpha, TxB2, and 6-oxo-PGF1 alpha, from the perfused lungs isolated from these rats was measured using as substrate either exogenous arachidonate or endogenous arachidonate stimulated by the calcium ionophore A23187. From exogenous or endogenous arachidonate, the major effects of endotoxin were increased TxB2 and PGF2 alpha output and decreased 6-oxo-PGF1 alpha output. Treatment with methylprednisolone 30 min after endotoxin prevented the pulmonary oedema and leucopenia. The output of TxB2 and PGF2 alpha was unaltered, whereas that of 6-oxo-PGF1 alpha was increased. Our results do not support the suggestion that the beneficial effects of methylprednisolone in this model of acute lung injury are due to inhibition of prostanoid synthesis. Benefit may be better correlated with increased PGI2 formation.

Topics: Animals; Endotoxins; Male; Methylprednisolone; Prostaglandins E; Prostaglandins F; Pulmonary Edema; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

Septic shock is known to involve increased metabolism of arachidonic acid and generation of certain eicosanoids. Recently, a new extracellular pool of unsaturated fatty acids including arachidonate has been found in relation to group-specific component (Gc), a vitamin D-binding plasma protein that sequesters monomeric G-actin. Since complexing with G-actin displaces fatty acids, possible alterations in plasma levels of Gc and extent of complexing were sought in serial samples obtained from rats with shock induced by Salmonella enteritidis endotoxin (12.5-15 mg kg-1). Gc levels in animals receiving endotoxin exhibited bimodal alterations, with a significant reduction (P less than 0.001) at 1 hour, followed by a progressive elevation to 160% of starting concentrations at 6 days in animals that survived, whereas in sham-injected animals the change observed was a continuous rise to 147% at 6 days. A statistically significant increase in the percentage of Gc complexed was observed in all endotoxemic rats from 2 hours onward (P less than 0.01), in contrast to sham-injected animals, in which the percentage of Gc complexed remained at less than 5%. Levels in survivors peaked at 30 +/- 5.2% at 8 hours and then decreased to normal (2 +/- 0.9%) by 6 days (n = 7), whereas in nonsurvivors complexed Gc continued to rise until time of death (66-80%) at 6-12 hours (n = 4). Correlation of these results with glucose, transaminases, and immunoreactive TXB2 and 6-keto-PGF1 alpha indicated that decreased absolute levels of Gc represent a consistent early change in endotoxic shock and that the percentage of Gc complexed is an accurate prognostic indicator of severity.

Topics: Actins; Animals; Rats; Shock, Septic; Thromboxane B2; Vitamin D-Binding Protein

The effect of the leukotriene D4, leukotriene E4 (LTD4/E4) receptor antagonist LY-171883 was studied in endotoxemia. Eighteen awake sheep were divided into three groups. In Group (n = 4) 4 mg/kg LY-171883 was twice injected intravenously. In Group II (n = 9) 1 microgram/kg E. coli endotoxin was administered intravenously. In Group III (n = 5) 4 mg/kg LY-171883 was given 15 min before, and 30 min after endotoxin. Infusion of LY-171883 in Group I did not alter baseline hemodynamic and pulmonary measurements. Infusion of endotoxin in Group II was followed by an initial rise of pulmonary artery pressure (PAP) to 51 torr (P less than 0.001), pulmonary microvascular pressure (Pmv) to 25 torr (P less than 0.005), pulmonary vascular resistance (PVR) to 1,019 dynes sec. cm-5 (P less than 0.001), systemic vascular resistance (SVR) to 2,830 dynes sec. cm-5 (P less than 0.001), plasma thromboxane B2 (TXB2) to 4,971 pg/ml (P less than 0.001), lymph TXB2 to 5,500 pg/ml (P less than 0.001), plasma 6-Keto PGF1 alpha to 1,469 pg/ml (P less than 0.005), and lymph 6-Keto PGF1 alpha to 2,518 pg/ml (P less than 0.005). The cardiac index (CI) fell to 100 ml/min. kg (P less than 0.01), PaO2 to 61 torr (P less than 0.01), and circulating WBC to 2,800 microliter (P less than 0.001). This was followed by a rise in pulmonary lymph flow (QL) to 35 ml/h (P less than 0.01) and lymph protein clearance (L/P.QL) to 23 ml/h (P less than 0.01). Pretreatment with LY-171883 in Group III resulted in rise of PAP to 35 torr (P less than 0.005), PmV to 18 torr (P less than 0.05), PVR to 398 dynes sec. cm-5 (P less than 0.01), SVR to 1,732 dynes sec. cm-5 (P less than 0.05), and CI increased to 170 ml/min.kg (P less than 0.005). L/P.QL, QL, Hgb, WBC, PaO2, PaCO2, Qs/QT, plasma and lymph TXB2, and plasma and lymph 6-Keto PGF1 alpha were not significantly changed by LY-171883. It is concluded that LY-171883 inhibited the smooth muscle effects of endotoxin, namely reduced PAP, Pmv, PVR, and SVR and increased cardiac output. Hypoxemia and increased pulmonary vascular permeability were unaffected by this leukotriene receptor antagonist.

Topics: 6-Ketoprostaglandin F1 alpha; Acetophenones; Animals; Azoles; Blood Pressure; Cardiac Output; Leukocyte Count; Lung; Lymph; Oxygen; Pulmonary Artery; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4; Sheep; Shock, Septic; Tetrazoles; Thromboxane B2; Vascular Resistance

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

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

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

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cells, Cultured; Dinoprost; Female; Macrophages; Mice; Peritoneal Cavity; Shock, Septic; Solanaceous Alkaloids; Thromboxane B2

