thromboxane-a2 and Shock

Several important eicosanoids are produced during ischemic and shock states that may mediate much of the pathogenesis of these disorders. The primary substances of interest are the thromboxanes (e.g., TxA2), and the peptide leukotrienes (e.g., LTC4 and LTD4). TxA2 and the peptide leukotrienes fulfill all the criteria for a mediator in ischemia and shock. They are potent agents that exhibit a multiplicity of serious pathogenic actions. Moreover, inhibition of the formation or actions of TxA2 and the LTs is salutary in shock. TxA2 and the peptide leukotrienes therefore should be considered as important mediators of ischemia and shock, and probably as potent mediators as any known humoral substances in shock.

Topics: Animals; Fatty Acids; Humans; Ischemia; Leukotriene B4; Shock; SRS-A; Thromboxane A2

Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple acti

Topics: Animals; Fatty Acids, Unsaturated; Humans; Leukotriene B4; Platelet Activating Factor; Prostaglandins; Shock; SRS-A; Thromboxane A2

Topics: Animals; Epoprostenol; Humans; Kidney; Neoplasms; Shock; Thrombosis; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vascular Resistance

Topics: Animals; Coronary Disease; Diabetes Mellitus; Epoprostenol; Humans; Hydronephrosis; Male; Platelet Aggregation; Shock; Thromboxane A2; Thromboxanes; Vasoconstriction

Topics: Blood Vessels; Homeostasis; Humans; Prostaglandins; Prostaglandins E; Shock; Thromboxane A2; Thromboxanes

This study has shown that multiple organ failure (MOF) is one of the major causes of death in patients with severe burns. Both the plasma and visceral levels of TXB2 and the TXB2/6-keto-PGF1 alpha ratio were significantly increased. The changed plasma levels of TXB2 and the TXB2/6-keto-PGF1 alpha ratio paralleled the deterioration of the general condition in MOF patients. The circulatory platelet aggregation ratios (CPAR) in the MOF patients initially declined then dropped profoundly at 5-7 days postburn, indicating more microaggregate formation. CPK, LDH and GOT had increased markedly by 1 day, were elevated further at 2-3 days, and remained at supranormal levels for the first 7 days postburn. Degeneration, destruction, oedema, haemorrhage and thrombosis were observed in tissues from patients who died due to heart, lung, renal and hepatic failure. Clinically, 13 of the 16 MOF cases developed organ failure and 11 died between 3 and 7 days postburn. These findings confirmed that the increases of TXA2 and the TXA2/PGI2 ratio in plasma and visceral tissues can be an important factor in the genesis and development of postburn MOF.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Body Surface Area; Burns; Female; Humans; Male; Middle Aged; Multiple Organ Failure; Prospective Studies; Shock; Thromboxane A2

Thromboxane (TXA2) and prostacyclin (PGI2) levels, circulatory platelet aggregate ratios (CPAR), CPK, LDH, GOT, platelet counts, blood viscosity, cortisol and urine epinephrine contents were determined in 42 burned patients who were divided into two groups: Group I control (n = 34) and Group II (n = 8) treated with TXA2 synthesis inhibitor, anisodamine. It was found that in controls, both TXA2 and the TXA2/PGI2 ratio increased significantly. There was no marked difference in PGI2 levels between the two groups. Platelet counts and CPAR decreased, while blood viscosity, CPK, LDH, GOT, cortisol and epinephrine in the controls were all significantly higher than those found in Group II patients. All these findings suggested that the changes of TXA2 and the TXA2/PGI2 ratios played an important role in the haemodynamics and haemorrheology in burn shock. The TXA2 synthesis inhibitor, anisodamine, showed beneficial effects by restoring the haemodynamic and rheological disturbances towards normal by virtue of their ability to induce vascular constriction, platelet aggregation, cellular destruction, destabilization of membranes and release of chemical mediators (including enzymes). Furthermore, at 1-3 days postburn, the levels of CPK, LDH and GOT in controls were higher than those measured at 12 h postburn, but this phenomenon was not marked in the treated group, suggesting that after resuscitation, reperfusion damage had occurred and TXA2 might be responsible for the damage. It is assumed that anisodamine could protect tissues from reperfusion damage. The findings also suggested that anisodamine could quicken the restoration of neuroendocrine disturbance initiated by shock (stress).

