thromboxane-a2 and Sepsis

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

Topics: Animals; Blood Platelets; Cardiomegaly; Cardiovascular Diseases; Dinoprost; Epoprostenol; Hemodynamics; Humans; Hypertension, Renovascular; Inflammation Mediators; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Prostaglandins; Receptors, Prostaglandin; Sepsis; Signal Transduction; Tachycardia; Thromboxane A2

The clinical condition sepsis and its sequelae are caused by numerous mediators that are released by various cell types. The purpose of this review is to describe the results of various studies performed with agents that either inhibited or stimulated the synthesis of, or affected the receptor-binding characteristics of a specific class of these mediators, the phospholipids.. Antagonists to platelet-activating factor and thromboxane A2 receptors, monoclonal antibodies to phospholipase A2, agents which increased levels of prostaglandins, and cyclooxygenase, lipoxygenase, and other specific pathway inhibitors, which block the production of leukotrienes and thromboxane A2, were used in the studies described to affect the physiologic correlates of sepsis animal models and human studies.. The matters discussed in this paper come from a wide variety of sources, including many broad-based clinical studies of humans with inflammatory disease. Many animal studies are discussed, along with some in vitro cell culture studies and work in molecular genetics.. This article reviews a subject that is rapidly evolving, with frequent discoveries. Thus, much of the article discusses research in basic science, particularly the use of experimental drugs in animals. Clinical studies are generally of large numbers of patients showing overt signs of sepsis.. Most cited literature was found in reputable, peer review journals, including such major basic science journals as Science, and clinical journals such as the Journal of the American Medical Association, New England Journal of Medicine, and Critical Care Medicine.. Occasionally, contradictions do occur in the results of various studies. These contradictions are discussed in this review, and may often be due to the use of different protocols and definitions of the various clinical states.. Increases of some mediators, such as platelet-activating factor, thromboxane A2, and the leukotrienes are associated with animal models of sepsis and seem to have a negative effect on the course of sepsis. Antagonists and blockers of these mediators increased survival in these studies. More research is needed to identify how these mediators of inflammation are associated with sepsis, and what the effects of blocking their actions will have on sepsis.

Topics: Animals; Cyclooxygenase Inhibitors; Humans; Leukotriene Antagonists; Phospholipids; Platelet Activating Factor; Prostaglandins, Synthetic; Sepsis; Shock, Septic; Thromboxane A2

To investigate whether plasma levels of prostacyclin (PGI2) and thromboxane A(2) (TxA2) are a function of the infusion rate of soybean-based fat emulsions, severity of systemic inflammation, and pulmonary organ failure.. Prospective, randomized, crossover study.. Intensive care unit of a university hospital.. Eighteen critically ill patients, ten presenting with severe sepsis, eight with SIRS or sepsis complicated with ARDS.. Patients were randomly assigned to receive rapid fat infusion over 6 h (rFI) or slow fat infusion over 24 h (sFI) along with parenteral nutrition.. The stable prostanoids 6-keto-PGF1alpha and TxB2 were measured in arterial and mixed venous blood samples, and at 6-h periods trans-pulmonary balances (TPB) were calculated. Free linoleic acid fraction was determined in arterial blood. rFI induced greater increase of linoleic acid than sFI in both groups. Enhanced prostanoid levels and correlations with linoleic acid availabilities were found, however, in ARDS patients only, revealing the highest sepsis- and lung injury scores. Averaged TPB per 24 h was positive in the sepsis group and negative in the ARDS group as rFI induced lowest TPB values for TxB2 at 6 h.. The quantity of prostanoids formed and their subsequent utilization are dependent on the availability of precursor linoleic acid and are probably affected by the severity of SIRS or sepsis and the existence of pulmonary organ failure, respectively. Because TxA2 might be extracted by the injured lung, rapid infusion of soybean-based fat emulsions should be avoided in patients suffering from severe pulmonary organ failure.