The effects of a highly selective 5-lipoxygenase inhibitor, CGS8515 [methyl 2-[(3,4-dihydro-3,4-dioxo-1-naphthalenyl) amino]benzoate], on endotoxic shock sequelae and eicosanoid synthesis by peritoneal macrophages were evaluated in the rat. Pretreatment of peritoneal macrophages in vitro with CGS8515 significantly inhibited the synthesis (P less than .01) of immunoreactive leukotriene C4/leukotriene D4 stimulated by the calcium ionophore (A23187). Inhibition of 5-lipoxygenase produced significant shunting to immunoreactive thromboxane B2 formation (P less than .05). In rats sedated with ketamine.HCl (82.5 mg/kg) and xylazine. HCl (27.5 mg/kg), i.v. injection of Salmonella enteritidis endotoxin (25 mg/kg i.v.) produced significant decreases at 30 min in mean arterial pressure (from 89 +/- 4 to 44 +/- 8 mm Hg, N = 5, P less than .001); in white blood cell count (from 10.8 +/- 0.6 to 6.5 +/- 0.8 x 10(3)/mm3, N = 5, P less than .01); in platelet count (from 687 +/- 66 to 392 +/- 65 x 10(3)/mm3, N = 5, P less than .01); and produced an increase of hematocrit (from 46 +/- 1.2 to 57.4 +/- 1.8%, N = 5, P less than .03). CGS8515 (5 mg/kg i.v. 30 min before endotoxin injection, N = 6) blunted the endotoxin-induced hypotension by 35% (P less than .001), the leukopenia by 24% (P less than .03), the thrombocytopenia by 45% (P less than .006) and the hemoconcentration by 16% (P less than .03), compared to the shocked control rats 30 min after endotoxin injection.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arachidonate Lipoxygenases; Blood Pressure; Hematocrit; Leukopenia; Lipoxygenase Inhibitors; Male; Naphthoquinones; ortho-Aminobenzoates; Rats; Shock, Septic; Thrombocytopenia; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Drugs, Chinese Herbal; Infusions, Intravenous; Male; Rats; Rats, Inbred Strains; Shock, Septic; Solanaceous Alkaloids; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Child; Child, Preschool; Female; Humans; Indomethacin; Infant; Male; Rabbits; Shock, Septic; Thromboxane B2

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

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

The effects of an opiate antagonist naloxone and a cyclooxygenase inhibitor ibuprofen on organ blood flow during endotoxic shock were evaluated in a fluid-resuscitated porcine endotoxic shock model. Radiolabeled microspheres were used to measure regional blood flow. Escherichia coli endotoxin (0.1 mg/kg), infused intravenously over 40 min, reduced mean arterial blood pressure to 50 mmHg and systemic vascular resistance to 57% of control without affecting cardiac output. Endotoxin reduced blood flow to cerebrum (to 49% of control), kidney (to 25% of control), spleen, and skeletal muscle, while blood flow to left ventricle, stomach, and small and large intestines were unaffected. Sixty minutes after endotoxin administration, animals were randomized to one of three groups. Group I animals were controls and received no drug, group II animals received ibuprofen (12.5 mg/kg iv), and group III animals received naloxone (2 mg/kg iv) 60 min after endotoxin. Ibuprofen increased mean arterial blood pressure to 80 mmHg and increased blood flow to both cerebrum (to 92% of control) and kidney (to 47% of control). Plasma levels of thromboxane B2 and 6-ketoprostaglandin F1 alpha were increased 8- and 16-fold, respectively, after endotoxin, and both were decreased by ibuprofen. Naloxone increased mean arterial blood pressure to 62 mmHg but had no effect on regional blood flow or plasma cyclooxygenase metabolite levels. These data suggest that cyclooxygenase metabolites may contribute to decreased mean arterial blood pressure and reduced organ blood flow during endotoxic shock in the pig.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hemodynamics; Ibuprofen; Microspheres; Naloxone; Regional Blood Flow; Shock, Septic; Swine; Thromboxane B2

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Temperature; Capillary Permeability; Endotoxins; Escherichia coli; Hemodynamics; Leukocyte Count; Lymph; Male; Platelet Count; Pyrazoles; Rats; Rats, Inbred Strains; Sheep; Shock, Septic; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Fibrin; Kidney Glomerulus; Lipopolysaccharides; Platelet Aggregation; Platelet Count; Rabbits; Shock, Septic; Thromboxane B2

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Male; Radioimmunoassay; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

Eicosanoids have been implicated in the pathophysiology of endotoxic shock. Drugs which alter eicosanoid production such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAID) are beneficial in treating endotoxic shock. Experiments were conducted to investigate the efficacy of dexamethasone, a corticosteroid, and/or flunixin meglumine, a NSAID, in treating endotoxin-induced changes in calves. Fourteen male calves were assigned to one of four treatment groups: group 1, endotoxin-untreated; group 2, endotoxin-flunixin meglumine treated; group 3, endotoxin-dexamethasone-treated; group 4, endotoxin-flunixin meglumine and dexamethasone-treated. Each calf was given three intravenous and intraperitoneal injections of E. coli endotoxin. Hemodynamic, blood gas, blood chemical and eicosanoid level determinations were obtained. Thirty minutes after endotoxin injection, pulmonary artery pressure (PAP) increased and cardiac output (CO) decreased compared with baseline, corresponding to increased thromboxaneB2 levels in groups 1 and 3. These groups exhibited a decreased mean arterial pressure (MAP) at three and five hours corresponding to increased 6-keto-prostaglandinF1 alpha. The MAP, PAP and CO of group 4 remained near baseline for the entire six hours, except for a late drop in MAP. Lactic acid levels were significantly increased and arterial bicarbonate levels were reduced by six hours in all groups except for group 4. These results indicate that the combination treatment of flunixin meglumine and dexamethasone prevents many of the metabolic derangements observed during endotoxic shock in calves.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Bicarbonates; Blood Pressure; Cardiac Output; Cattle; Cattle Diseases; Clonixin; Dexamethasone; Drug Therapy, Combination; Endotoxins; Heart Rate; Hydrogen-Ion Concentration; Lactates; Lactic Acid; Male; Nicotinic Acids; Respiration; Shock, Septic; Thromboxane B2

We studied the effects of a selective leukotriene (LT) antagonist (FPL 57231, 2 mg kg-1 min-1) on the acute cardiopulmonary changes observed in feline endotoxin shock. LTC4 and LTD4 (0.1-3.0 micrograms kg-1) given intravenously had little or no activity on pulmonary arterial pressure (PAP), dynamic lung compliance (Cdyn), and airways resistance (Raw). They did, however, produce a systemic hypertension, which was significantly attenuated during the FPL 57231 infusion. E. coli endotoxin (2 mg kg-1) administration resulted in decreases in systemic arterial blood pressure and Cdyn, together with increases in both PAP and Raw. During infusion of FPL 57231, all these endotoxin-induced cardiopulmonary changes were attenuated. Radioimmunoassay of blood samples taken from cats given FPL 57231 showed that levels of 6-keto prosta-glandin F1 alpha and thromboxane B2 were not significantly increased by endotoxin, as would normally be expected in cats administered endotoxin. FPL 57231 was also found to antagonise the pulmonary effects of the thromboxanemimetic U46619 and of prostaglandin F2 alpha. These results indicate that it is unlikely that the leukotrienes are involved as important mediators of the acute phase of endotoxin shock in cats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Airway Resistance; Animals; Blood Pressure; Cats; Chromones; Dinoprost; Endotoxins; Escherichia coli; Evaluation Studies as Topic; Hypertension, Pulmonary; Infusions, Intravenous; Lung Compliance; Male; Prostaglandin Endoperoxides; Prostaglandin Endoperoxides, Synthetic; Prostaglandins F; Pulmonary Circulation; Shock, Septic; SRS-A; Thromboxane B2

