6-ketoprostaglandin-f1-alpha 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

Prostacyclin prevents pulmonary vascular injury and shock by inhibiting increases in lung tissue levels of TNF in rats administered endotoxin. We previously reported that NO derived from eNOS increases endothelial production of prostacyclin. Because neutrophil elastase has been shown to decrease endothelial production of prostacyclin by inhibiting NOS activity, we examined whether neutrophil elastase inhibitors reduce pulmonary vascular injury and hypotension by inhibiting the decrease in pulmonary endothelial production of prostacyclin in rats administered endotoxin. Animals were pretreated with sivelestat or L-658,758, neutrophil elastase inhibitors, before endotoxin administration. Lung tissue levels of 6-keto-prostaglandin F1alpha were markedly increased after endotoxin administration, followed by a rapid decrease to baseline levels. Sivelestat and L-658,758 inhibited these decreases as well as inhibiting increases in lung tissue levels of TNF and lung wet-to-dry weight ratios in animals administered endotoxin. These inhibitors also reduced hypotension and inhibited increases in lung tissue levels of mRNA of the inducible form of NOS in animals administered endotoxin. The effects of neutrophil elastase inhibitors were completely reversed by pretreatment with nitro-L-arginine methyl ester, an inhibitor of NOS, or indomethacin, a nonspecific cyclooxygenase inhibitor. These observations suggested that neutrophil elastase might decrease the pulmonary endothelial production of prostacyclin by inhibiting endothelial NO production, thereby contributing to the development of pulmonary vascular injury and shock through increases in lung tissue levels of TNF in rats administered endotoxin.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cephalosporins; Endotoxins; Enzyme Inhibitors; Leukocyte Elastase; Lung; Lung Diseases; Male; Nitric Oxide; Rats; Shock, Septic; Tumor Necrosis Factor-alpha; Vascular Diseases

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

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

Although polymicrobial sepsis is characterized by an early hyperdynamic phase (2-10 hrs after cecal ligation and puncture [CLP]), followed by a late hypodynamic phase (20 hrs after CLP), it remains unknown whether prostacyclin or prostaglandin I2 (PGI2) plays a significant role in modulating the hyperdynamic state during early sepsis. The aim of this study was to determine whether inhibition of PGI2 synthesis prevents the occurrence of the hyperdynamic response during early sepsis.. Prospective, controlled animal study.. A university research laboratory.. Adult male Sprague-Dawley rats were subjected to sepsis by CLP.. Blood samples were collected at 2, 5, 10, or 20 hrs after CLP, and plasma concentrations of PGI2, in the form of its stable product 6-keto-PGF1alpha, were measured by radioimmunoassay. In additional studies, a PGI2 synthase inhibitor, tranylcypromine, was administered subcutaneously at the time of CLP and again at 3 hrs after CLP. At 5 hrs after the onset of sepsis, the maximal rates of the left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax) were determined by an in vivo heart performance analyzer. Microvascular blood flow in the liver, small intestine, and spleen was assessed by laser Doppler flowmetry.. Plasma concentrations of 6-keto-PGF1alpha increased significantly at 2-20 hrs after CLP. At 5 hrs after the onset of sepsis, +/-dP/dt(max) and microvascular blood flow in the tested tissues increased significantly. Inhibition of PGI2 synthase activity did not prevent the occurrence of hypercardiovascular responses under such conditions. Moreover, the administration of tranylcypromine significantly reduced circulating concentrations of 6-keto-PGF1alpha at 5 hrs after CLP.. Because inhibition of PGI2 production did not prevent the occurrence of the hyperdynamic and hypercardiovascular response during the early stage of sepsis, mediators other than PGI2 appear to play a major role in producing the hyperdynamic response under such conditions.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Flow Velocity; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Epoprostenol; Hemodynamics; Intestine, Small; Intramolecular Oxidoreductases; Liver; Male; Microcirculation; Rats; Rats, Sprague-Dawley; Shock, Septic; Spleen; Tranylcypromine

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 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

