thromboxane-a2 and Pulmonary-Embolism

Acute massive pulmonary embolism has a high mortality rate. Fatal haemodynamic deterioration is caused by an acute increase in pulmonary vascular resistance. Traditionally, the degree of mechanical obstruction of the pulmonary vasculature by the embolic thrombus is considered to be the major determinant of this increase in right ventricular afterload. However, there is evidence to suggest that another factor plays an important role, since there is a marked discrepancy between the haemodynamic manifestations of acute pulmonary embolism and the degree of mechanical obstruction. Historic studies indicate that this discrepancy is largely explained by pulmonary vasoconstriction caused by vasoactive mediators, released mainly by activated platelets. Thromboxane-A(2) and serotonin are probably the two most important pulmonary vasoconstrictors in this context. Antagonising their effects dramatically increases tolerance to experimental pulmonary embolism in animals. In humans, this concept should eventually find its way into clinical practice. In the future, acute massive pulmonary embolism could be treated with antagonists to pulmonary vasoconstrictors, or with direct pulmonary vasodilators.

Topics: Acute Disease; Animals; Fibrinolytic Agents; Humans; Platelet Activation; Pulmonary Embolism; Serotonin; Serotonin Antagonists; Species Specificity; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasodilator Agents

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Asthma; Bronchi; Heart Defects, Congenital; Humans; In Vitro Techniques; Lung; Mucus; Prostaglandin Antagonists; Prostaglandins; Pulmonary Embolism; Respiratory Distress Syndrome; Respiratory Tract Diseases; Smoking; Thromboxane A2

Topics: Animals; Arachidonic Acids; Chemotaxis, Leukocyte; Chromones; Dogs; Guinea Pigs; Humans; Hypertension, Pulmonary; Inflammation; Ketanserin; Leukocyte Count; Leukocytes; Lung; Piperidines; Platelet Activating Factor; Pulmonary Embolism; Respiratory Distress Syndrome; Serotonin; Serotonin Antagonists; SRS-A; Thromboxane A2

Topics: Animals; Arachidonic Acids; Aspirin; Dipyridamole; Dogs; Epoprostenol; Hemostasis; Humans; Platelet Adhesiveness; Platelet Aggregation; Pulmonary Embolism; Thromboembolism; Thrombophlebitis; Thromboxane A2

Essentials Statins, especially rosuvastatin, may reduce venous thrombosis risk, but the mechanism is unclear. We performed a randomized trial investigating the effect of rosuvastatin on platelet reactivity. Thromboxane-A2 mediated platelet aggregation was measured before and after rosuvastatin therapy. Rosuvastatin did not inhibit thromboxane-mediated platelet aggregation in venous thrombosis patients.. Background Statins may exert a protective effect against the risk of venous thrombosis (VT), but the mechanism is unclear. Objectives In this open-label, randomized clinical trial (www.clinicaltrials.gov NCT01613794), we aimed to determine the ex vivo effect of rosuvastatin on platelet reactivity in patients with a history of VT. Methods Platelet reactivity, in platelet reaction units (PRUs), was measured at baseline and after 28 days with VerifyNow, which uses arachidonic acid to determine thromboxane-mediated platelet aggregation, in 50 consecutive patients included in our study (25 receiving rosuvastatin and 25 without intervention). Results Forty-seven of 50 (94.0%) consecutively enrolled patients had two valid PRU measurements. The mean PRUs in rosuvastatin users were 609 at baseline and 613 at the end of the study (mean change 5; 95% confidence interval [CI] - 18 to 27). The mean PRUs in non-users were 620 at baseline and 618 at the end of the study (mean change - 2; 95% CI - 15 to 12). The mean difference in PRU change between users and non-users was 6 (95% CI - 20 to 33). After exclusion of patients who used antiplatelet medication, or had thrombocytopenia, similar results were obtained, i.e. no apparent effect of rosuvastatin on PRUs, with a mean difference in PRU change between users and non-users of - 1 (95% CI - 20 to 19). Conclusions Rosuvastatin does not affect platelet reactivity when arachidonic acid is used as an agonist in patients with a history of VT.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Arachidonic Acid; Blood Platelets; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Pulmonary Embolism; Rosuvastatin Calcium; Thromboxane A2; Venous Thrombosis; Young Adult

