Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P24557 (thromboxane A2 synthase)
 124 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The discovery of thromboxanes and prostacycline has opened up a new therapeutic approach to vascular and thrombotic diseases. Aspirin is no longer considered to be an antiaggregant drug, but an inhibitor of cyclooxygenase which, depending on the dose, may have an effect on platelets and the vessel. Thromboxane synthetase inhibitors and thromboxane receptor blockers represent a new mode of inhibition of platelet activation. Therapeutic trials of the vasodilator and antiaggregant prostacycline have been carried out in obliterative arterial disease and Raynaud' syndrome with a certain degree of success. The production of a stable analogue of prostacycline and the manipulation of the leukotrienes are the therapeutic hopes for the future.
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PMID:[Therapeutic prospects and prostaglandins in vascular pathology]. 393 43

We examined the pulmonary vascular response to an intravenous leukotriene D4 (LTD4) injection of (1 microgram X kg-1 X min-1 for 2 min) immediately followed by infusion of 0.133 microgram X kg-1 X min-1 for 15 min in awake sheep prepared with lung lymph fistulas. LTD4 resulted in rapid generation of thromboxane A2 as measured by an increase in plasma thromboxane B2 concentration. The thromboxane B2 generation was associated with increases in pulmonary arterial and pulmonary arterial wedge pressures while left atrial pressure did not change significantly. Pulmonary lymph flow (Qlym) increased (P less than 0.05) transiently from base line 6.87 +/- 1.88 (SE) ml/h to maximum value of 9.77 +/- 1.27 at 15 min following the LTD4 infusion. The maximum increase in Qlym was associated with an increase in the estimated pulmonary capillary pressure. The increase in Qlym was not associated with a change in the lymph-to-plasma protein concentration (L/P) ratio. Thromboxane synthetase inhibition with dazoxiben (an imidazole derivative) prevented thromboxane B2 generation after LTD4 and also prevented the increases in pulmonary vascular pressures and Qlym. We conclude that LTD4 in awake sheep increases resistance of large pulmonary veins. The small transient increase in Qlym can be explained by the increase in pulmonary capillary pressure. Thromboxane appears to mediate both the pulmonary hemodynamic and lymph responses to LTD4 in sheep.
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PMID:Pulmonary vascular response to leukotriene D4 in unanesthetized sheep: role of thromboxane. 395 28

Selective modulation of cellular arachidonic acid metabolism with thromboxane synthetase inhibitors temporarily reduced the yield of viruses hosted by human lung fibroblasts in vitro. The results were similar for several viruses including type I herpes simplex virus, vaccinia, vesicular stomatitis virus, chikungunya virus, and Newcastle disease virus. Thromboxane synthetase inhibitors of different structural classes were effective and their effects were confined to cells that contain the thromboxane synthetase. Virus yields were unaltered by total inhibition of arachidonic acid oxidative metabolism or exogenous addition of prostaglandins. In contrast to most cytopathic agents, viruses destroyed host cells without stimulating prostaglandin synthesis unless interferon induction accompanied the infection in vitro. The results suggest that cellular arachidonic acid metabolism may contribute to the host defense response during virus infections.
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PMID:Influence of thromboxane synthetase inhibitors on virus replication in human lung fibroblasts in vitro. 631 4

Electrical stimulation in the presence of ADP of arterioles of the hamster cheek pouch caused endothelial damage and white thrombus formation. The thrombus formation was inhibited by cyclo-oxygenase inhibitors aspirin and sulphinpyrazone and its thioether derivative G 25671. Thromboxane synthetase inhibitors N-(7-carboxyheptyl) imidazole and butylimidazole failed to inhibit thrombus formation, although in the same doses both compounds inhibited serum levels of thromboxane. These results indicate that thromboxane is not important in thrombus formation in the hamster, but that prostaglandin endoperoxides are more significant. However, it is possible that the inhibition of white thrombus formation by aspirin, sulphinpyrazone and G 25671 may be mediated by a different mechanism altogether.
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PMID:Prostaglandin endoperoxides and thromboxane A2 in thrombus formation in the hamster cheek pouch in vivo. 643 86

The quantitative study of the processes that accompany nonenzymatic degradation of prostaglandin H2 has been carried out. The thiobarbituric acid test which shows the content of malonic dialdehyde in the reaction mixture has been used to study kinetics of the degradation. The apparent rate constants of this process have been pH-independent over the pH-range 5,5-9,5, and the calculated conversion halftime changes from 5,8 to 3,6 min at these pH values. Thromboxane synthetase from human platelets has been chosen to demonstrate the possibility of application of thiobarbituric acid test for determination of the activity of prostaglandin endoperoxide convertase. It has been shown that the apparent rate constant of the reaction in the presence of the enzyme is the linear function of its concentration.
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PMID:[Kinetics of prostaglandin H2 degradation. A method of determining prostaglandin H-convertase activity]. 643 39

1 Insertion of a cotton thread into an arteriovenous shunt of an anaesthetized rat causes an increase in the weight of the thread due to deposition of thrombus. 2 The thrombus formed was of the venous (red) type, being sensitive to heparin, yet possessed important characteristics of an arterial thrombus, in that it was dependent on platelets and on rate of blood flow. 3 Thromboxane synthetase inhibitors had no effect on thrombus deposition. 4 Cyclo-oxygenase inhibitors did not significantly depress thrombus formation at doses which inhibited platelet function ex vivo. 5 Compounds which can modify the release or action of adenosine 5' -diphosphate partly inhibited thrombus formation. 6 A depression in clotting factor levels induced by sodium warfarin led to a highly significant reduction in thrombus formation at doses which caused a prolongation of prothrombin clotting time.
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PMID:Fibrin, red cell and platelet interactions in an experimental model of thrombosis. 681 74