Topics: Adolescent; Adult; Aspartate Aminotransferases; Burns; Creatine Kinase; Epinephrine; Female; Humans; Hydrocortisone; Infusions, Intravenous; L-Lactate Dehydrogenase; Male; Middle Aged; Shock; Solanaceous Alkaloids; Thromboxane A2; Thromboxane B2; Vasodilator Agents

Thromboxane A2 (TXA2) is a labile metabolite of arachidonic acid that has potent biological effects. Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiological functions of TP receptors, we generated TP receptor-deficient mice by gene targeting. Tp-/- animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding cannot be detected in tissues from Tp-/- mice. Bleeding times are prolonged in Tp-/- mice and their platelets do not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation are also delayed, although ADP-stimulated aggregation is normal. Infusion of the TP receptor agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynamic effect in Tp-/- mice. Tp-/- mice are also resistant to arachidonic acid-induced shock, although arachidonic acid signifi-cantly reduced blood pressure in Tp-/- mice. In summary, Tp-/- mice have a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Our studies suggest that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Animals; Arachidonic Acid; Bleeding Time; Blood Coagulation Disorders; Collagen; Female; Hemodynamics; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptors, Thromboxane; Shock; Thromboxane A2

Splanchnic artery occlusion shock was induced in male anaesthetized rats by clamping the splanchnic artery for 45 min. The arteries were then released and survival rate, mean survival time, mean arterial blood pressure, plasma levels of thromboxane B2 and 6-keto-PGF1 alpha, macrophage phagocytosis activity and plasma levels of myocardial depressant factor were evaluated. In addition, the neutrophilic infiltrate was quantified in the ileum and lung using a myeloperoxidase (MPO) assay. Sham splanchnic-artery-occlusion-shocked rats were used as controls. Splanchnic-artery-occlusion-shocked rats died within 93 +/- 7 min, while all sham-shocked animals survived more than 3 h. Splanchnic artery occlusion shock caused changes in mean arterial blood pressure, significantly increased the plasma levels of thromboxane B2 (7.5 +/- 1.3 ng/ml; p < 0.001 vs. sham), 6-keto-PGF1 alpha (8.9 +/- 1.7 ng/ml; p < 0.001 vs. sham) and myocardial depressant factor (114 +/- 11 U/ml), and reduced macrophage phagocytosis. Furthermore, MPO activity was significantly elevated (0.12 +/- 0.03 x 10(-3) and 1.8 +/- 0.5 x 10(-3) U/g protein in the ileum and lung, respectively) 70 min after starting reperfusion. Administration of BAY u3405, a novel thromboxane A2 receptor antagonist (30 mg/kg i.v., 30 min before occlusion), significantly increased survival time (187 +/- 3.7 min) and survival rate, improved mean arterial blood pressure, reduced the plasma levels of myocardial depressant factor (54 +/- 3 U/ml), partially restored macrophage phagocytosis and lowered MPO activity in both the ileum and the lung. Our data are consistent with an involvement of thromboxane A2 in splanchnic artery occlusion shock and suggest that BAY u3405 might be of benefit in low-flow states such as circulatory shock.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Arterial Occlusive Diseases; Blood Pressure; Carbazoles; Macrophages; Male; Myocardial Depressant Factor; Peroxidase; Phagocytosis; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Shock; Splanchnic Circulation; Sulfonamides; Survival Rate; Thromboxane A2; Thromboxane B2