To investigate changes in the plasma concentrations of cardiac troponin I (CTnI), thromboxane A2 (TXA2), prostaglandin I2 (PGI2) and endothelin-1 (ET-1) in rabbits with massive pulmonary embolism (AMPE) and the impact of nitric oxide inhalation (NOI) on these indices.. A total of 30 Japanese rabbits were used to construct an MPE model and were divided into 3 groups equally (n=10), including an EXP group (undergoing modeling alone), an NOI group (receiving NOI 2 h post-modeling) and a CON group (receiving intravenous physiological saline).. In the model group, plasma concentration of CTnI peaked at 16 h following modeling (0.46±0.10 µg/ml) and significantly decreased following NOI. Plasma levels of TXB2, PGI2 and ET-1 peaked at 12, 16 and 8 h following modeling, respectively, and significantly decreased at different time points (0, 2, 4, 8, 12, 16, 20 and 24 h) following NOI. A significant correlation was observed between the peak plasma CTnI concentration and peak TXB2, 6-keto prostaglandin F1α and ET-1 concentrations in the model and NOI groups.. Increases in plasma TXA2, PGI2 and ET-1 levels causes myocardial damage in a rabbit model of AMPE; however, NOI effectively down regulates the plasma concentration of these molecules to produce a myocardial-protective effect.

Topics: Acute Disease; Administration, Inhalation; Animals; Bronchodilator Agents; Down-Regulation; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Epoprostenol; Female; Male; Nitric Oxide; Pulmonary Embolism; Rabbits; Random Allocation; Reference Values; Reproducibility of Results; Thromboxane A2; Time Factors; Treatment Outcome; Troponin I

A novel benzimidazole derivative, nstpbp5185, was discovered through in vitro and in vivo evaluations for antiplatelet activity. Thromaboxane receptor (TP) is important in vascular physiology, haemostasis and pathophysiological thrombosis. Nstpbp5185 concentration-dependently inhibited human platelet aggregation caused by collagen, arachidonic acid and U46619. Nstpbp5185 caused a right-shift of the concentration-response curve of U46619 and competitively inhibited the binding of 3H-SQ-29548 to TP receptor expressed on HEK-293 cells, with an IC50 of 0.1 µM, indicating that nstpbp5185 is a TP antagonist. In murine thrombosis models, nstpbp5185 significantly prolonged the latent period in triggering platelet plug formation in mesenteric and FeCl3-induced thrombi formation, and increased the survival rate in pulmonary embolism model with less bleeding than aspirin. This study suggests nstpbp5185, an orally selective anti-thrombotic agent, acting through blockade of TXA2 receptor, may be efficacious for prevention or treatment of pathologic thrombosis.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arachidonic Acid; Aspirin; Benzimidazoles; Blood Platelets; Calcium; Collagen; Humans; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Microvessels; P-Selectin; Platelet Aggregation; Pulmonary Embolism; Receptors, Thromboxane A2, Prostaglandin H2; Thrombosis; Thromboxane A2

L-sulforaphane was identified as an anticarcinogen that could produce quinine reductase and a phase II detoxification enzyme. In recent decades, multi-effects of L-sulforaphane may have been investigated, but, to the authors' knowledge, the antiplatelet activation of L-sulforaphane has not been studied yet.In this study, 2 μg/ml of collagen, 50 μg/ml of ADP and 5 μg/ml of thrombin were used for platelet aggregations with or without L-sulforaphane. L-sulforaphane inhibited the platelet aggregation dose-dependently. Among these platelet activators, collagen was most inhibited by L-sulforaphane, which markedly decreased collagen-induced glycoprotein IIb/IIIa activation and thromboxane A2 (TxA2) formation in vitro. L-sulforaphane also reduced the collagen and epinephrine-induced pulmonary embolism, but did not affect prothrombin time (PT) in vivo. This finding demonstrated that L-sulforaphane inhibited the platelet activation through an intrinsic pathway.L-sulforaphane had a beneficial effect on various pathophysiological pathways of the collagen-induced platelet aggregation and thrombus formation as a selective inhibition of cyclooxygenase and glycoprotein IIb/IIIa antagonist. Thus, we recommend L-sulforaphane as a potential antithrombotic drug.