Effect of IV infusions of smooth and rough Pasteurella hemolytica lipopolysaccharides (LPS; 24 ng/kg/min for 500 min) on circulating levels of arachidonic acid, prostaglandins (PG), thromboxane B2 (TxB2), histamine, and serotonin in calves was evaluated. Both smooth and rough LPS had no effects on plasma PGE but caused maximal increases in arachidonic acid, TxB2, and PGF2 alpha at 1 hr and 6-keto-PGF1 alpha at 3 hr of infusion, respectively. The increases in arachidonic acid and its metabolites were greater and more prolonged for smooth LPS than for rough LPS. Although both rough and smooth LPS increased plasma serotonin transiently at 25 min of infusion, only rough LPS decreased serotonin in the later period of endotoxemia. In contrast, smooth, but not rough, LPS decreased plasma histamine during endotoxemia. These results indicate that during endotoxemia there is increased PG and TxA2 synthesis secondary to marked arachidonic acid release into circulation. The data also demonstrate that smooth and rough LPS differ in their abilities to release histamine, serotonin, and eicosanoids. These effects might be due to differences in the in vivo mechanisms of action of smooth and rough LPS and may partly explain the differential potency of smooth and rough LPS in producing pathophysiological changes.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Autacoids; Cattle; Fatty Acids; Histamine; Lipopolysaccharides; Male; Pasteurella; Prostaglandins; Serotonin; Shock, Septic; Thromboxane B2

Altered macrophage arachidonic acid metabolism may play a role in endotoxic shock and the phenomenon of endotoxin tolerance induced by repeated injections of endotoxin. Studies were initiated to characterize both lipoxygenase and cyclooxygenase metabolite formation by endotoxin tolerant and non-tolerant macrophages in response to 4 different stimuli, i.e. endotoxin, glucan, zymosan, and the calcium ionophore A23187. In contrast to previous reports of decreased prostaglandin synthesis by tolerant macrophages, A23187-stimulated immunoreactive (i) leukotriene (LT)C4/D4 and prostaglandin (PG)E2 production by tolerant cells was greater than that by non-tolerant controls (p less than 0.001). However, A23187-stimulated i-6-keto-PGF1 alpha levels were lower in tolerant macrophages compared to controls. Stimulation of prostaglandin and thromboxane (Tx)B2 synthesis by endotoxin or glucan was significantly less in tolerant macrophages compared to controls (p less than 0.05). iLTC4/D4 production was not significantly stimulated by endotoxin or glucan, but was stimulated by zymosan in the non-tolerant cells. Synthesis of iLTB4 by control macrophages was stimulated by endotoxin (p less than 0.01). These results demonstrate that arachidonic acid metabolism via the lipoxygenase and cyclooxygenase pathways in macrophages is differentially altered by endotoxin tolerance.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Calcimycin; Dinoprostone; Drug Tolerance; Endotoxins; Glucans; Lipoxygenase; Macrophages; Phospholipases A; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Rats; Shock, Septic; SRS-A; Thromboxane B2; Zymosan

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

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

Previous studies have suggested that increased alpha adrenergic activity stimulated prostaglandin synthesis and may be involved in the modulation of eicosanoid metabolism. These observations prompted investigation of the effect of the alpha adrenergic receptor antagonist phenoxybenzamine and the cyclo-oxygenase inhibitor indomethacin on endotoxin-induced shock severity, and on plasma immunoreactive iTxB2 and i6-keto-PGF1 alpha, the stable metabolites of TxA2 and PGI2, respectively. Pretreatment with indomethacin alone blunted the endotoxin- (8 mg/kg) induced hypoglycemia. Phenoxybenzamine pretreatment also blunted endotoxin-induced mortality (LD80), hypoglycemia, hemoconcentration, and decreased plasma beta-glucuronidase (BG). The combination of phenoxybenzamine and indomethacin resulted in the improvement of all indices of shock severity. Rats pretreated with phenoxybenzamine and indomethacin alone or conjointly also exhibited significantly (P less than 0.05) enhanced survival compared to that of shocked control rats. Percent survival at 48 hr was 24, 64, 80, and 92 in untreated, indomethacin, phenoxybenzamine, and indomethacin + phenoxybenzamine treated, respectively. Mean plasma iTxB2 values at 30 min postendotoxin (15 mg/kg i.v.) were 1,532 +/- 319 pg/ml (N = 10). Phenoxybenzamine pretreatment decreased iTxB2 to 719 +/- 114 pg/ml (N = 10). Phenoxybenzamine pretreatment decreased iTxB2 to 719 +/- 114 pg/ml (N = 10) (P less than 0.05). Plasma i6-keto-PGF1 alpha was increased 4 hr after endotoxin in shocked controls to 4,161 +/- 885 pg/ml (N = 5) and attenuated by phenoxybenzamine to a value of 1,184 +/- 363 pg/ml (N = 4) (P less than 0.05). The results suggest that increased alpha adrenergic activity may be an important stimulus for arachidonic acid metabolism during endotoxemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Arachidonic Acids; Indomethacin; Male; Phenoxybenzamine; Rats; Shock, Septic; Thromboxane B2

Topics: Animals; Digestive System; Endothelium; Humans; Interleukin-1; Lung; Macrophages; Multiple Organ Failure; Neutrophils; Prostaglandins; Rabbits; Respiratory Distress Syndrome; Shock, Septic; Syndrome; Thromboxane B2

Activated complement, thromboxane A2, prostacyclin, and activated granulocytes have been implicated in hemodynamic dysfunction after trauma, in sepsis, and in hypovolemic and septic shock. This study evaluated the interaction of plasma concentrations of complement components C3a and C5a, thromboxane B2 (TxB), prostaglandin 6-keto-F1 alpha (PGI), and granulocyte aggregation in clinical sepsis and hypotension. Forty-eight critically ill patients were followed clinically for as long as 10 days. Plasma C3a, C5a, TxB, and PGI were measured daily by the radioimmunoassay method. Granulocyte aggregation, the percentage of maximum aggregation of zymosan-activated plasma standard curves, was performed with patient plasma and normal human leukocytes. Patients were studied in four groups: group I, nonseptic, normotensive; group II, hypovolemic shock, group III, normotensive severe sepsis; and group IV, septic shock. Plasma from 12 normal adults was the control value. PGI, TxB, C3a, C5a, and granulocyte aggregation in patients were greater than that in the control subjects. Granulocyte aggregation was increased in groups III and IV versus groups I and II. C3a was increased in group IV versus groups II and III. C5a and TxB did not vary between groups. PGI was greatly increased in group IV compared with groups I through III. C3a and C5a decreased in nonsurvivors. PaO2/FiO2 ratios correlated directly with PGI and inversely with C3a and TxB/PGI. Plasma PGI and C3a are increased in septic shock. C3a and TxB/PGI imbalances are involved in hypovolemic and septic shock.