Defibrotide (DEF), a compound previously found to stimulate vascular prostacyclin (PGI2) formation, has been investigated in an experimental model of septic shock. Anesthetized pigs were subjected to i.v. infusion of lipid A (1.5 mg/kg per hr for 4 hr). DEF (50 mg/kg per hr) or vehicle were infused i.v. throughout the experiments, starting 1 hr prior to lipid A. Two out of 7 pigs receiving vehicle survived lipid A infusion for 4 hr, whereas 6 out of 7 DEF treated animals survived this period (P less than 0.05). DEF delayed the shock-induced depression of platelet count and preserved platelet secretory function (collagen-induced ATP-secretion). DEF increased plasma PGI2 by 45% (P less than 0.05) during lipid A infusion and tended to reduce thromboxane levels. DEF did not change eicosanoid formation in sham-shock pigs (n = 4 per group). In vivo treatment with DEF significantly increased the stimulatory effect of bradykinin (1 microM) and arachidonic acid (100 microM) on PGI2 formation ex vivo of mesenteric and iliac artery segments. The improvement of survival in lipid A-induced shock by DEF may be related to an enhancement of vascular PGI2 generation, potentially due to a reduction of shock-induced platelet activation and microcirculatory dysfunction.

Topics: Animals; Arachidonic Acid; Blood Platelets; Bradykinin; Disease Models, Animal; Drug Synergism; Epoprostenol; Lipid A; Platelet Count; Polydeoxyribonucleotides; Shock; Survival Rate; Swine; Thromboxane A2

The anti-helminthic drug levamisole has been used as an adjunct in the treatment of some immunologic defects including cancer. Recently, it has been shown that this drug inhibits thromboxane synthetase as well. Since Forssman shock in guinea pig is used as a model for pulmonary thromboembolism involving thromboxane A2, we studied the interference of levamisole with bronchoconstriction, thrombocytopenia, endothelial cells and pulmonary damage induced by Forssman antiserum. Levamisole inhibited dose-dependently the pathological changes produced by Forssman antiserum raising the possibility that levamisole may be effective for the treatment of pulmonary thromboembolism in man.

Topics: Animals; Antibodies; Disease Models, Animal; Endothelium, Vascular; Forssman Antigen; Guinea Pigs; Levamisole; Lung; Male; Platelet Count; Pressure; Pulmonary Embolism; Shock; Thromboxane A2

The role of thromboxane and prostacyclin in circulatory shock of intestinal origin was investigated in anesthetized dogs by measuring their stable metabolites, thromboxane B2 (TXB2) and 6-keto-PGF1 alpha, respectively, in superior mesenteric vein (SMV), right ventricle (RV), and aorta during superior mesenteric artery occlusion-induced (SMAO) shock and by inhibiting prostanoid synthesis with indomethacin (IM). Release of the SMAO caused a dramatic decrease in mean arterial blood pressure and a significant increase in 6-keto-PGF1 alpha levels in SMV, RV, and aorta within 5 min. Thereafter, 6-keto-PGF1 alpha concentration decreased so that at 60-min postrelease it was not significantly different from the control values. TXB2 levels rose continuously during shock. IM significantly attenuated the magnitude of postocclusion hypotension and reduced both TXB2 and 6-keto-PGF1 alpha production.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Pressure; Dogs; Epoprostenol; Indomethacin; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Shock; Thromboxane A2; Thromboxane B2

Topics: Animals; Cats; Coronary Disease; Myocardial Reperfusion Injury; Phenylacetates; Platelet Aggregation; Rabbits; Shock; Sulfonamides; Thromboxane A2; Thromboxanes