Background-The inability to inhibit multiple mediators of septic shock represents a major hurdle in the treatment of septic shock. In vivo inhibition of nuclear factor (NF)-kappaB activation, a transcription factor regulating expression of many proinflammatory genes, could provide a useful strategy for the treatment of septic shock. Methods and Results-In rats challenged with lipopolysaccharide (LPS) 8 mg/kg IV, we determined the time course of NF-kappaB activation and expression of multiple inflammatory signals: tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM)-1. We studied the effects of in vivo inhibition of NF-kappaB activation using pyrrolidine dithiocarbamate (PDTC) on the expression of these mediators. NF-kappaB activation preceded the induction of TNF-alpha, COX-2, CINC, and ICAM-1 mRNAs. PDTC prevented the LPS-induced NF-kappaB activation but did not inhibit activation of the transcription factors AP-1, Sp-1, and CREB. PDTC inhibited the LPS-induced expression of TNF-alpha, COX-2, CINC, and ICAM-1 mRNA and proteins and reduced the LPS-induced increases in plasma TNF-alpha, 6-keto-prostaglandin F(1alpha), and CINC concentrations. Inhibition of expression of these mediators prevented the increases in myeloperoxidase activity (a measure of neutrophil sequestration) in the heart, lungs, and liver. Conclusions-NF-kappaB activation correlates with LPS-induced expression of TNF-alpha, COX-2, CINC, and ICAM-1 genes in vivo. PDTC inhibits NF-kappaB activation and expression of these proinflammatory genes and their products. Thus, blocking NF-kappaB activation may be an effective strategy in the treatment of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Chemokines, CXC; Chemotactic Factors; Cyclooxygenase 2; Gene Expression; Growth Substances; Intercellular Adhesion Molecule-1; Intercellular Signaling Peptides and Proteins; Isoenzymes; Male; NF-kappa B; Prostaglandin-Endoperoxide Synthases; Pyrrolidines; Rats; Rats, Sprague-Dawley; Shock, Septic; Thiocarbamates; 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

1. We compared the effects of calpain inhibitor I (inhibitor of the proteolysis of I kappa B and, hence, of the activation of nuclear factor kappa B (NF kappa B) and dexamethasone on (i) the circulatory failure, (ii) multiple organ dysfunction and (iii) induction of the inducible isoforms of nitric oxide (NO) synthase (iNOS) and cyclo-oxygenase (COX-2) in anaesthetized rats with endotoxic shock. 2. Injection of lipopolysaccharide (LPS, E. coli, 10 mg kg-1, i.v.) resulted in hypotension and a reduction of the pressor responses elicited by noradrenaline. This circulatory dysfunction was attenuated by pretreatment of LPS-rats with calpain inhibitor I (10 mg kg-1, i.v., 2 h before LPS) or dexamethasone (1 mg kg-1, i.v.). 3. Endotoxaemia also caused rises in the serum levels of (i) urea and creatinine (renal dysfunction), (ii) alanine aminotransferase (ALT), aspartate aminotransferase (AST) (hepatocellular injury), bilirubin and gamma-glutamyl transferase (gamma GT) (liver dysfunction), (iii) lipase (pancreatic injury) and (iv) lactate. Calpain inhibitor I and dexamethasone attenuated the liver injury, the pancreatic injury, the lactic acidosis as well as the hypoglycaemia caused by LPS. Dexamethasone, but not calpain inhibitor I, reduced the renal dysfunction caused by LPS. 4. Endotoxaemia for 6 h resulted in a substantial increase in iNOS and COX-2 protein and activity in lung and liver, which was attenuated in LPS-rats pretreated with calpain inhibitor I or dexamethasone. 5. Thus, calpain inhibitor I and dexamethasone attenuate (i) the circulatory failure, (ii) the multiple organ dysfunction (liver and pancreatic dysfunction/injury, lactic acidosis, hypoglycaemia), as well as (iii) the induction of iNOS and COX-2 protein and activity in rats with endotoxic shock. We propose that prevention of the activation of NF-kappa B in vivo may be useful in the therapy of circulatory shock or of disorders associated with local or systemic inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calpain; Cysteine Proteinase Inhibitors; Dexamethasone; DNA-Binding Proteins; Endotoxemia; I-kappa B Proteins; Lipopolysaccharides; Male; Mice; Multiple Organ Failure; Nitric Oxide Synthase; Proto-Oncogene Proteins; Rats; Rats, Wistar; Shock, Septic; Tosylphenylalanyl Chloromethyl Ketone; Tumor Necrosis Factor-alpha