Topics: Adult; Cross-Over Studies; Epoprostenol; Fat Emulsions, Intravenous; Glycine max; Humans; Lung; Prospective Studies; Respiratory Distress Syndrome; Sepsis; Thromboxane A2

To investigate whether rapid or slowly infused intravenous fat emulsions affect the ratio of prostaglandin I2/thromboxane A2 in arterial blood, pulmonary hemodynamics, and gas exchange.. Prospective, controlled, randomized, crossover study.. Operative intensive care unit of a university hospital.. Eighteen critically ill patients. Ten patients were stratified with severe sepsis, and eight patients had acute respiratory distress syndrome (ARDS).. Patients were assigned randomly to receive intravenous fat emulsions (0.4 x resting energy expenditure) over 6 hrs (rapid fat infusion) or 24 hrs (slow fat infusion) along with a routine parenteral nutrition regimen, by using a crossover study design.. Systemic and pulmonary hemodynamics as well as gas exchange measurements were recorded via respective indwelling catheters. Arterial thromboxane B2 and 6-keto-prostaglandin-F1alpha plasma concentrations were obtained by radioimmunoassay, and 6-keto-prostaglandin-F1alpha/thromboxane B2 ratios (P/T ratios) were calculated. Data were collected immediately before and 6, 12, 18, and 24 hrs after onset of fat infusion. In the ARDS group, P/T ratio increased by rapid fat infusion. Concomitantly, pulmonary shunt fraction, alveolar-arterial oxygen tension difference [P(a-a)o2]/Pao2, and cardiac index increased as well, whereas pulmonary vascular resistance and Pao2/Fio2 declined. After slow fat infusion, a decreased P/T ratio was revealed. This was accompanied by decreased pulmonary shunt fraction, lowered P(a-a)o2/Pao2, and increased Pao2/Fio2. Correlations between plasma concentrations of 6-keto-prostaglandin-F1alpha or thromboxane B2 and measures of respiratory performance could be shown during rapid and slow fat infusion, respectively. In the sepsis group, the P/T ratio remained unchanged at either infusion rate, but pulmonary shunt fraction and P(a-a)o2/Pao2 decreased after rapid fat infusion, whereas Pao2/Fio2 increased.. Pulmonary hemodynamics and gas exchange are related to changes of arterial prostanoid levels in ARDS patients, depending on the rate of fat infusion. In ARDS but not in sepsis patients clear of pulmonary organ failure, a changing balance of prostaglandin I2 and thromboxane A2 may modulate gas exchange, presumably via interference with hypoxic pulmonary vasoconstriction.

Topics: Adult; APACHE; Cross-Over Studies; Epoprostenol; Fat Emulsions, Intravenous; Female; Hemodynamics; Humans; Lung; Male; Oxygen Consumption; Respiratory Distress Syndrome; Sepsis; Thromboxane A2

Arachidonic acid metabolites, especially thromboxane-A2 and prostacyclin, have been shown to be increased in experimental models of sepsis and the adult respiratory distress syndrome (ARDS) and play a major pathophysiologic role. This study was designed to determine if these metabolites are increased in human sepsis syndrome and if inhibition of fatty acid cyclooxygenase affects their formation and their pathophysiologic sequelae. We conducted a double-blind, placebo-controlled trial of ibuprofen (800 mg given rectally every 4 h for three doses) in 30 patients with sepsis syndrome defined by abnormal vital signs, the appearance of serious infection, and at least one major organ failure. Urinary concentrations of the metabolite of thromboxane-A2, 2,3-dinor-TxB2, and prostacyclin, 2,3-dinor-6-keto-prostaglandin F2 alpha, were elevated 10 to 20 times normal and declined to four to five times normal by 12 h after entry in the ibuprofen-treated group and remained elevated in the placebo-treated patients. The urinary concentration of TxB2 and 6-keto-prostaglandin F1 alpha, which reflect renal production of TxA2 and prostacyclin, respectively, were also increased approximately 10-fold over normal and were subsequently decreased by ibuprofen. Coincident with the reduction in metabolite levels, the ibuprofen-treated group, but not the placebo-treated group, experienced a significant decline in temperature, heart rate, and peak airway pressure, and a trend towards more rapid reversal of shock (p = 0.12).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Cyclooxygenase Inhibitors; Double-Blind Method; Epoprostenol; Humans; Ibuprofen; Multiple Organ Failure; Sepsis; Syndrome; Thromboxane A2; Time Factors