Topics: Adenosine Diphosphate; Animals; Blood Coagulation; Blood Platelets; Collagen; Female; Fibrinolytic Agents; Humans; Isothiocyanates; Mice; Mice, Inbred ICR; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Glycoprotein GPIIb-IIIa Complex; Pulmonary Embolism; Sulfoxides; Thiocyanates; Thrombin; Thromboxane A2

Andrographolide is a novel NF-κB inhibitor from the leaves of Andrographis paniculata. Platelet activation is relevant to a variety of thrombotic diseases. However, no data are available concerning the effects of andrographolide in platelet activation. The aim of this study was to examine the mechanisms of andrographolide in preventing platelet activation. Andrographolide (25-75 μΜ) exhibited a more potent activity of inhibiting platelet aggregation stimulated by collagen. Andrographolide inhibited collagen-stimulated platelet activation accompanied by relative Ca(2+) mobilization; thromboxane A(2) formation; and phospholipase C (PLC)γ2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Andrographolide markedly increased cyclic GMP, but not cyclic AMP levels. Andrographolide also stimulated endothelial nitric oxide synthase (eNOS) expression, NO release, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. ODQ, an inhibitor of guanylate cyclase, markedly reversed the andrographolide-mediated inhibitory effects on platelet aggregation, p38 MAPK and Akt phosphorylation, and the andrographolide-mediated stimulatory effect on VASP phosphorylation. Furthermore, a PI3 kinase inhibitor (LY294002) but not a PKC inhibitor (Ro318220) significantly diminished p38 MAPK phosphorylation; nevertheless, a p38 MAPK inhibitor (SB203580) and LY294002 diminished PKC activity stimulated by collagen. Andrographolide also reduced collagen-triggered hydroxyl radical (OH([Symbol: see text])) formation. In vivo studies revealed that andrographolide (22 and 55 μg/kg) is effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism and significantly prolonged platelet plug formation in mice. This study demonstrates for the first time that andrographolide possesses a novel role of antiplatelet activity, which may involve the activation of the eNOS-NO/cyclic GMP pathway, resulting in the inhibition of the PI3 kinase/Akt-p38 MAPK and PLCγ2-PKC cascades, thereby leading to inhibition of platelet aggregation.

Topics: Adenosine Diphosphate; Animals; Blood Platelets; Calcium; Collagen; Cyclic GMP; Diterpenes; Humans; Mice; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase Type III; Platelet Activation; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Pulmonary Embolism; Thromboxane A2

Actinostemma lobatum Maxim, a wildlife plant of Cucurbitaceae family, has been utilized for the prevention or treatment of cardiovascular diseases as a folk remedy in Korea. However, its scientific evidence remains unclear. Thus, in the present study, we examined the effects of butanol fraction of Actinostemma lobatum Maxim (BFALM) on the in vitro and in vivo antithrombotic activity and possible mechanisms were elucidated for the first time.. To elucidate the antithrombotic mechanism of BFALM, platelet aggregation assay, coagulation assay, glycoprotein IIb/IIIa assay, thromboxane A(2) assay and in vivo pulmonary thromboembolism experiment were performed.. BFALM significantly inhibited collagen, adenosine diphosphate (ADP) and thrombin-induced platelet aggregation in a concentration dependent manner. Consistently, oral administration of BFALM resulted in a dose-dependent increase of survival rates of mice with pulmonary thromboembolism induced by intravenous injection of collagen and epinephrine. In mechanism assays for the antithrombotic activity of BFALM, BFALM significantly inhibited the fibrinogen binding to the platelet surface Glycoprotein IIb/IIIa (GP IIb/IIIa) receptor in a concentration dependent fashion, as well as reduced the level of thromboxane A(2) at 400microg/ml. Furthermore, BFALM significantly prolonged the prothrombin time (PT) and activated partial thromboplastin time (APTT) compared with untreated control.. These results suggest that BFALM may exert antithrombotic activity through inhibition of platelet aggregation via GP IIb/IIIa and thromboxane A(2) pathways, along with anticoagulatory activity through intrinsic and extrinsic pathways.

Topics: Animals; Blood Coagulation; Blood Platelets; Butanols; Cucurbitaceae; Dose-Response Relationship, Drug; Female; Fibrinogen; Fibrinolytic Agents; Integrin beta3; Mice; Mice, Inbred ICR; Phytotherapy; Plant Extracts; Platelet Aggregation; Platelet Membrane Glycoprotein IIb; Pulmonary Embolism; Rutin; Survival Analysis; Thromboxane A2