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

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

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

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 study deals with an animal model for the problems of surgical intensive care patients. Following repeated applications of E. coli endotoxin WO 111:B4 under standard conditions, specific hemodynamic and biochemical (TNF, TXA2, PGI2, IL-6, PAF) and morphological (endothelium of the lung) alterations were detected. ARDS patterns induced by the sepsis were analyzed by high-frequency measurement of pressure and flow (385 measurements per breathing cycle). The role of the intestine in sepsis was investigated by ion-selective monitoring of surface potassium activity comparing mucosa and serosa. Every injection of endotoxin was followed by a selective increase of the potassium activity revealing relative ischemia induced by the endotoxin. The profile of the potassium levels on the surface correlates both with the cardiac output and with the prostacyclin levels. The continuous narrowing of the difference between mucosa and serosa, potassium during the period of investigation can be regarded as evidence for pathologic change in permeability fostering the septic course.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Critical Care; Epoprostenol; Escherichia coli Infections; Hemodynamics; Interleukin-6; Intestinal Mucosa; Intestines; Ion Channels; Ischemia; Lung; Microscopy, Electron; Multiple Organ Failure; Platelet Activating Factor; Postoperative Complications; Potassium; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Shock, Septic; Swine; Thromboxane A2; Tumor Necrosis Factor-alpha

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

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

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

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

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

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

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

We tested the hypothesis that prostaglandins (PGs) and thromboxane (Tx) A2 are important mediators of the hemodynamic derangements occurring in a rabbit model of hyperdynamic endotoxicosis. Rabbits were injected with either normal saline (NS) or Escherichia coli lipopolysaccharide (LPS; 1-3 micrograms/kg) and studied 6 hr later. Cardiac index (CI) and regional blood flow were determined using thermodilution and radioactive microspheres, respectively. Systemic and regional hemodynamics were determined before and 40 min after administering indomethacin (cyclo-oxygenase inhibitor; 5 mg/kg), UK38485 (Tx synthetase inhibitor; 10 mg/kg), or NS. LPS increased CI (P = .0024) and decreased mean arterial pressure (P = .0031) and systemic vascular resistance index (P = .0001). LPS increased flow to the heart and small intestine and decreased flow to the hepatic artery and pancreas. The systemic and regional hemodynamic effects of indomethacin were similar in NS- and LPS-treated rabbits. UK38485 decreased perfusion of skeletal muscle and diaphragm in both endotoxemic and control animals. This agent increased splenic perfusion only in NS-treated rabbits. Plasma levels of 6-keto PGF1 alpha (PGI2 metabolite) were typically undetectable in both NS- and LPS-treated rabbits. These data do not support the hypothesis that PG's or TxA2 are major determinants of the hemodynamic perturbations that occur in this endotoxicosis model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclooxygenase Inhibitors; Disease Models, Animal; Endotoxins; Escherichia coli; Hemodynamics; Imidazoles; Indomethacin; Lipopolysaccharides; Male; Prostaglandins; Rabbits; Shock, Septic; Thromboxane A2; Thromboxane-A Synthase

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

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: 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

An evaluation was made of 106 surgical patients with Gram-negative septic shock, both for clinical criteria as well as the biochemical mediators endotoxin, prostaglandin F2 alpha, prostaglandin I2 (prostacyclin), and thromboxane. These data were correlated to various defined shock phases, functional data of vital organs, and clinical outcome. Patients underwent invasive organ function monitoring and the usual laboratory tests of intensive care. Prostaglandins and thromboxane were measured radioimmunologically, endotoxin by the limulus amebocyte lysate test. Endotoxin proved to be a more accurate predictor of severe sepsis than did positive blood cultures. Endotoxin as well as prostaglandins and thromboxane are predominantly released in early shock phases, appearing in plasma concentrations, which correlate with the severity of organ failure. Sepsis-induced respiratory failure coincides with a deterioration of pulmonary prostaglandin inactivation, which contributes to the release mechanism. High systemic prostacyclin activity benefits the patients' organ functions and clinical outcomes, while a predominance of thromboxane seems to effect the opposite. Transpulmonary-thromboxane gradients correlate significantly with pulmonary hypertension in the early phases of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Acute Kidney Injury; Adolescent; Adult; Aged; Dinoprost; Endotoxins; Epoprostenol; Humans; Middle Aged; Peritonitis; Prostaglandins; Prostaglandins F; Respiratory Insufficiency; Shock, Septic; Surgical Wound Infection; Thromboxanes