To explore the influence of intensive insulin therapy on the intestinal microcirculatory dysfunction of rats suffering from sepsis.. The sepsis model of rat was reproduced by cecal ligation and puncture. Forty-eight male Sprague-Dawley (SD) rats were randomly divided into control group, sepsis group, and insulin treatment group (n =16 in each group). The intestinal tissue was harvested in the experimental groups before and 3, 6, 12 and 24 hours after insulin administration. Platelet activating factor (PAF), prostacyclin (PGI(2)) and thromboxane (TXA(2)) in the intestine were measured by radioimmunoassay.. The levels of PAF, PGI and TXA(2) were significantly elevated in sepsis group at 3 hours, and peaked at 6 hours, then decreased gradually. At each time point they were higher in sepsis group compared with that of control group (all P<0.05), especially TXA(2), which was more evident, while PGI(2)/TXA(2) ratio showed a lowering. In contrast, PAF, PGI(2) and TXA(2) were significantly decreased in insulin treatment group compared with the sepsis group, especially TXA(2), which was more evident ( all P<0.05), but PGI(2)/TXA(2) ratio showed an elevation.. Insulin plays an important role in amelioration of microcirculatory dysfunction in sepsis. Through improving the disorder of PGI(2)/TXA(2)system and antagonising the expression of PAF, insulin alleviates vasospasm, inhibits platelet aggregation and thrombosis, thus protecting the function of intestine.

Topics: Animals; Disease Models, Animal; Epoprostenol; Insulin; Intestinal Mucosa; Intestines; Male; Microcirculation; Platelet Activating Factor; Random Allocation; Rats; Rats, Sprague-Dawley; Sepsis; Thromboxane A2

Alpha-adrenergic agents contract vascular smooth muscle (VSM) and stimulate endothelial release of secondary factors which modulate VSM contraction. Our study examined constrictor prostanoid (cPN) and nitric oxide (NO) as secondary factors which could alter alpha-1 adrenoceptor-mediated contraction during sepsis.. Sepsis was induced in rats by inoculation of an implanted sponge with Escherichia coli and Bacteroides fragilis. Aortic rings at 24 h from septic (n = 21) and control (n = 21) rats were suspended in physiological salt solution (PSS) with or without blockers to NO (N(G)-monomethylarginine), cPN (mefenamic acid, MFA), or thromboxane A2 (SQ29548). Contraction dose-response curves were generated to determine maximal contraction force (F(max)) and pD2 (sensitivity) to phenylephrine in each experimental group.. Sepsis increased F(max) to phenylephrine (PHE) (1.18 vs 0.90 g, SEM 0.0703). COX inhibition reduced the F(max) in control (0.63 vs 0.90 g, SEM 0.0675) but not in septic animals (1.19 vs 1.18 g, SEM 0.0433). TXA2 receptor inhibition did not alter F(max) in control (1.017 vs 0.973 g, SEM 0.0959) or septic animals (1.28 vs 1.12 g, SEM 0.0823). NOS inhibition enhanced the F(max) in both nonseptic (2.03 vs 0.83 g, SEM 0.0523) and septic rats (1.96 vs 1.15 g, SEM 0.0526), but did less so in the septic animals.. PHE-induced F(max) is determined by a balance between PHE-stimulated VSM alpha-adrenoceptor activity, and PHE-stimulated endothelial release of cPN and NO. Sepsis enhances total PHE-induced F(max) by increasing VSM alpha-adrenoceptor activity and reducing PHE-stimulated endothelial release of dilator NO. Sepsis abolishes the PHE-stimulated endothelial release of cPN. PHE-stimulated cPN is not thromboxane A2, but could be a nonprostanoid dilator in the lipoxygenase (HETE) or cytochrome P450 (EET) pathways.

Topics: Animals; Aorta; Bacteroides Infections; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Escherichia coli Infections; In Vitro Techniques; Male; Models, Animal; Muscle, Smooth, Vascular; Nitric Oxide; Nitric Oxide Synthase; Phenylephrine; Prostaglandin Antagonists; Prostaglandins; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Sepsis; Thromboxane A2; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

In this study, gram-positive Staphylococcus aureus lipoteichoic acid (LTA) dose-dependently (0.1-1.0 microg/ml) and time-dependently (10-60 min) inhibited platelet aggregation in human platelets stimulated by agonists. LTA also dose-dependently inhibited phosphoinositide breakdown and intracellular Ca+2 mobilization in human platelets stimulated by collagen. LTA (0.5 and 1.0 microg/ml) also significantly inhibited thromboxane A2 formation stimulated by collagen in human platelets. Moreover, LTA (0.1-1.0 microg/ml) dose-dependently decreased the fluorescence of platelet membranes tagged with diphenylhexatrience. Rapid phosphorylation of a platelet protein of Mr. 47,000 (P47), a marker of protein kinase C activation, was triggered by PDBu (30 nM). This phosphorylation was markedly inhibited by LTA (0.5 and 1.0 microg/ml) within a 10-min incubation period. These results indicate that the antiplatelet activity of LTA may be involved in the following pathways: LTA's effects may initially be due to induction of conformational changes in the platelet membrane, leading to a change in the activity of phospholipase C, and subsequent inhibition of phosphoinositide breakdown and thromboxane A2 formation, thereby leading to inhibition of both intracellular Ca+2 mobilization and phosphorylation of P47 protein. Therefore, LTA-mediated alteration of platelet function may contribute to bleeding diathesis in gram-positive septicemic and endotoxemic patients.