The aim of this study was to evaluate the effect of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea], a dual thromboxane A2 synthase inhibitor and receptor antagonist, on the hemodynamic response to acute pulmonary embolism. Six anesthetized pigs were infused with placebo (placebo group) and compared with six other pigs receiving a continuous infusion of BM-573 (BM group). Pulmonary embolization with 0.3 g/kg autologous blood clots was carried out 30 min after the start of the infusion. Right ventricular pressure-volume loops were recorded using a conductance catheter, and end-systolic ventricular elastance was periodically assessed by varying right ventricular preload. Pulmonary vascular properties were studied by use of a four-element windkessel model. Hemodynamic data, including assessment of right ventricular-arterial coupling, were collected at baseline and every 30 min for 4 h. Blood samples were collected to assess gas exchange, thromboxane A2, and prostacyclin plasma levels and to evaluate platelet aggregation. Mean pulmonary arterial pressure in the placebo group increased significantly more than in the BM group, mainly because of an additional increase in pulmonary vascular resistance. Arterial and end-systolic ventricular elastances increased also more in the placebo group, whereas right ventricular efficiency decreased. BM-573 prevented both platelet aggregation induced by U-46619 (9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F2alpha) or by arachidonic acid, and thromboxane A2 overproduction, whereas prostacyclin liberation was preserved. Oxygenation, however, was not significantly improved. We conclude that in this animal model of acute pulmonary embolism, infusion of BM-573 reduced pulmonary vasoconstriction. As a result, right ventricular-vascular coupling values were maintained at a maximal efficiency level.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; 6-Ketoprostaglandin F1 alpha; Animals; Arachidonic Acid; Blood Coagulation; Epoprostenol; Female; Hemodynamics; Male; Platelet Aggregation; Pulmonary Embolism; Receptors, Thromboxane; Sulfonylurea Compounds; Swine; Thromboxane A2; Thromboxane B2; Thromboxane-A Synthase

Decreased expression of prostacyclin synthase (PGIS) is observed in the lung vasculature of patients with pulmonary arterial hypertension and the biosynthesis of prostacyclin (PGI2) may be impaired in chronic thromboembolic pulmonary hypertension (CTEPH). Whether it is genetically determined or develops as the disease progresses is unclear. A variable-number tandem repeat (VNTR) polymorphism has been detected in the 5'-upstream promoter region of the PGIS gene. It has been demonstrated that the alleles vary in size from three to seven repeats of nine base pairs, and transcriptional activity increased with the number of repeats. The purpose of the present study was to elucidate the association between the VNTR polymorphisms of the PGIS gene and CTEPH in Japanese subjects.. Ninety patients with CTEPH and 144 control subjects were investigated for the presence of VNTR polymorphisms. Sixty-two blood samples were obtained from CTEPH patients and the plasma concentrations of prostacyclin and thromboxane A2 metabolites were measured.. VNTR polymorphisms in the prostacyclin synthase gene were grouped into L alleles (five, six and seven repeats) and S alleles (three and four repeats). The overall distribution of the alleles and genotypes were not significantly different between CTEPH patients and the control subjects. The patients with the LL genotype had higher plasma concentrations of 6-keto-prostaglandin F1alpha than patients with the LS and SS genotypes.. Our results suggested that the specific VNTR polymorphism in the 5'-upstream promoter region of the PGIS gene regulated prostacyclin production, but did not seem to be associated with the development of CTEPH in this patient population.

Topics: Chronic Disease; Cytochrome P-450 Enzyme System; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Intramolecular Oxidoreductases; Male; Middle Aged; Minisatellite Repeats; Polymorphism, Genetic; Promoter Regions, Genetic; Pulmonary Embolism; Thromboxane A2

To study the significance of thrombosis after experimental pulmonary thromboembolism (PTE).. Acute PTE models of rabbits were established with injection of autologous blood clots (0.04 g/kg) stabilized in a temperature-controlled (70 degrees C) of distilled water for 10 minutes through the femoral vein, then the regulation of thrombosis was explored at dissection and upon microscopic examination after PTE. Moreover, the coagulability of blood and the plasma level of thromboxane A2(TXA2) and endothelin (ET) were examined.. Thrombotic propensity was found at 1 h, and fresh thrombosis started to form at 24 h following clots infusion. Emboli were completely or partly dissolved at 5 d and organized at 10 and 14 d after clots infused. Prothrombin time was significantly lower [(7.15 +/- 0.06)s], and fibrinogen was higher [(5.86 +/- 1.50) g/L] at 24 h post-clots, compared with pre-clots [(7.34 +/- 0.19)s, (3.37 +/- 1.02) g/L] (P < 0.05). Venous plasma level of TXA2 began to increase at 5 min [(2.5 +/- 0.7) micrograms/L] and continued to rise to its maximum at 15 min [(2.5 +/- 0.6) micrograms/L], then declined at 60 min after clots infusion. The level of ET in both arterial and venous blood increased at 5 d post-clots [(0.84 +/- 0.15) micrograms/L and (0.23 +/- 0.05) micrograms/L] separately, while most of emboli resolved.. There is thrombus formation after autologous-blood-clots-induced PTE. Furthermore, thrombus formation, fibrinolysis and organization may always interact on each other consistently, and control the pathogenesis of PTE. Abnormalities of ET metabolism occur after PTE and the major mediator of TXA2 plays an important role in the early phase of PTE.