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: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Dogs; Female; Male; Parasympatholytics; Platelet Aggregation; Shock, Septic; Solanaceous Alkaloids

Central venous plasma concentrations of 6-keto-prostaglandin F1 alpha (PGF1 alpha), the stable hydrolysis product of prostacyclin (PGI2, a vasodilator and antiaggregatory metabolite of arachidonic acid), were determined in patients with septic shock. In eight nonsurvivors, the median plasma 6-keto-PGF1 alpha level was 229 pg/ml (range 31 to 21,998), compared to 30 pg/ml (range 22 to 194) in six survivors. In three control patients who were not septic or in shock, the levels were less than 4 pg/ml. This study demonstrates that human septic shock is associated with elevated plasma levels of 6-keto-PGF1 alpha, and raises the possibility that increased PGI2 formation may play a role in human septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Blood Pressure; Fibrinogen; Humans; Partial Thromboplastin Time; Platelet Count; Prothrombin Time; Shock, Septic

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

Previous reports have suggested that sulindac is a unique non-steroidal anti-inflammatory (NSAID) agent, because it does not inhibit renal prostaglandin synthesis in doses that inhibit platelet thromboxane B2 synthesis when tested ex vivo. NSAIDS are of potential therapeutic benefit in the treatment of septic or endotoxic shock. Therefore, this study was designed to investigate the proposed unique action of sulindac in experimental endotoxemia. In the current study, the effect of sulindac on aortic, portal and renal venous immunoreactive (i) 6-keto-PGF1 alpha levels, the stable metabolite of prostacyclin, was investigated during endotoxemia in the rat. In doses sufficient to reduce the elevation in aortic and portal venous plasma i6-keto-PGF1 alpha levels, sulindac also significantly (p less than 0.05) attenuated the elevated renal venous plasma 6-keto-PGF1 alpha levels, compared to the vehicle group. Using lower doses, sulindac failed to reduce the endotoxin associated increase in either aortic or renal venous plasma i6-keto- PGF1 alpha levels. Thus, sulindac failed to demonstrate any selective sparing effect on renal prostacyclin generation during endotoxemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Indenes; Kidney; Male; Rats; Shock, Septic; Sulindac

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

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Animals; Child; Child, Preschool; Dinoprost; Dogs; Epoprostenol; Female; Humans; Infant; Male; Prostaglandins E; Prostaglandins F; Shock, Septic; Solanaceous Alkaloids; Vasodilator Agents

This study investigates the role of prostaglandins (PG) in hyperdynamic sepsis. Thirteen chronically instrumented dogs were rendered septic by implanting in the peritoneal cavity a fibrin clot containing viable Escherichia coli. One day later, cardiac output (CO) increased from 2.80 +/- 0.22 to 3.72 +/- 0.32 l/min (p = 0.011); heart rate (HR) increased from 122 +/- 8 to 147 +/- 6 beats/min (p = 0.005); mean pulmonary artery pressure (PAP) increased from 15 +/- 1 to 19 +/- 1 mmHg (p = 0.003); mean systemic arterial pressure (MAP) decreased from 120 +/- 5 to 107 +/- 7 mmHg; and systemic vascular resistance (SVR) decreased from 44.1 +/- 2.6 to 29.3 +/- 1.9 mmHg/l/min (p less than 0.001). Sixty minutes after intravenous injection of indomethacin (2 mg/kg) or ibuprofen (25 mg/kg), CO decreased to 2.60 +/- 0.21 l/min (p less than 0.001); HR decreased to 118 +/- 5 beats/min (p less than 0.001); PAP decreased to 17 +/- 1 mmHg (p = 0.021); and SVR increased to 43.7 mmHg/l/min (p less than 0.001). In seven control dogs, laparotomy alone did not significantly affect any of these parameters. Infusion of indomethacin caused a slight increase in MAP (106 +/- 4 to 116 +/- 4 mmHg, p = 0.035) but otherwise did not alter hemodynamics. It is concluded that administration of indomethacin or ibuprofen restores normal hemodynamics in a canine model of high-output sepsis, probably by inhibiting PG synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Disease Models, Animal; Dogs; Escherichia coli Infections; Female; Hemodynamics; Ibuprofen; Indomethacin; Male; Oxygen Consumption; Peritonitis; Prostaglandin Antagonists; Prostaglandins; Sepsis; Shock, Septic; Thromboxane A2