Topics: Calcium Signaling; Cell Membrane; Collagen; Cytosol; Dose-Response Relationship, Drug; Endotoxemia; Enzyme Activation; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Hemorrhagic Disorders; Humans; L-Lactate Dehydrogenase; Lipopolysaccharides; Membrane Fluidity; Membrane Lipids; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Peptides; Phorbol 12,13-Dibutyrate; Phosphatidylinositols; Phosphorylation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Kinase C; Protein Processing, Post-Translational; Sepsis; Shock, Septic; Staphylococcus aureus; Teichoic Acids; Thromboxane A2; Thromboxane B2

The early phase of endotoxin-induced acute hemodynamic disturbances and hypoxemia is mediated by various factors, including eicosanoids and tumor necrosis factor-alpha (TNF alpha). Thromboxane A2 is the major mediator of the early pulmonary hypertension associated with endotoxemia, but the mechanisms underlying the prolonged hemodynamic disturbances observed in ongoing endotoxemia are not well understood. The authors used a chronically instrumental young piglet model to determine the roles of several eicosanoids and of TNF alpha in the prolonged endotoxin-induced pulmonary hypertension and other cardiovascular derangements. Animals were given 40 micrograms/kg endotoxin intravenously per hour for 30 minutes, followed by 20 micrograms/kg per hour. In all animals, persistent pulmonary hypertension, lowered cardiac output, any hypoxemia developed during endotoxin infusion. After 3 hours of endotoxin infusion, randomly ordered infusions of 1 mg/kg dazmegrel (a thromboxane A2 synthesis inhibitor), 5mg/kg nordihydroguaiaretic acid (a 5-lipoxygenase inhibitor), and 20 mg/kg pentoxifylline (A TNF alpha inhibitor) were given intravenously at 30-to-60-minute intervals. Dazmegrel and pentoxifylline lowered pulmonary arterial pressure and resistance and raised arterial oxygen tension. Cardiac output increased significantly after pentoxifylline. These hemodynamic effects persisted for 30-60 minutes, despite continued endotoxin infusion. The elevated plasma concentrations of thromboxane B2 and TNF alpha returned toward preendotoxin baseline values after dazmegrel and pentoxifylline treatment, respectively. No beneficial effects were noted after administration of nordihydroguaiaretic acid. Based on these results, both thromboxane A2 and TNF alpha, but not 5-lipoxygenase products, play active roles in prolonged endotoxin-induced pulmonary hypertension and hypoxemia in young piglets. Combined thromboxane A2 and TNF alpha blockade may be clinically useful in treatment of advanced sepsis in neonates.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Endotoxins; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Leukotriene Antagonists; Leukotrienes; Lipoxygenase; Masoprocol; Pentoxifylline; Sepsis; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase; Toxemia; Tumor Necrosis Factor-alpha

In urine of healthy man, the major metabolite of prostacyclin is 2,3-dinor-6-oxo-prostaglandin F1 alpha. The excretion rates of this compound as well as of 2,3-dinor-thromboxane B2, a major metabolite of thromboxane A2, in two newborns with septic persistent pulmonary hypertension were about 30- to 50-fold higher than the normal range (2,3-dinor-6-oxo-prostaglandin F1 alpha: 3-15 ng/h/1.73 m2; 2,3-dinor-thromboxane B2: 8-25 ng/h/1.73 m2). The ratios of 2,3-dinor-6-oxo-13,14-dihydro-prostaglandin F1 alpha/2,3-dinor-6-oxo-prostaglandin F1 alpha in these two infants were about 100% and 800%, respectively whereas in controls the excretion of the 13,14-dihydro metabolite was found to be about 10-25% of 2,3-dinor-6-oxo-prostaglandin F1 alpha. Thus in patients with septic persistent pulmonary hypertension and extremely high excretion rates of prostacyclin and thromboxane A2 metabolites, the pattern of metabolites differs from those of healthy man.