We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.
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PMID:Role of thromboxane A2 in bradykinin-induced human isolated small bronchi contraction. 754 24

The present study was undertaken to investigate the factors involved in determining the metastatic potential of cultured cells derived from solid tumors. We first investigated the effects of cell source and culture conditions on lung colony formation by i.v. injected B16a (B16 amelanotic melanoma) cells and inhibition of tumor colony formation by the thromboxane A2 synthase inhibitor, CGS14854. Prolonged culture resulted in a 10-fold decrease in the incidence of B16a lung colonies, whereas passage in vivo for 150 days did not affect lung colony formation by tumor cells isolated from enzymatic dispersates by centrifugal elutriation. Cultured B16a cells maintained at low density (LD) and harvested at low passage (LP) formed significantly more lung colonies than B16a cells harvested at high densities (HD) or high passage (HP). Over-confluent tumor cells produced even lower number of lung colonies. Lung colony formation by elutriated B16a cells (i.e., cells freshly isolated from tumor tissue) was consistently inhibited by CGS14854, whereas inhibition of lung colony formation by cultured B16a cells was dependent upon culture conditions. CGS14854 was ineffective or less effective against HD/HP B16a cells. The differences in lung colony formation between LD, HD and elutriated B16a cells were not due to differential cell-cycle distribution. Mechanistic studies indicated that LD/LP tumor cells induced aggregation of homologous platelets, whereas HD/HP B16a cells failed to induce significant platelet aggregation. Aggregation of homologous platelets correlated positively with lung-colonizing ability. Additionally, LD/LP cells demonstrated higher adhesion to endothelium than HD/HP B16a cells. Finally, LD/LP B16a cells expressed higher levels of alpha IIb beta 3 integrins than HD/HP tumor cells, as determined by flow cytometry and immunofluorescence.
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PMID:Phenotypic properties of cultured tumor cells: integrin alpha IIb beta 3 expression, tumor-cell-induced platelet aggregation, and tumor-cell adhesion to endothelium as important parameters of experimental metastasis. 768 32

A 3-D model of human thromboxane A2 synthase (TXAS) was constructed using a homology modeling approach based on information from the 2.0 A crystal structure of the hemoprotein domains of cytochrome P450BM-3 and P450cam. P450BM-3 is a bacterial fatty acid monooxygenase resembling eukaryotic microsomal cytochrome P450s in primary structure and function. TXAS shares 26.4% residue identity and 48.4% residue similarity with the P450BM-3 hemoprotein domain. The homology score between TXAS and P450BM-3 is much higher than that between TXAS and P450cam. Alignment between TXAS and the P450BM-3 hemoprotein domain or P450cam was determined through sequence searches. The P450BM-3 or P450cam main-chain coordinates were applied to the TXAS main chain in those segments where the two sequences were well aligned. These segments were linked to one another using a fragment search method, and the side chains were added to produce a 3-D model for TXAS. A TXAS substrate, prostaglandin H2 (PGH2) was docked into the TXAS cavity corresponding to the arachidonic acid binding pocket in P450BM-3 or camphor binding site in P450cam. Regions of the heme and putative PGH2 binding cavities in the TXAS model were identified and analyzed. The segments and residues involved in the active-site pocket of the TXAS model provide reasonable candidates for TXAS protein engineering and inhibitor design. Comparison of the TXAS model based on P450BM-3 with another TXAS model based on the P450cam structure indicated that P450BM-3 is a more suitable template for homology modeling of TXAS.
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PMID:Comparison of the construction of a 3-D model for human thromboxane synthase using P450cam and BM-3 as templates: implications for the substrate binding pocket. 770 Aug 66

We have investigated the contractile effect of bradykinin (BK) in guinea pig lung in vitro. BK induces a dose-related contraction of lung parenchymal strips which is increased significantly in the presence of 10(-5) M captopril (an angiotensin converting enzyme inhibitor) or 10(-5) M DL-thiorphan (a neutral endopeptidase inhibitor). The kininase I inhibitor, DL-2-mercaptomethyl-3-guanidino-ethylthiopropionic acid (MGTPA), has no effect on the BK-induced contraction. BK is more potent in contracting parenchymal lung strips than other contractile agents (histamine, carbachol and substance P), however the BK-induced maximal contraction is lower than those obtained with histamine and carbachol. The B1 agonist, des-Arg9-BK, does not contract lung parenchymal strips. The new BK B2 receptor antagonists (Hoe 140, NPC 17731 and NPC 17761), which possess binding affinities in the nanomolar range, inhibit the BK-induced contractile response in a dose-dependent manner. The BK-induced contraction was unaffected by propranolol, atropine, tetrodotoxin, capsaicin pre-treatment, triprolidine, methysergide, Ro 19-3704 and N omega-nitro-L-arginine-methyl-ester (L-NAME), excluding the involvement of nervous pathways, preformed mast cell mediators, platelet-activating factor and nitric oxide. However, indomethacin, a cyclooxygenase inhibitor, AA-861, a 5-lipoxygenase inhibitor, and furegrelate, a thromboxane A2 synthase inhibitor, decreased the contractile response to BK, suggesting that both cyclooxygenase and 5-lipoxygenase products are involved in this contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin-induced contraction of guinea pig lung in vitro. 799 Sep 78


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