Topics: Adolescent; Adult; Aged; Cell Aggregation; Complement Activation; Complement C3; Complement C3a; Complement C5; Complement C5a; Epoprostenol; Female; Granulocytes; Humans; Hypotension; Infections; Male; Middle Aged; Prospective Studies; Prostaglandins; Radioimmunoassay; Shock, Septic; Thromboxane B2

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

The thromboxane receptor antagonist EP 092 inhibits the acute pulmonary vascular response to E. coli endotoxin in the anaesthetized, closed-chest sheep. The increase in the TXB2 level in arterial blood was not suppressed by EP 092. Intravenous infusion of the thromboxane mimetic 11,9-epoxymethano PGH2, but not PGF2 alpha, raises pulmonary artery pressure and lowers arterial pO2 similar to the endotoxin. Isolated strips of lobar pulmonary veins but not lobar arteries are contracted by low concentrations of 11,9-epoxymethano PGH2 - the effects are potently inhibited by EP 092.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Blood Pressure; Dose-Response Relationship, Drug; Endotoxins; Escherichia coli; Prostaglandin Endoperoxides, Synthetic; Prostaglandin H2; Prostaglandins H; Prostaglandins, Synthetic; Pulmonary Circulation; Receptors, Cell Surface; Receptors, Prostaglandin; Receptors, Thromboxane; Sheep; Shock, Septic; Thromboxane B2; Vasoconstriction

Drugs that inhibit prostaglandin (PG) biosynthesis improve hemodynamics and survival in experimental endotoxic and septic shock. The therapeutic utility of these agents in the management of septic patients may be limited, however, by their tendency to decrease renal blood flow (RBF) in animals and humans stressed by experimental manipulations or disease states that promote renal vasoconstriction. In the present study, we addressed this question: can low-dose intravenous (iv) dopamine (4 micrograms/kg/min), a known renal vasodilator, improve renal perfusion in endotoxin-shocked dogs treated with the PG synthesis inhibitor, ibuprofen. RBF was measured in pentobarbital anesthetized dogs using an electromagnetic flow meter. After obtaining baseline hemodynamics, Escherichia coli endotoxin (1.5 mg/kg) was given iv. The dogs were randomized 30 min later into three groups: Group I received saline; Group II received ibuprofen (12.5 mg/kg, iv); Group III received ibuprofen plus dopamine. Comparison of Groups I and II revealed that ibuprofen increased mean arterial pressure (MAP) and systemic vascular resistance (SVR) (P less than 0.0001 and P = 0.002, respectively) and decreased RBF (P = 0.019). Adding low-dose dopamine (Group II vs Group III) did not significantly affect MAP or SVR, but did augment RBF (P less than 0.001). We conclude that low-dose dopamine improves renal hemodynamics in ibuprofen-treated endotoxemic dogs.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Diuresis; Dogs; Dopamine; Female; Hemodynamics; Ibuprofen; Infusions, Parenteral; Male; Radioimmunoassay; Renal Circulation; Shock, Septic; Thromboxane B2

Previous studies have suggested an important role of thromboxane (Tx) in the pathogenesis of endotoxin shock in the rat. The present study evaluated the role of thromboxane in an LD70 primate model of endotoxin shock by administering 6 mg/kg of endotoxin to three groups of animals that were pretreated with either saline (5 ml), OKY 1581 (2 mg/kg, 10 min prior), or imidazole (25 mg/kg/hr starting 30 min prior), groups I, II, and III, respectively. There were significant differences between the groups with respect to changes in MAP, PAP, and CO. OKY 1581 effectively blocked endotoxin-induced increase in plasma Tx. However, as a result of shunting of the endoperoxides into the prostacyclin pathway, there was a greater increase in plasma 6-keto PGF1 alpha, the stable hydrolysis product of prostacyclin. Imidazole augmented the formation of both prostacyclin and Tx. Despite the differences in plasma prostanoids, there was no difference between the groups with respect to changes in platelet or WBC counts, nor in survival: I (4/10); II (4/10); III (2/6).. (i) endotoxin-induced neutropenia and decrease in the platelet count are not Tx mediated; (ii) Tx is not solely responsible for the decrease in CO during endotoxin shock; (iii) it is possible to prevent endotoxin-induced increase in the PAP by either blocking Tx formation or by increasing endogenous PGI2 production; and (iv) Tx may not be a major contributing factor in the mortality of endotoxin shock in baboons.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Hemodynamics; Imidazoles; Leukocyte Count; Male; Methacrylates; Papio; Random Allocation; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes; Time Factors

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

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

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

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

This study investigates the interaction of thromboxane, prostacyclin, and the hemodynamic dysfunction of graded bacteremia. Arterial, venous, and pulmonary artery catheters were inserted into eight adult female pigs under barbiturate anesthesia. After a 60-min control period Aeromonas hydrophila (1.0 X 10(9)/ml) was infused intravenously at 0.2 ml/kg/hr, increasing gradually to 4.0 ml/kg/hr at 4 hr. Hemodynamic measurements, blood gases, and radioimmunoassay of thromboxane B2 (TxB) and prostaglandin 6-keto-F1 (PGI) were performed during the control period, at 10, 20, 30, 45, 60, 75, and 90 min of bacteremia and at 30-min intervals thereafter. During the bacterial infusion, cardiac index (CI), mean arterial pressure (MAP), paO2, pvO2, stroke volume (SV), and left ventricular stroke work (LVSW) decreased significantly, and pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), and intrapulmonary shunt (Qs/Qt) increased significantly. TxB was significantly increased at 30 min and remained elevated thereafter. PGI did not rise above control levels until after 240 min of bacterial infusion. TxB cross-correlated most frequently with CI, PVR, SV, paO2, and Qs/Qt, changes in TxB preceding the other variables by 0-60 min. PGI cross-correlated significantly with MAP, LVSW, CI, paO2, and Qs/Qt, changes in PGI preceding MAP, LVSW, and CI by 0-60 min, but following paO2 and Qs/Qt by 30-60 min. TxB is increased early in graded bacteremia and appears related to cardiorespiratory dysfunction. PGI increases late in graded bacteremia, following the onset of respiratory failure, and may mediate the arterial hypotension of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Aeromonas; Animals; Epoprostenol; Female; Hemodynamics; Respiration; Sepsis; Shock, Septic; Swine; Thromboxane B2