Topics: Chromatography, Gas; Epoprostenol; Humans; Infant, Newborn; Male; Mass Spectrometry; Persistent Fetal Circulation Syndrome; Sepsis; Thromboxane A2

Topics: Hemodynamics; Humans; Respiratory Function Tests; Sepsis; Thromboxane A2

We investigated the role of prostacyclin (PGI2) and thromboxane A2 (TxA2), as evidenced by changes in their stable metabolites, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2), in the pathophysiology of acute bacteremic gram-negative pneumonia. Three groups of dogs were inoculated endotracheally: Group I (n = 5) with sterile broth, and Groups II (n = 5) and III (n = 10) with Pseudomonas aeruginosa. Gas exchange, hemodynamics, and plasma prostaglandins were measured before inoculation and hourly thereafter for 5 h in Groups I and II but only once in Group III, 5 h after inoculation. All animals were then killed, and the extent of pneumonia was assessed by lung wet weight and measurement of the percentage of cardiac output (CO) perfusing pneumonic lung using radionuclide-labeled microspheres. None of these measurements changed significantly in Group I, but all dogs in Groups II and III developed severe pneumonia. In Group II, mean arterial oxygen tension fell from 575 +/- 17 to 237 +/- 59 mm Hg (FIO2 = 1.0), with an increase in pulmonary shunt from 6 +/- 2% to 24 +/- 6%. Although TxB2 levels did not change, plasma 6-keto-PGF1 alpha rose progressively as pneumonia developed from baseline levels (less than 100 pg/ml) to a peak level of 890 +/- 114 pg/ml 5 h after inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Animals; Dogs; Epoprostenol; Hemodynamics; Pneumonia; Pseudomonas Infections; Pulmonary Circulation; Sepsis; Thromboxane A2

The purpose of this study was to determine whether or not thromboxane A2 (TXA2) was necessary or sufficient for the development of end-organ pathology during graded bacteremia. Pulmonary artery catheters were placed in 21 adult male pigs under pentobarbital anesthesia and breathing room air. After a control period, animals were studied in four groups: Group 1, anesthesia only; Group 2, infusion of 1 X 10(9) ml Aeromonas hydrophila which was gradually increased from 0.2 ml/kg/hr to 4.0 ml/kg/hr over 4 hours; Group 3, pretreatment with SQ 29,548 (TXA2 antagonist) then Aeromonas h. infusion; Group 4, infusion of U46619 (TXA2 agonist) to pulmonary artery pressures measured in Group 2. Animals were sacrificed after 4 hours and the lungs, liver, spleen, kidneys, and heart were examined under light microscopy by a pathologist unaware of study groups. The results indicated that physiologic thromboxane A2 agonist (Group 4) was sufficient alone to cause pulmonary inflammation. Thromboxane A2 was neither necessary nor sufficient for significant renal, hepatic, pulmonary, or splenic pathology to occur in graded bacteremia, manifested in similar microanatomic abnormalities in these organs in Groups 2 and 3 and in Groups 1 and 4. Pulmonary leukocyte infiltration was significantly increased in Group 3 compared to all other groups, suggesting that TXA2 impairs inflammatory responses.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bridged Bicyclo Compounds, Heterocyclic; Fatty Acids, Unsaturated; Hydrazines; Kidney; Liver; Lung; Male; Myocardium; Prostaglandin Endoperoxides, Synthetic; Radioimmunoassay; Sepsis; Spleen; Swine; Thromboxane A2; Thromboxane B2

The effects of selectively inhibiting synthesis of thromboxane A2 (TXA2) with dazoxiben and of all cyclooxygenase products with indomethacin were studied in goats after infusion of 5 X 10(8) live Escherichia coli bacteria/kg. Pulmonary and systemic pressures, cardiac output, and double indicator dilution extravascular lung water (EVLW) were measured at 15-min intervals. EVLW was determined gravimetrically at 6 hr to confirm the final double indicator dilution values. Plasma levels of TXA2 and prostacyclin (PGI2) were measured as their stable metabolites, TXB2 and 6-keto-PGF1 alpha, respectively. Dazoxiben blocked the increase in plasma TXB2, prevented pulmonary hypertension, and attenuated the increase in EVLW after E. coli. Mean gravimetric EVLW was 8.7 ml/kg in the dazoxiben-treated group compared to 11.3 ml/kg in the untreated control group. Indomethacin blocked the increased plasma TXB2 and 6-keto-PGF1 alpha, attenuated pulmonary hypertension, and prevented almost all increases in EVLW. Mean gravimetric EVLW was 8.2 ml/kg after indomethacin. We conclude that in acute bacteremia, the early pulmonary hypertension is mediated largely by TXA2 (however, a second phase of hypertension results from non-cyclooxygenase products), either production of cyclooxygenase products (perhaps PGI2) inhibits part of the action of pulmonary vasoconstrictors, or indomethacin stimulates the production of other vasoconstrictors (such as lipoxygenase products), and indomethacin prevents the accumulation of EVLW by blocking formation of cyclooxygenase products or by other nonspecific actions.