Topics: Animals; Disease Models, Animal; Endothelins; Female; Fibrinogen; Lung; Male; Prothrombin Time; Pulmonary Embolism; Rabbits; Thrombosis; Thromboxane A2

Topics: Animals; Aspirin; Cause of Death; Cyclooxygenase Inhibitors; Disease Models, Animal; Humans; Platelet Aggregation Inhibitors; Pulmonary Embolism; Risk Factors; Thromboembolism; Thromboxane A2; Vasoconstrictor Agents

Topics: Aspirin; Cause of Death; Humans; Platelet Aggregation Inhibitors; Pulmonary Embolism; Survival Rate; Thromboxane A2; Vasoconstriction

It is well known that lung embolism is associated with an increase in pulmonary vascular resistance. Since the mechanisms of pulmonary vascular reactions during embolism are still unclear, the aim of this study was to investigate the potential involvement of endothelin-1 (ET-1) and thromboxane A2 (TXA2) as mediators of the pulmonary artery pressure (PAP) increase after embolism using the selective ETA receptor antagonist LU135252 [1], the ETB receptor antagonist BQ788 [2], and the cyclooxygenase inhibitor diclofenac.. Prospective experimental study in rabbits.. Experimental laboratory in a university teaching hospital.. 36 adult rabbits of either sex.. The experiments were performed in 36 isolated and ventilated rabbit lungs which were perfused with a buffer solution containing 10% of autologous blood. Embolism was induced by the injection of 0.75 ml air into the pulmonary artery.. PAP and lung weight, reflecting edema formation, were continuously recorded. Perfusate samples were drawn intermittently to determine TXA2 and ET-1 concentrations. Air injection resulted in an immediate increase in PAP up to 22.8 +/- 1.4 mm Hg at 2.5 min (control, n = 6), which was parallelled by an enhanced generation of TXA2. No relevant edema formation occurred during the observation period. Pretreatment with the ETA receptor antagonist LU135252 significantly reduced the pressure reaction after air embolism (p < 0.001) whereas the ETB receptor antagonist BQ788 (n = 6) was without marked effects. The administration of diclofenac (n = 6) did not alter the PAP increase 2.5 min after embolism, but significantly reduced the pressure reaction during the further observation period (p < 0.001). The application of LU135252 and diclofenac together (n = 6) also significantly reduced the PAP increase from 2.5 min during the total observation period (p < 0.001).. The acute pressure reaction after air embolism is mainly mediated via ET-1 by an ETA receptor related mechanism. TXA2 seems to maintain this reaction for a longer time.

Topics: Analysis of Variance; Animals; Cyclooxygenase Inhibitors; Diclofenac; Disease Models, Animal; Embolism, Air; Endothelin Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Hypertension, Pulmonary; In Vitro Techniques; Oligopeptides; Perfusion; Phenylpropionates; Piperidines; Pulmonary Artery; Pulmonary Embolism; Pyrimidines; Rabbits; Radioimmunoassay; Thromboxane A2; Time Factors; Vascular Resistance

The inhibitory effects of vapiprost hydrochloride (vapiprost), a novel thromboxane A2 receptor antagonist, on platelet aggregation and ATP release were studied using platelet rich plasma (PRP) of humans, guinea pigs, rabbits and rats. In in vitro experiments with human platelet, vapiprost inhibited the aggregation and ATP release stimulated with U-46619, collagen or arachidonic acid (AA) at an IC50 of less than 2.1 x 10(-8) M. Vapiprost did not inhibit the primary aggregation or ATP release of human platelets stimulated with adenosine 5'-diphosphate (ADP), epinephrine (Epi) or platelet activating factor (PAF), but inhibited the secondary aggregation stimulated with those agonists at an IC50 of less than 1.3 x 10(-7) M. The sensitivity of platelets in various species of animals to vapiprost was in the following order: human > or = guinea pigs > rats > rabbits. In ex vivo experiments with guinea pigs which received a single oral dose of vapiprost, the agent demonstrated strong inhibition of ATP release from platelets stimulated with U-46619, collagen or AA at an ID50 of less than 25.8 micrograms/kg. These inhibitory effects were observed within 30 min and sustained for 24 h at a single dosage of 5 mg/kg of vapiprost. In AA-induced pulmonary infarction models of mice, the sudden death rates decreased significantly with the oral administration of 10 mg/kg or more of vapiprost. These results indicate that vapiprost effectively inhibits the secondary aggregation and ATP release of human platelets stimulated with various agonists, and that guinea pig and human platelets are similar in response to vapiprost. Furthermore, it was demonstrated in ex vivo experiments with guinea pigs that the inhibitory action of vapiprost appears rapidly and lasts for long periods.