Infusion of Escherichia coli endotoxin (41.7 micrograms kg-1 min-1 i.v. for 4 h; 10 mg kg-1 total) in conscious unrestrained rats produced an increase in heart rate and a gradual decrease in arterial blood pressure. Initially plasma glucose was transiently elevated but fell to hypoglycaemic values in the 1-2 h before death. There was a marked elevation in the plasma concentrations of lactate, thromboxane B2, and 6-keto prostaglandin F1 alpha, (PGF1 alpha). Methylprednisolone treatment (two doses of 30 mg kg-1) significantly reduced mortality, provided the first dose was given before commencing the endotoxin infusion; there was no effect on mortality if it was given 2 h after starting the endotoxin infusion. Methylprednisolone pretreatment maintained arterial blood pressure and plasma glucose and prevented the increase in plasma lactate in rats given endotoxin. Methylprednisolone treatment did not modify the increase in plasma thromboxane B2 but attenuated the increase in plasma 6-keto PGF1 alpha concentrations. Pretreatment with BW755C, an inhibitor of both cyclooxygenase and lipoxygenase enzymes, completely prevented the increase in plasma prostanoid concentrations but did not improve survival or significantly modify any other detrimental effects of endotoxin. It is suggested that the beneficial effects of methylprednisolone in this model of endotoxin shock are not related to a reduction in the formation of pharmacologically active arachidonic acid metabolites.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; 6-Ketoprostaglandin F1 alpha; Animals; Antimetabolites; Arachidonic Acids; Blood Pressure; Heart Rate; Male; Methylprednisolone; Methylprednisolone Hemisuccinate; Pyrazoles; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2

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

The effect of exchange transfusion with the perfluorated blood substitute (Fluosol-43) on endotoxin-induced synthesis of immunoreactive (i) thromboxane (Tx)B2, the stable metabolite of TxA2, was investigated in rats. Fluosol-43 was infused via the femoral vein with matched, incremental blood withdrawal from the carotid artery. Blood was replaced with Fluosol-43 to a final hematocrit of less than 3% in anesthetized rats maintained on 95% O2 and 5% CO2. Circulating platelet counts were reduced from 875 +/- 47 X 10(3)/mm3 in sham controls (N = 21) to 75 +/- 10 X 10(3)/mm3 in Fluosol-43 exchange transfused rats (N2 = 19, P less than 0.001). Circulating leukocytes were decreased from 105 +/- 6.3 X 10(2)/mm2 in sham controls (N = 21) to 17 +/- 1.4 X 10(2)/mm3 in the exchange transfused group (N = 19, P less than 0.001). Immunoreactive (i)TxB2 was measured in plasma or Fluosol-43 obtained from rats prior to and after injection of Salmonella enteritidis endotoxin (20 mg/kg). The iTxB2 levels at 30 minutes after endotoxin increased from 438 +/- 83 pg/ml (N = 4) to 2,895 +/- 663 pg/ml (N = 7) (P less than 0.01) in sham controls. iTxB2 also increased from 242 +/- 23 pg/ml (N = 7) to 2,213 +/- 589 pg/ml (N = 7) in the Fluosol-43 group (P less than 0.002) following endotoxin. The iTxB2 levels also remained significantly elevated (P less than 0.01) in both the sham and the Fluosol-43 groups 2 hours after endotoxin treatment. Endotoxin-stimulated iTxB2 levels at both 30 minutes and 2 hours in sham and Fluosol-43 exchange transfused rats did not vary significantly from each other. Indomethacin pretreatment (2 mg/kg) inhibited the increase in iTxB2 levels by greater than 85% in both groups (P less than 0.004). Blood and Fluosol-43 were taken from sham and exchange transfused rats and incubated ex vivo with the calcium ionophore, A23187 (10 microM). These studies demonstrated that ionophore-stimulated iTxB2 synthesis in the ex vivo Fluosol-43 samples was only 2.6% that of whole blood. Collectively these observations suggest that tissues other than blood components are potential sources of iTxB2 synthesis in endotoxin shock.

Topics: Animals; Blood Substitutes; Exchange Transfusion, Whole Blood; Fluorocarbons; Leukocyte Count; Male; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2; Thromboxanes

Twenty-five patients with sepsis were studied retrospectively to examine the effects of methylprednisolone on plasma thromboxane B2 levels. Although the plasma iTxB2 level was elevated in patients dying from sepsis, the use of glucocorticoids did not reduce plasma iTxB2. Aspirin, a cyclo-oxygenase inhibitor, did reduce the plasma iTxB2 value in four patients. It does not appear that glucocorticosteroids significantly affect the conversion of arachidonic acid to thromboxane in septic patients.

Topics: Aspirin; Blood Coagulation; Glucocorticoids; Humans; Methylprednisolone; Oxygen; Oxygen Consumption; Radioimmunoassay; Shock, Septic; Thromboxane B2; Thromboxanes

Septicemia by gram-negative organisms is a common cause of the adult respiratory distress syndrome (ARDS). The role of neutrophils in causing parenchymal lung damage in ARDS has recently been emphasized. A single intraperitoneal injection of Escherichia coli endotoxin in rats causes acute neutrophil alveolitis similar to that of ARDS. We studied the ability of pretreatment with either ibuprofen (IBU) or methylprednisolone (MP) to ablate directly the alveolar inflammatory response to endotoxin in the rat model. To compare the severity of inflammation, we quantified inflammatory cell recovery by whole lung lavage 24 hours after injection of endotoxin, the time point at which neutrophil alveolitis due to endotoxin is most intense. Pretreatment with a single dose of IBU 3.75 mg/kg prior to endotoxin injections was associated with a significant increase in the total number of inflammatory cells, and in both the percentage and the absolute number of neutrophils recovered from the lung, despite significantly decreasing the plasma level of thromboxane B2, which increased 10-fold after endotoxin. Paradoxically, IBU 30 mg/kg significantly decreased the intensity of neutrophil alveolitis. MP 30 mg/kg had no effect on recovery of inflammatory cells from the lung by bronchoalveolar lavage following endotoxin. Cyclooxygenase inhibitors such as ibuprofen may cause a dose-dependent biphasic effect on lung inflammation following endotoxin: enhancement of inflammation at a low dose and suppression of inflammation at a high dose.