Forssman shock is a bronchospastic reaction mounted in guinea pigs on intravenous administration of an antiserum obtained from rabbits immunized against sheep erythrocytes. The involvement of thromboxane receptors in Forssman shock was determined with SQ 30,741, which was characterized as a selective antagonist of these receptors in guinea pig airways in vitro and in vivo. A volume of antiserum producing consistent, sublethal bronchoconstriction was given either alone (control) or 3 min after SQ 30,741 (0.03, 0.3, or 1.0 mg/kg iv) to urethan-anesthetized guinea pigs. In controls, maximum reductions in dynamic compliance (-59 +/- 6%, P less than 0.01) and increases in airways resistance (383 +/- 97%, P less than 0.01) were detected 1 min after antiserum. Both responses were significantly inhibited by SQ 30,741, either partially at 0.03 mg/kg or completely at 0.3 mg/kg. An accompanying thrombocytopenia was not abated by SQ 30,741. In separate experiments, bronchospasm was reduced by aerosol administration of 0.1% SQ 30,741 and completely prevented by aspirin (10 mg/kg iv). When Forssman antiserum was injected in lethal quantities to other guinea pigs, SQ 30,741 (1 mg/kg iv) attentuated only the resistance component of bronchospasm and did not prevent death. These data demonstrate that thromboxane receptor stimulation is a pivotal step in the pulmonary manifestations of sublethal Forssman shock but is less crucial in more severe forms of the reaction.

Topics: Animals; Antigens, Heterophile; Bronchial Spasm; Forssman Antigen; Guinea Pigs; Male; Receptors, Prostaglandin; Receptors, Thromboxane; Shock; Thromboxane A2; Trachea

Splanchnic artery occlusion (SAO) followed by release of the occlusive clamps produces circulatory shock characterized by an abrupt hypotension, cardiac depression and high lethality. We studied the effects of the thromboxane receptor antagonist, BM-13505, in rats during SAO shock. Anesthetized rats subjected to total occlusion of the celiac and superior mesenteric arteries for 40 minutes developed a severe shock state following reperfusion, usually resulting in death within 90-120 minutes of release of the occlusion. BM-13505 was started at reperfusion for 10 minutes. SAO shock rats treated with BM-13505 (1 mg/kg) maintained post-reperfusion mean arterial blood pressure (MABP) at significantly higher values compared to those receiving only the vehicle (0.9% NaCl). Treatment with BM-13505 attenuated the plasma activity of the lysosomal protease cathepsin D (p less than 0.05 from vehicle) and the plasma accumulation of free amino-nitrogen compounds (p less than 0.01 from vehicle). Furthermore, the plasma activity of a myocardial depressant factor was significantly lower in BM-13505 treated rats than in non-treated rats (p less than 0.01 from vehicle). SAO shock rats treated with BM-13505 also exhibited a higher survival rate than the vehicle group (75% vs. 20%). These results suggest an important role of thromboxane A2 in the pathophysiology of SAO shock.

Topics: Animals; Blood Pressure; Cathepsin D; Disease Models, Animal; Hematocrit; Male; Mesenteric Vascular Occlusion; Myocardial Depressant Factor; Nitrogen; Phenylacetates; Rats; Rats, Inbred Strains; Shock; Splanchnic Circulation; Sulfonamides; Thromboxane A2

The pathogenesis of shock is discussed on the basis of important results from world literature under the special point of view of the significance of eicosanoids. It results from a lower mortality of shock animals with a diet poor in polyunsaturated fatty acids and a specifically increased release of arachidonic acid as prostaglandin precursor in shock animals. Of particular importance is an increased formation of thromboxane B2 (TXB2). It this formation is specifically inhibited, the survival rate increases, the decrease of blood pressure is reduced, also the increase of the plasma-cathepsin-D-activity and of the myocardial depressant factor and the increased formation of microthrombi in renal glomeruli of shock animals. Also in patients who survived the shock the TXB2-values were only 1/10 of the values in decreased shock patients. Another therapeutic way is the infusion of prostacyclin which leads to a specific increase of the arterial blood supply of the liver and the superior mesenteric artery and also increases the ATP and creatine phosphate level. The importance of the findings of animal experiments for the pathogenesis and therapy in patients is discussed.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Cathepsin D; Dogs; Fatty Acids, Unsaturated; Humans; Lipoxygenase; Prognosis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Shock; Shock, Hemorrhagic; Shock, Septic; Thromboxane A2; Thromboxane B2