Topics: Adenosine Triphosphate; Animals; Arachidonic Acid; Aspirin; Biphenyl Compounds; Blood Platelets; Guinea Pigs; Heptanoic Acids; Humans; Male; Mice; Platelet Aggregation; Platelet Aggregation Inhibitors; Pulmonary Embolism; Rabbits; Rats; Rats, Wistar; Receptors, Thromboxane; Species Specificity; Thromboxane A2

Topics: Animals; Arachidonic Acids; Disease Models, Animal; Dogs; Embolism, Fat; Epoprostenol; Female; Hypoxia; Indomethacin; Lung; Lung Injury; Male; Methacrylates; Microcirculation; Oleic Acid; Oleic Acids; Pulmonary Circulation; Pulmonary Embolism; Respiratory Distress Syndrome; Thromboxane A2; Vasoconstriction; Vasodilation

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 method of infusion of hardened red blood cells described by Clement et al. (1983) to induce pulmonary hypertension in the minipig has been modified to obtain a model of pulmonary microembolism in the mouse. In this model, the infusion of hardened red blood cells causes the death of about 90% of control animals in 2-5 min, and the efficacy of a given pharmacological treatment can be assessed in terms of the percentage of animals protected from death 15 min after the infusion. Platelets are not apparently involved, since the number of circulating platelets, plasma levels of TxB2, and PF-4 are not modified, and the mortality in thrombocytopenic animals is not different from controls. Furthermore, aspirin and heparin are totally inactive in this model. Preliminary results with some Ca++ channel blockers (nitrendipine and nicardipine) indicate that these compounds may be active. This experimental model offers an easy and relatively inexpensive test for the characterization of compounds to prevent pulmonary microembolism, acting via a platelet-independent mechanism.

Topics: Animals; Disease Models, Animal; Erythrocytes; Fibrinolytic Agents; Mice; Platelet Count; Platelet Factor 4; Pulmonary Embolism; Thrombocytopenia; Thromboxane A2

We compared the effects of inhibition of thromboxane synthetase with antagonism of thromboxane A2 (TxA2)/prostaglandin H2 receptors on the changes in pulmonary hemodynamics and pulmonary transvascular fluid and protein exchange following thrombin-induced pulmonary microembolism. Studies were made in chronically instrumented unanesthetized sheep prepared with lung lymph fistulas. Control thrombin challenged sheep (n = 5) were compared to animals pretreated with Dazoxiben (the Dazoxiben-thrombin group, n = 8) or animals pretreated with L-640,035 (the L-640,035-thrombin group, n = 5). In the control-thrombin sheep, plasma TxA2 concentration rose after thrombin and the response was inhibited in the Dazoxiben-thrombin group. The rise in the plasma TxA2 concentration was greater in the L-640,035-thrombin group than in the control-thrombin group. In the control-thrombin group, thrombin produced a sustained increase in the pulmonary transvascular protein clearance (pulmonary lymph flow x lymph/plasma protein concentration ratio) and pulmonary vascular resistance (PVR). In the Dazoxiben-thrombin group, increases in both pulmonary transvascular protein clearance and PVR after thrombin were less than in the control-thrombin group. In the L-640,035-thrombin group, thrombin initially increased pulmonary transvascular protein clearance and PVR to the same levels as the control group; however, both protein clearance and PVR declined with time, in contrast to the sustained responses in the control-thrombin group. These differences may be related to the initially greater increase in plasma TxA2 concentrations after thrombin in the L-640,035-treated animals. The results indicate that TxA2 plays a role in mediating the increases in PVR and contributes to increases in pulmonary transvascular fluid and protein exchange after thrombin-induced pulmonary microembolism.