Topics: Animals; Bronchitis; Gram-Negative Bacteria; Ibuprofen; Leukocyte Count; Methylprednisolone; Neutrophils; Rats; Rats, Inbred Strains; Respiratory Distress Syndrome; Shock, Septic; Thromboxane B2; Time Factors

The effects of two thromboxane synthetase inhibitors ( dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. Infusion of E. coli endotoxin (41.7 ng kg-1 min-1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin-treated 935 +/- 150 pg ml-1 at 1 h compared with pre-endotoxin values of 125 +/- 30 pg ml-1). The administration of either dazoxiben (30 mg kg-1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg-1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations. Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.

Topics: Animals; Blood Glucose; Blood Pressure; Escherichia coli; Heart Rate; Imidazoles; Lactates; Lactic Acid; Male; Platelet Count; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2; Thromboxanes

Topics: Animals; Blood Platelets; Female; Male; Platelet Aggregation; Rabbits; Shock, Septic; Thromboxane B2; Thromboxanes

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

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

Plasma concentrations of thromboxane and prostaglandin I2 (PGI2) before and after IV injection of endotoxin and resulting hemodynamic changes were evaluated. Effects of flunixin meglumine on plasma concentrations of these prostaglandins and the related hemodynamic changes were also determined. Shock was induced in 2 groups of anesthetized dogs. Four dogs were given endotoxin only and 4 dogs were given endotoxin and then were treated with flunixin meglumine. Arterial blood pressure (BP), cardiac output (CO), and heart rate were measured, and blood samples were collected at postendotoxin hours (PEH) 0, 0.1, 0.25, 0.5, 1, 2, 3, and 4. Plasma thromboxane and PGI2 concentrations were increased in canine endotoxic shock. Thromboxane concentration was highest early in shock, and appeared to be associated with an initial decrease in BP and CO. The increased concentration of PGI2 was associated with systemic hypotension at PEH 1 to 2. Treatment of dogs with flunixin meglumine at PEH 0.07 prevented further increase of thromboxane and blocked the release of PGI2, resulting in an increased CO, BP, and tissue aerobic metabolism.

Topics: Animals; Clonixin; Dog Diseases; Dogs; Endotoxins; Epoprostenol; Escherichia coli; Female; Hemodynamics; Male; Prostaglandins F; Shock, Septic; Thromboxane B2; Thromboxanes

The arachidonic acid metabolites thromboxane A2, a potent platelet aggregator, and prostacyclin, a potent vasodilator, are released early in endotoxin shock and may contribute to its pathologic sequelae. Plasma levels of thromboxane (Tx) A2 and prostacyclin were measured via radioimmunoassay of their stable metabolites immunoreactive (i) TxB2 and i6-keto-PGF1 alpha in tolerant and nontolerant rats after endotoxin. Long-Evans rats were made tolerant to endotoxin by four daily IV injections of S enteritidis (endotoxin) (0.1, 0.5, 1, and 5 mg/kg). In normal rats (N = 15) given LPS (IV, 15 mg/kg), only 11% survived at 24 h; in contrast, tolerant rats (N = 13) all survived even at a dose of 50 mg/kg. At 1 h, after endotoxin (15 mg/kg) IV, plasma i6-keto-PGF1 alpha in nontolerant rats was 1,005 +/- 149 pg/ml (N = 14) and continued to rise to 4,209 +/- 757 pg/ml (N = 5) (P less than 0.001) after 4 h. In tolerant rats, given endotoxin (15 mg/kg), plasma i6-keto-PGF1 alpha at 1 h was 800 +/- 203 pg/ml (N = 5) and was not significantly different (734 +/- 254 pg/ml) at 4 h. Plasma iTxB2 at both 1 and 4 h was significantly (P less than 0.01) lower in tolerant than nontolerant rats. Both iTxB2 and i6-keto-PGF1 alpha were significantly (P less than 0.01) lower in tolerant rats given 50 mg/kg IV endotoxin than nontolerant rats. Endotoxin-induced elevation in fibrin degradation products was significantly decreased (P less than 0.05) during endotoxin tolerance although there was no difference in the severity of thrombocytopenia. These composite observations demonstrate that endotoxin tolerance in the rat is associated with altered arachidonic acid metabolism.

Topics: Acid Phosphatase; Animals; Arachidonic Acid; Arachidonic Acids; Aspartate Aminotransferases; Blood Platelets; Disease Susceptibility; Fibrin Fibrinogen Degradation Products; Glucuronidase; Macrophages; Male; Prostaglandins F; Rats; Shock, Septic; Thrombocytopenia; Thromboxane B2

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

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

Topics: Animals; Blood Pressure; Dogs; Glutathione; Oxygen Consumption; Shock, Septic; Thromboxane B2

Thromboxane (TX) has been reported to cause mortality in endotoxin or septic shock. Cyclooxygenase inhibition improves survival in gram-negative or gram-positive shock. The exact level in the prostaglandin system of which the protection occurs is unknown. This study was designed to compare the effects of a cyclooxygenase inhibitor (indomethacin, IND) to a thromboxane synthetase inhibitor (IMI) on survival and on the production of Tx and prostacyclin (PGI2) in a clinically relevant rat gram-negative sepsis model. Three groups were studied: 1) control (N = 35) animals received E coli only; 2) IND (N = 35) treated animals received 3 mg/kg IP; 3) IMI (N = 35) treated animals received 30 mg/kg IP. All drugs were given 1 h after an IP injection of E coli (LD70) organisms. In this model only IND significantly improved survival. IND and IMI significantly blocked the production of Tx seen in septic shock. IND blocked PGI2 production whereas IMI increased the production. These results show that Tx may not be important in the irreversible stages of shock. Shunting prostaglandin production to PGI2 with thromboxane synthetase inhibitors needs to be considered when using this group of compounds. The mechanism of protection by IND remains unknown.

Topics: Animals; Depression, Chemical; Imidazoles; Indomethacin; Male; Oxidoreductases; Prostaglandins F; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase

1 We investigated the effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive ortho isomer on arachidonic acid metabolism and pathophysiological sequelae of endotoxic shock. In vehicle-treated rats, 30 min after intravenous S. enteritidis endotoxin (15 mg/kg), plasma iTxB2 (the stable metabolite of thromboxane A2) increased from non-detectable levels (less than 100 pg/ml) to 763 +/- 250 pg/ml (n = 10). Plasma i6-keto-PGF1 alpha (the stable metabolite of prostacyclin, PGI2) increased to 1850 +/- 426 pg/ml, (n = 9) and plasma iPGE increased to 2350 = 560 (n = 5). Pretreatment with the pyridine active (PA) meta isomer (30 mg/kg i.p.) significantly (P less than 0.05) suppressed iTxB2 to 390 +/- 31 pg/ml (n = 10) although 6-keto-PGF1 alpha levels (1294 +/- 358 pg/ml, n = 5) and plasma iPGE (2847 +/- 1103 pg/ml, n = 5) were not significantly different from the shocked control values. In contrast, pretreatment with, the pyridine inactive (PI) ortho isomer did not significantly affect endotoxin-induced iTxB2 (1431 +/- 194 pg/ml, n = 5) or i6-keto-PGF1 alpha synthesis (628 +/- 266 pg/ml, n = 5). 2 Pretreatment of rats with the Tx synthetase inhibitor, PA, significantly enhanced (P less than 0.05) survival and prevented splanchnic infarction relative to both endotoxin shocked control rats and those pretreated with the PI isomer. 3 Significantly reduced lysosomal labilization, hepatocellular dysfunction and elevations in serum fibrin/fibrinogen degradation products were seen only in groups pretreated with the PA isomer. 4 The beneficial effects of the latter compound in endotoxic shock thus appear to be due to inhibition of Tx synthesis, since its ortho isomer did not inhibit TxA2 synthesis nor did it protect against endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Aminobenzoates; Animals; Blood Glucose; Lysosomes; Macrophages; Male; Oxidoreductases; Prostaglandins E; Radioimmunoassay; Rats; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase

Endotoxic shock is associated with increased metabolism of arachidonic acid into thromboxanes and prostaglandins. This study assessed the effects of varied doses of aspirin, an inhibitor of arachidonic acid metabolism, on Salmonella enteritidis endotoxin-induced mortality, plasma levels of arachidonate metabolites, and other pathophysiologic sequelae in Long-Evans rats. Aspirin in doses of 3.75, 15, and 30 mg/kg given 30 minutes prior to endotoxin challenge significantly (p less than 0.01) improved 24-hour survival rates from 11 percent to approximately 65 percent, but 100 mg/kg afforded no protection. Pretreatment with aspirin (15 or 100 mg/kg) 30 minutes prior to endotoxin also significantly (p less than 0.001) decreased the endotoxin-induced elevations in plasma levels of immunoreactive thromboxane B2, a stable metabolite of thromboxane A2, and immunoreactive 6-keto prostaglandin F1 alpha, a stable metabolite of prostacyclin. Aspirin doses of 15 or 100 mg/kg given 24 hours prior to challenge with endotoxin significantly improved 24-hour survival rates from 17 percent to 42 percent (p less than 0.01) and 44 percent (p less than 0.005), respectively. Pretreatment with an aspirin dose of 15 mg/kg 24 hours prior to challenge with endotoxin significantly (p less than 0.05) inhibited thrombin-induced immunoreactive thromboxane B2 synthesis in platelet-rich plasma (in vitro) and endotoxin-induced immunoreactive 6-keto-prostaglandin F1 alpha and immunoreactive thromboxane B2 synthesis by rat peritoneal macrophages. Although 24-hour pretreatment with aspirin (15 or 100 mg/kg) significantly (p less than 0.001) reduced endotoxin-induced elevations in immunoreactive thromboxane B2, only the 100 mg/kg dose significantly lowered plasma levels of immunoreactive 6-keto prostaglandin F1 alpha. These observations are consistent with the notion that the beneficial effects of aspirin seen in experimental endotoxic shock may be mediated, in part, via inhibition of arachidonic acid metabolism.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acids; Aspirin; Blood Platelets; Fibrin Fibrinogen Degradation Products; Macrophages; Male; Radioimmunoassay; Rats; Shock, Septic; Thromboxane B2

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

The relationship between prostacyclin and thromboxane activity in plasma or lymph of endotoxemia sheep was studied to better understand the physiologic significance of these two vasoactive compounds. Conscious sheep received either endotoxin alone or endotoxin plus a five-hour infusion of prostacyclin. Endotoxin alone produced a pulmonary arterial hypertension, a significant decrease in cardiac output, an increase in the lung lymph flow rate, and a leukopenia. Plasma prostacyclin and thromboxane concentrations were elevated to the same extent, while pulmonary lymph thromboxane concentrations were greater than those of prostacyclin. The administration of exogenous prostacyclin significantly attenuated the hemodynamic changes following endotoxin, but not the leukopenia. During the prostacyclin infusion, plasma and lymph prostacyclin concentration were tenfold higher than those seen with endotoxin alone, while thromboxane concentrations were six to eightfold lower. Thus, high circulating prostacyclin concentrations resulted in an inhibition of thromboxane production with an associated attenuation of the hemodynamic response to endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cardiac Output; Endotoxins; Epoprostenol; Escherichia coli; Leukocyte Count; Platelet Count; Prostaglandins; Pulmonary Artery; Sheep; Shock, Septic; Thromboxane B2; Thromboxanes; Vascular Resistance

Endotoxin-induced pulmonary hypertension can be attenuated by nonsteroidal anti-inflammatory drugs and is associated with increased plasma levels of thromboxane (Tx) B2, prostaglandin (PG) F2, PGE and PGI2. Because nonsteroidal anti-inflammatory drugs block prostacyclin production and may also shift arachidonic acid into the lipoxygenase pathway, we have evaluated a selective Tx synthetase inhibitor (OKY 1581) as a means for preventing endotoxin-induced pulmonary hypertension. An LD70 dose of Escherichia coli endotoxin (6 mg/kg) was given i.v. to two groups of unanesthetized baboons. Group I received endotoxin alone and Group II was pretreated with i.v. OKY 1581 (2 mg/kg) 10 min before the endotoxin. OKY 1581 produced a significant decrease in the basal plasma TxB2 from 0.432 +/- 0.82 to 0.147 +/- 0.032 ng/ml (P less than .01), but no significant change in plasma 6-keto PGF1 alpha. After the administration of the endotoxin, Group I developed pulmonary hypertension (from 11 +/- 1 to 19 +/- 2 mm Hg. P less than .005) and an 8-fold increase in plasma TxB2 (P less than .02), whereas Group II did not develop pulmonary hypertension or an increase in plasma TxB2. However, Group II had a 26-fold increase in plasma 6-keto PGF1 alpha (P less than .05). From these studies, we conclude that: 1) OKY 1581 is an effective Tx synthetase inhibitor in vivo; 2) endotoxin-induced pulmonary hypertension is mediated largely by increased Tx; and 3) the inhibition of Tx synthetase results in shunting of endoperoxides into the prostacyclin pathway.