Intravenous endotoxin injection in rabbits led to complement activation, a biphasic hypotension and elevated arterial levels of prostacyclin and/or 6-oxo-prostaglandin F1 alpha. Primary hypotension and stimulation of prostacyclin biosynthesis were completely dependent on complement activation whereas the secondary changes of these parameters were partly complement dependent, as indicated by experiments with cobra venom factor pretreated rabbits. Prostacyclin, which was never detectable in arterial blood, contributed to the development of hypotension in rabbit endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Complement Activation; Epoprostenol; Hypotension; Rabbits; Shock, Septic

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

1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated 2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (less than 200 pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875 +/- 90 pg/ml (n = 9), iPGE was 1670 +/- 271 (n = 9) and i6-keto-PGF1 alpha was 1191 +/- 209 pg/ml (n = 10). By 4 h plasma iTXB2 was 1743 +/- 328 pg/ml (n = 5), iPGE was 2589 +/- 494 pg/ml (n = 9) and i6-keto-PGF1 alpha was 4251 +/- 984 pg/ml (n = 10). UK 37248 pretreatment resulted in a significant (P less than 0.001) decrease in plasma iTXB2 at 30 min and 4 h to 193 +/- 28 pg/ml (n = 5) and 421 +/- 57 pg/ml (n = 5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6-keto PGF1 alpha at 30 min and 4 h to 360 +/- 75 pg/ml (n = 10) (P less than 0.005) and 1920 +/- 513 pg/ml (n = 10) (P less than 0.05), respectively, iPGE plasma levels were not significantly changed in the UK 37248-pretreated rats 30 min (2210 +/- 370 pg/ml (n = 9) or 4 h 3529 +/- 1093 pg/ml (n = 13) after endotoxin compared to the vehicle-treated rats. 3 UK 37248 significantly (P less than 0.05) reduced the endotoxin mortality rate at 24 h from 69% (n = 13) to 30% (n = 13), UK 37248 also reduced splanchnic infarction from 90% (n = 20) to 6% (n = 16). 4 UK 37248 significantly improved the endotoxin-induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization. 5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Glucose; Endotoxins; Imidazoles; Macrophages; Male; Oxidoreductases; Platelet Count; Prostaglandins E; Radioimmunoassay; Rats; Salmonella enteritidis; Shock, Septic; Splanchnic Circulation; 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