Topics: Animals; Body Water; Hemodynamics; Imidazoles; Male; Proteins; Pulmonary Circulation; Pulmonary Embolism; Sheep; Thrombin; Thromboxane A2; Vascular Resistance

Drugs with pharmacological activity limited to the pulmonary circulation are not at present available. Serotonin antagonists, specific thromboxane A2 inhibitors and prostacyclin may offer new possibilities for the treatment of certain forms of pulmonary arterial hypertension (PAH), but their clinical efficacy remains to be evaluated. Vasodilators simultaneously influence the pulmonary and systemic vascular resistances, and their overall hemodynamic effects in patients with PAH are therefore unpredictable. Therapeutic trials with such drugs should be closely monitored to avoid serious adverse reactions. Oral administration of beta-adrenergic agents, such as salbutamol or terbutaline, is preferable to digoxin in the treatment of patients with right ventricular failure due to chronic obstructive bronchitis. Right ventricular failure following massive pulmonary embolism may be aggravated by reduced blood flow through the right coronary artery. Increase of aortic perfusion pressure (e.g. noradrenaline) should be considered as a therapeutic measure in patients with arterial hypotension.

Topics: Adrenergic beta-Agonists; Epoprostenol; Fibrinolytic Agents; Humans; Hypertension, Pulmonary; Phenylephrine; Pulmonary Circulation; Pulmonary Embolism; Serotonin Antagonists; Theophylline; Thromboxane A2; Vascular Resistance; Vasodilator Agents

The effect of PSK (Krestin) on the metabolism of prostaglandins was investigated. The effect of PSK on the thromboxane A2 (TXA2) level, which stimulates tumor proliferation and platelet aggregation, was examined using platelets. PSK suppressed platelet aggregation and the production of malondialdehyde (MDA) and TXB2 which is a stable metabolite of TXA2. The effect of PSK on the production of prostacyclin (PGI2), which is an anti-tumor PG, was then examined using rat arterial rings. It was found that PGI2 production was stimulated by PSK. The in vivo inhibition of platelet activation by PSK was then examined using two thrombosis models in which platelet aggregation was mainly involved. PSK exerted its anti-platelet effect by regulation of PG production. It was concluded that not only an immune regulating effect but also PG regulation are involved in the pharmacological action of PSK.

Topics: Animals; Epoprostenol; Humans; In Vitro Techniques; Male; Malondialdehyde; Mice; Platelet Aggregation; Prostaglandins; Proteoglycans; Pulmonary Embolism; Rabbits; Rats; Rats, Inbred Strains; Shock, Septic; Thromboxane A2; Thromboxane B2

Topics: Animals; Embolism, Air; Hemodynamics; Lymph; Methacrylates; Pulmonary Embolism; Sheep; Thromboxane A2; Thromboxane B2; Thromboxanes

The contributions of thromboxane A2 (TXA2) and prostacyclin (PGI2) to the effects of acute pulmonary embolism were evaluated in 18 open-chest rabbits. All rabbits received autologous whole-blood-clot embolus (.4 cc) by way of a catheter in the right ventricle. Pulmonary artery (PA) and left atrial (LA) pressures, and aortic flow (AOQ) were recorded. The stable metabolites of TXA2 (TXB2) and PGI2 (6-Keto PGF1) were assayed by radioimmunoassay at pre- and post-embolization periods (+5, +10, +20, +30, and +40 minutes). Significant elevations of pulmonary vascular resistance (PVR) (normalized), PA pressure, and reduction of AOQ were noted comparing pre-embolus to +5 minute time intervals. A negative correlation was reached between PGI2 and AOQ at +40 minutes (p less than .05). Five of the 13 rabbits died prematurely. At +5 minutes these 5 rabbits had higher PVR (p less than .001) and lower AOQ (p less than .01) than their living counterparts. At +10 minutes AOQ was still significantly lower (p less than .005) and TXB2 was higher (p less than .05) in the premature death group. We conclude that TXB2 is significantly but transiently elevated early following acute pulmonary embolism and may contribute to mortality. In contrast PGI2 does not appear to play an immediate role in the hemodynamic events following embolization but does rise to significant levels later in the course possibly in an attempt to compensate for reduced flow.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Blood Pressure; Epoprostenol; Kinetics; Male; Models, Biological; Prostaglandins; Pulmonary Artery; Pulmonary Embolism; Rabbits; Regional Blood Flow; Thromboxane A2; Thromboxane B2; Thromboxanes; Vascular Resistance

Arachidonic acid (1 mg/kg) or 9,11-azo PGH2 (35 micrograms/kg) injected intravenously into anesthetized rabbits results in sudden death characterized by a marked loss of circulating platelets, a dramatic rise in circulating thromboxane B2 concentrations and a precipitous drop in blood pressure. Death ensues in 3 to 5 minutes from pulmonary thrombosis and pulmonary artery constriction. Administration of dazoxiben (2 mg/kg) prior to arachidonic acid, prevents all of these changes. However, dazoxiben failed to prevent any of these effects after injection of azo-PGH2, a synthetic agonist of the endoperoxide and thromboxane receptor. These results demonstrate the importance of endoperoxide-thromboxane accumulation in eicosanoid induced sudden death and suggests that there is no significant functional difference between the actions of these agents in the rabbit.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Death, Sudden; Imidazoles; Male; Platelet Aggregation; Prostaglandin Endoperoxides; Prostaglandins H; Pulmonary Embolism; Rabbits; Thromboxane A2; Thromboxanes; Vasoconstriction