Topics: 6-Ketoprostaglandin F1 alpha; Acrylates; Animals; Hypertension, Pulmonary; Male; Methacrylates; Oxidoreductases; Papio; Shock, Septic; Thromboxane B2; Thromboxane-A Synthase

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

Anisodamine hydrochloride is a vasoactive drug produced in the People's Republic of China that appears efficacious in clinical and experimental bacteremic shock, and about whose mode of action little is known. Suspecting that the drug might work by inhibition of platelet or granulocyte aggregation, or both, we tested it in these systems. Anisodamine proved a modest inhibitor of granulocyte aggregation and a powerful inhibitor of platelet aggregation; thromboxane synthesis was inhibited in anisodamine-treated platelets, further suggesting that the biochemical mode of action might be inhibition of cyclo-oxygenase or thromboxane synthetase.

Topics: Animals; Cell Aggregation; Cricetinae; Depression, Chemical; Granulocytes; Humans; Ibuprofen; Platelet Aggregation; Scopolamine Derivatives; Shock, Septic; Solanaceous Alkaloids; Structure-Activity Relationship; Thromboxane B2; Thromboxanes; Vasodilator Agents

Topics: Animals; Arachidonic Acids; Ascitic Fluid; Carbon; Colloids; Fatty Acids, Essential; Fibrin Fibrinogen Degradation Products; Glucans; Macrophages; Male; Prostaglandins F; Rats; Shock, Septic; Thromboxane B2

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

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

Endotoxic shock is associated with increased metabolism of arachidonic acid to thromboxanes (TX) and prostaglandins (PG). This study assessed the effects of varied doses of aspirin, an inhibitor of arachidonic acid metabolism, on Salmonella enteriditis endotoxin (20 mg/kg)-induced mortality, plasma levels of arachidonate metabolites and other pathophysiological sequelae in Long-Evans rats. Aspirin, in doses of 3.75, 15 an 30 mg/kg, given 30 min before endotoxin significantly (P less than .01) improved 24-hr survival from 11% to 60 to 70%, but 100 mg/kg afforded no protection. Pretreatment with aspirin (15 or 100 mg/kg) 30 min before endotoxin significantly (P less than .001) decreased the endotoxin-induced elevations in plasma levels of immunoreactive (i) TXB2, a stable metabolite of TXA2, i6-keto PGF1 alpha, a stable metabolite of PGI2 and significantly (P less than .05) inhibited thrombin-induced in vitro platelet iTXB2 synthesis. Endotoxin-induced hypoglycemia and elevations in serum acid phosphatase and beta-glucuronidase activities, lysosomal enzymes, were all significantly (P less than .01) attenuated by pretreatment with aspirin (15 mg/kg) 30 min before endotoxin. Aspirin (15 or 100 mg/kg) given 24 h before challenge with endotoxin significantly improved 24-hr survival to 42 (P less than .01) and 44% (P less than .005), respectively. Although 24 hr pretreatment with aspirin (15 or 100 mg/kg) significantly (P less than .001) reduced endotoxin-induced elevations in iTXB2, only the 100 mg/kg dose significantly lowered plasma levels of i6-keto PGF1 alpha. These observations are consistent with the notion that the beneficial effects of aspirin seen in experimental endotoxic shock may be mediated, in part, via reduction of platelet TXA2 synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aspirin; Blood Glucose; Fibrin Fibrinogen Degradation Products; Lysosomes; Male; Platelet Aggregation; Prostaglandins F; Rats; Shock, Septic; Thromboxane B2

The role of prostacyclin and thromboxane during endotoxic shock is unknown. Using new radioimmunoassay techniques, we have studied the plasma levels of stable metabolites of prostacyclin (6-keto-PGF1 alpha) and thromboxane (TxB2) in a porcine model of endotoxic shock. TxB2 levels were markedly elevated but the production of prostacyclin appears to be impaired. Correction of this prostanoid imbalance by the infusion of prostacyclin or pre-treatment with a specific thromboxane synthetase inhibitor produces significant and beneficial effects on blood pressure and pre-kallikrein activation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Pressure; Epoprostenol; Kallikreins; Leukocyte Count; Platelet Count; Rabbits; Shock, Septic; Swine; Thromboxane B2; Thromboxane-A Synthase; Thromboxanes

Topics: Animals; Arachidonic Acids; Endotoxins; Fatty Acids, Essential; Fibrin Fibrinogen Degradation Products; Platelet Count; Rats; Shock, Septic; Thromboxane A2; Thromboxane B2; Thromboxanes

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

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arteries; Blood Pressure; Haplorhini; Indomethacin; Lidocaine; Papio; Prostaglandins F; Shock, Septic; Thromboxane B2; Thromboxanes

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Fibrin Fibrinogen Degradation Products; Imidazoles; Lysosomes; Male; Oxidoreductases; Prostaglandins E; Rats; Shock, Septic; Thrombocytopenia; Thromboxane B2; Thromboxane-A Synthase

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

During endotoxemia, there is a significant increase in arachidonic acid-derived metabolites. To test the hypothesis that one or more of these metabolites play a significant role in the pathogenesis of endotoxic shock we investigated the therapeutic efficacy of varying doses of ibuprofen, a cyclooxygenase inhibitor, on the pathophysiologic sequelae of endotoxic shock in the Long-Evans rat, induced by S. enteritidis endotoxin (20 mg/kg). Pretreatment with ibuprofen (1-3.75 mg/kg) produced an optimal survival rate of 80% compared to only 11% in the vehicle-treated group. Doses of 0.1, 0.5 and 30 mg/kg of ibuprofen also significantly (P < .05) improved survival over nontreated shocked controls. Plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha(PGF1 alpha) levels rose from < 200 pg/ml to 2207 +/- 282 (N = 16) and 840 +/- 59 (N = 8), respectively, within 30 min after injection. The rise in plasma thromboxane B2 and 6-keto-PGF1 alpha levels was reduced with ibuprofen (3.75 and 30 mg/kg) to < 200 pg/ml. Ibuprofen (3.75 and 30 mg/kg) reduced thrombin-induced in vitro platelet thromboxane B2 synthesis by 95 and 99%, respectively. The severity of coagulopathies as reflected by elevations in serum fibrogen/fibrin degradation products and lysosomal integrity were likewise significantly reduced (40%) with ibuprofen (3.75 mg/kg) pretreatment. These results are consistent with the hypothesis that arachidonic acid metabolites play a significant early role in the pathogenesis of endotoxic shock. Our observations suggest potential benefits from agents which inhibit fatty acid cyclooxygenase.

Topics: Acid Phosphatase; Animals; Fibrin Fibrinogen Degradation Products; Glucuronidase; Ibuprofen; Lysosomes; Male; Prostaglandins F; Rats; Shock, Septic; Thromboxane B2