We investigated a rat fecal peritonitis model of acute intraabdominal sepsis in order to evaluate the potential role of arachidonic acid metabolites in septic shock. Immunoreactive TxB2, the stable metabolite of thromboxane A2, and i6-keto-PGF1 alpha, the stable metabolite of prostacyclin, were measured by radioimmunoassay. Plasma levels of iTxB2 rapidly increased from nondetectable (ND less than 200 pg/ml) to 1,052 +/- 208 pg/ml, one hour after feces injection. iTxB2 then increased to 1,681 +/- 248 pg/ml at four hours and remained unchanged through six hours. Plasma i6-keto-PGF1 alpha increased from ND to 3,848 +/- 489 pg/ml a one hour. Four hours after feces, i6-keto-PGF1 alpha levels rose to 7, 450 +/- 933 pg/ml then continued to rise to 9,465 +/- 792 pg/ml at six hours. Either essential fatty acid deficiency (arachidonic acid depletion) or indomethacin treatment (cyclo-oxygenase inhibition) significantly decreased (P less than 0.01) the elevation of plasma iTxB2 and i6-keto-PGF1 alpha associated with fecal peritonitis. Thrombocytopenia occurred within six hours after injection of feces and was significantly improved (P less than 0.05) by indomethacin. Elevated fibrin degradation products at six hours (18 +/- 3 micrograms/ml) were significantly reduced in essential fatty acid-deficient (7 +/- 2 micrograms/ml; P less than 0.05) and indomethacin-treated (4 +/- 0.7 micrograms/ml; P less than 0.01) rats. Survival time (8.6 +/- 0.2 hours) was significantly enhanced by essential fatty acid-deficiency (10.2 +/- 0.4 hours; P less than 0.01) or indomethacin treatment (13.3 +/- 0.6 hours; P less than 0.01). These studies show that fecal peritonitis is associated with increased synthesis of thromboxane A2 and prostacyclin and suggest that these arachidonic acid metabolites may play a role in the pathophysiology of septic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Fatty Acids, Essential; Female; Fibrin Fibrinogen Degradation Products; Indomethacin; Peritonitis; Prostaglandins; Rats; Rats, Inbred Strains; Shock, Septic; Thrombocytopenia; Thromboxane A2; Thromboxanes; Time Factors

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

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dogs; Histamine; Indomethacin; Serotonin; Shock, Septic; Thromboxane A2; Thromboxanes

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

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

During endotoxemia there is increased synthesis of arachidonic-acid-derived metabolites. We investigated the potential deleterious role of the proaggregatory vasoconstrictor, thromboxane A2, an arachidonic acid metabolite, in the endotoxic shocked rat. Plasma levels of thromboxane B2, the stable metabolite of thromboxane A2, 6-keto-PGF1 alpha, the stable metabolite of PGI2, and PGE were measured via radioimmunoassay. We also investigated the therapeutic efficacy of the fatty acid cyclo-oxygenase imidazole and 7(1-imidazolyl)-heptanoic acid (7-IHA), in endotoxic shocked rats. Thirty minutes after intravenous (IV) administration of Salmonella enteritidis endotoxin (20 mg/kg), plasma immunoreactive thromboxane B2 (TxB2) was increased from nondetectable levels (less than 200 pg/ml) in normal nonshocked rats to 2207 +/- 282 pg/ml (N = 16). The 6-keto-PGF1 alpha level was increased from nondetectable levels to 840 +/- 59 pg/ml (N = 8), and prostaglandin E rose from 146 +/- 33 to 2160 +/- 606 pg/ml (N = 5). Ibuprofen (3.75 mg/kg) or indomethacin (10 mg/kg) administered IV 30 min prior to endotoxin (20 mg/kg) improved the survival rate to 81% (N = 15, P less than 0.001) and 78% (N = 17, P less than 0.001), respectively, compared to the 24-hr survival of 8% (N = 26) in the vehicle-treated rats. Ibuprofen also inhibited the endotoxin-induced elevation of TxB2, 6-keto-PGF1 alpha, and fibrinogen/fibrin degradation products. Imidazole (30 mg/kg) or 7-IHA (30 mg/kg), IV, 30 min prior to endotoxin improved survival 65% (N = 11) and 81% (N = 15), respectively. These drugs also inhibited endotoxin-induced elevations in TxB2 and fibrinogen/fibrin degradation products, but did not inhibit endotoxin-induced elevations in plasma PGE. These results are consistent with the suggestion that TxA2 plays a role in the pathogenesis of endotoxic shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Dinoprost; Disseminated Intravascular Coagulation; Fibrin Fibrinogen Degradation Products; Ibuprofen; Indomethacin; Male; Muridae; Prostaglandins E; Prostaglandins F; Shock, Septic; Thromboxane A2; Thromboxanes

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: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Carbon Dioxide; Female; Hypotension; Male; Oxygen; Prostaglandins F; Rabbits; Shock, Septic

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