Topics: Animals; Cell Adhesion; Imidazoles; Leukocyte Count; Leukocytes; Pulmonary Artery; Pulmonary Embolism; Sheep; Thromboxane A2; Thromboxane-A Synthase; Thromboxanes; Vascular Resistance

Humoral factors released from platelets during pulmonary embolism may be the cause of several attendant cardiopulmonary abnormalities. This study examines the role of thromboxanes (Tx) after experimental embolism induced with 0.5 g/kg autologous clot in four groups of five dogs: (a) untreated embolized controls; (b) pretreatment with the Tx synthetase inhibitor, imidazole 25 mg/kg . h i.v., starting 30 min before embolization; (c) pretreatment with the cyclooxygenase inhibitor indomethacin, 5 mg/kg, 12 h per os and 1 mg/kg, 1 h i.v. before the experiment; (d) treatment with prostacyclin (PGI(2)) 100 etag/kg . min i.v. for 1 h, 1 h after embolization. Within 30 min, embolization led to increases of 6-keto-PGF(1alpha), the stable hydrolysis product of PGI(2), from 0.11+/-0.08 etag/ml (mean+/-SD) to 0.33+/-0.10 etag/ml (P < 0.005) and TxB(2), the stable product of TxA(2), from 0.10+/-0.04 etag/ml to 0.38+/-0.06 etag/ml (P < 0.001). Increases were observed in total dead space (V(D)/V(T)) from 0.46+/-0.03 to 0.61+/-0.08 (P < 0.025, physiologic shunting (Q(S)/Q(T)) from 16+/-4% to 38+/-9% (P < 0.01), pulmonary vascular resistance (PVR) from 2.27+/-0.59 mm Hg.min/liter to 9.21+/-1.90 mm Hg.min/liter (P < 0.005) and mean pulmonary arterial pressure from 14+/-6 mm Hg to 34+/-1 mm Hg (P < 0.001). Cardiac index (CI) fell from 139+/-11 ml/kg.min to 95+/-17 ml/kg.min in 4 h (P < 0.025). Imidazole pretreatment prevented a rise of TxB(2), but not 6-keto-PGF(1alpha); indomethacin blocked both. Both agents maintained V(D)/V(T) at base line and limited increases in Q(S)/Q(T) and PVR. CI was higher after imidazole pretreatment compared with controls (P < 0.025). Indomethacin led to intermediate levels of CI. PGI(2) lowered TxB(2) (P < 0.025), V(D)/V(T) (P < 0.025), Q(S)/Q(T) (P < 0.025) and PVR (P < 0.05) within 30 min. During PGI(2) infusion, CI was higher than controls. Concentrations of TxB(2) correlated with V(D)/V(T), r = 0.79 and Q(S)/Q(T), r = 0.69 (P < 0.001). Treatment of three dogs with the imidazole derivative ketoconazole, 10 mg/kg IV, 30 min after 0.75 g/kg autologous clot resulted in a lowering of physiologic dead space, but no other improvement of cardiopulmonary function. These results show that a number of cardiopulmonary abnormalities induced by pulmonary embolism are related directly or indirectly to platelet secretions and that V(D)/V(T) is closely allied to TxA(2) levels.

Topics: Animals; Dogs; Epoprostenol; Female; Heart; Imidazoles; Indomethacin; Ketoconazole; Male; Piperazines; Platelet Count; Pulmonary Embolism; Thromboxane A2; Thromboxanes; Time Factors; Vascular Resistance

Topics: Animals; Burns; Capillary Permeability; Dogs; Epoprostenol; Hypertension, Pulmonary; Infections; Microcirculation; Prostaglandin Antagonists; Prostaglandins; Pulmonary Circulation; Pulmonary Embolism; Pulmonary Valve Insufficiency; Sheep; Shock, Hemorrhagic; Thromboxane A2

Topics: Acute Disease; Animals; Blood Pressure; Cardiac Output; Dogs; Femoral Artery; Heart; Lung; Prostaglandins F; Pulmonary Artery; Pulmonary Embolism; Thromboxane A2; Thromboxanes