Topics: Animals; Body Water; Cyclooxygenase Inhibitors; Escherichia coli Infections; Female; Imidazoles; Indomethacin; Lung; Male; Prostaglandin-Endoperoxide Synthases; Sepsis; Thromboxane A2

Thromboxane A2 has been implicated as a mediator of cardiorespiratory dysfunction in sepsis. This study evaluated whether or not thromboxane A2 was necessary or sufficient for these adverse effects to occur during bacteremia. Fourteen adult swine under barbiturate anesthesia and breathing room air were monitored with arterial and pulmonary artery catheters. Animals were studied for 4 hours in three groups: group I, graded infusion of 10(9)/ml Aeromonas hydrophila; group II, Aeromonas hydrophila infusion plus SQ 29,548 (thromboxane A2 antagonist); and group III, U46619 (thromboxane A2 agonist) infusion in normal swine to pulmonary artery pressures observed in group I. Hemodynamic parameters, arterial and mixed venous blood gases, and plasma thromboxane B2 and prostaglandin 6-keto-F1 were measured. At sacrifice after 4 hours, wet-to-dry lung weights were calculated. Results indicated that thromboxane A2 was necessary and sufficient for the development of pulmonary hypertension and impaired alveolar-capillary oxygen diffusion in graded bacteremia. It was necessary but not sufficient for increased lung water to occur and sufficient but not necessary for decreased cardiac index and stroke volume index. Thromboxane A2 was neither sufficient nor necessary to the pathophysiology of systemic hypotension during graded bacteremia. Plasma prostaglandin 6-keto-F1 levels were increased in hypotensive animals with sepsis, suggesting its involvement in hypotension during sepsis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Aeromonas; Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Capillary Permeability; Cardiac Output; Epoprostenol; Fatty Acids, Unsaturated; Hemodynamics; Hydrazines; Hypertension, Pulmonary; Hypoxia; Male; Prostaglandin Endoperoxides, Synthetic; Pulmonary Gas Exchange; Sepsis; Shock, Septic; Swine; Thromboxane A2; Thromboxane B2

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

The relationship between plasma levels of thromboxane A2, radioimmunoassayed as thromboxane B2 (TxB), and cardiopulmonary dysfunction in graded bacterial sepsis was investigated. Five adult female pigs under anesthesia were intubated and allowed to breathe room air spontaneously. Femoral arterial, venous, and pulmonary artery catheters were inserted. After a 60-minute control period Aeromonas hydrophila (1.0 X 10(9)/ml) was infused intravenously at 0.2 ml/kg/hr, gradually increasing to 4.0 ml/kg/hr over 4 hours. Arterial and mixed venous blood gases, hemodynamic measurements, and TxB plasma concentrations were obtained during the control period, at 10, 20, 30, 45, and 60 minutes and at 30-minute intervals thereafter. Cardiac index increased significantly from control at 20 minutes, remained above control levels for 1 hour, and then declined to significantly low values at 150 minutes. TxB was increased from control at 20 minutes, rising to four times control at 120 minutes. Mean arterial pressure, pulmonary capillary wedge pressure, left ventricular stroke work, paO2, and pvO2 decreased significantly during the experiment. Pulmonary artery pressure and pulmonary vascular resistance increased significantly. Changes in TxB were significantly cross-correlated with changes in cardiac index, pulmonary vascular resistance, stroke volume, left ventricular stroke work, and paO2. TxB elevations led the cross-correlated variables by 0 to 60 minutes. Pulmonary vascular resistance cross-correlated with mean arterial pressure and cardiac index. TxB is increased early in graded bacterial sepsis. Changes in TxB appear to precede impaired cardiopulmonary function. The data suggest that TxB is involved in the detrimental hemodynamic effects of early septicemia.

Topics: Animals; Blood Pressure; Cardiac Output; Female; Guinea Pigs; Hematocrit; Hemodynamics; Pulmonary Circulation; Respiration; Sepsis; Thromboxane A2; Thromboxanes; Vascular Resistance

Topics: Animals; Body Water; Escherichia coli Infections; Goats; Hemodynamics; Imidazoles; Lung; Oxidoreductases; Sepsis; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes