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)

We designed the present study to clarify whether the intracellular pH change by ammonium chloride influences endothelium-dependent relaxation in thoracic aorta of 9-week-old Sprague-Dawley rats. Intracellular alkalinization with 3 mmol/L ammonium chloride, which did not affect resting vascular tone, attenuated acetylcholine-induced relaxation but not nitroglycerin vasodilation. Acetylcholine relaxation was more inhibited by a shorter duration of treatment. Thus, change in intracellular pH may be important in the effect because the alkalinizing effect of ammonium chloride disappears gradually. In support of this, the proton ionophore nigericin abolished the effect. Also, amiloride shortened the effect of ammonium chloride, suggesting that intracellular pH plays a role: sodium-proton antiport antagonizes the disappearance of ammonium chloride-induced intracellular alkalinization. The synthesis of vasoconstrictor prostaglandins, such as thromboxane A2, may be stimulated during acetylcholine treatment, resulting in the attenuation of acetylcholine relaxation, because the relaxation was abolished by treatment with the phospholipase A2 inhibitor quinacrine, cyclooxygenase inhibitor indomethacin, prostaglandin H2/thromboxane A2 receptor antagonist S1452, and thromboxane A2 synthase inhibitor dazmegrel. Phospholipase A2 may contribute to the effect of intracellular alkalinization, which is compatible with the fact that the optimal pH of phospholipase A2 is neutral to alkaline. In addition, superoxide dismutase attenuated the effect of ammonium chloride. In conclusion, intracellular alkalinization by ammonium chloride attenuated acetylcholine-induced relaxation, possibly through the interrelated production of both thromboxane A2 and superoxide radicals.
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PMID:Inhibitory effect of ammonium chloride on acetylcholine-induced relaxation. 803 43

Using 50 mongrel dogs with alveolar flooding produced by oleic acid administration, the possible roles of vasoactive cyclooxygenase products on intrapulmonary shunt flow (QS/QT) and extravascular lung water (ETVI) in acutely injured lungs were assessed. Suppressing cyclooxygenase activity with indomethacin administration diminished the concentrations of thromboxane (TX) B2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) in arterial blood, resulting in a significant reduction in QS/QT. Furthermore, indomethacin completely suppressed the increase in ETVI. Inhibition of TXA2 generation by OKY-046 (thromboxane A2 synthase blocker) diminished the concentration of TXB2 while increasing that of 6-keto-PGF1 alpha in blood. Administration of either OKY-046 or synthetic prostacyclin (PGI2) markedly enhanced QS/QT, in association with an increase in ETVI. In conclusion, the potent vasodilator prostacyclin was considered to enhance shunt flow, leading to the augmentation of edema formation.
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PMID:[Effects of vasoactive cyclooxygenase products on shunt flow and extravascular lung water in acute lung injuries]. 804 Oct 36

The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo[b]thiophene-6-carboxylate) , a thromboxane A2 synthase inhibitor, on eosinophil accumulation and activation were investigated in an experimental asthmatic guinea pig model and several cellular models. In the in vivo studies, CS-518 inhibited the biphasic eosinophil accumulation in the bronchoalveolar lavage fluid, potently in the early phase, but less potently in the delayed phase. On the other hand, even at the lower dose, CS-518 completely inhibited the hypodensity of eosinophils in the delayed phase. In the in vitro studies, CS-518 suppressed thromboxane A2 production and potentiated prostaglandin I2 production from guinea pig eosinophils. Moreover, CS-518 and prostaglandin I2 suppressed chemotaxis, peroxidase release and superoxide generation in guinea pig eosinophils. In addition, the present studies provide further support for the possibility that thromboxane A2 and prostaglandin I2, which are produced in bronchoalveolar tissue and within eosinophils, are involved in modulation of eosinophil function and suggest that CS-518 is a potent inhibitor of eosinophil activation.
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PMID:Effects of CS-518, a thromboxane synthase inhibitor, on eosinophil function. 822 90

Human umbilical cord contains two arteries and a vein surrounded by Wharton's jelly with amnion covering the exterior surface. The cord blood and amniotic fluid contain human CG (hCG). Whether hCG can directly regulate cord functions is unknown. We now report that human umbilical cords contain a major 4.4-kilobase and minor 2.6- and 1.8-kilobase hCG/LH receptor messenger RNA transcripts. The cords also contain a 50-kilodalton immunoreactive receptor protein which can bind hCG and LH, but not hFSH or hTSH. Rat testis used as a positive tissue control contained the same major and minor receptor transcripts and an 80-kilodalton receptor protein which can bind [125I]hCG. Rat liver used as a negative control contained neither receptor transcripts nor receptor protein. The smooth muscle and endothelial cells of umbilical arteries and vein, umbilical amnion, and cells in Wharton's jelly contain the receptor transcripts and receptor protein which can bind [125I]hCG. The receptor expression was higher in umbilical vessels closer to the baby and decreased toward placenta, becoming barely detectable once the vessels were inside the placental tissue. In vitro treatment of umbilical cords with highly purified hCG resulted in an increase of immunoreactive cyclooxygenase-1, cyclooxygenase-2, prostacyclin synthase, and 6-keto-prostaglandin F1 alpha, little change in thromboxane A2 synthase and a decrease of prostaglandin E2 and thromboxane B2 as compared to the controls, indicating that the cord receptors are functional. In summary, these novel findings suggest that hCG present in cord blood and amniotic fluid may directly regulate the vascular tone and quite possibly other functions of human umbilical cord.
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PMID:Novel expression of functional human chorionic gonadotropin/luteinizing hormone receptor gene in human umbilical cords. 826 61

The goal of the present study was to characterize the role of the endothelium in the 5-hydroxytryptamine (5-HT)-induced contraction of the rat basilar artery. Rat basilar artery segments were mounted in myographs to study their isometric tension development. 5-HT caused dose-dependent contractions that were minimally affected by endothelium removal. The dose-response curve obtained with the 5-HT1 receptor agonist, 5-carboxamidotryptamine (5-CT), was biphasic in arteries with endothelium; removal of the endothelium eliminated the first phase of the contraction. The 5-HT2 receptor antagonist, ketanserin (30 nM), shifted the dose-response curve to 5-HT to the right; in arteries with endothelium, the curve became biphasic. Ketanserin inhibited the second phase of the dose-response curve to 5-CT. The mixed 5-HT1/5-HT2 receptor antagonist, metergoline (30 nM), shifted the dose-response curve to 5-HT non-competitively to the right and depressed both phases of the dose-response curve to 5-CT. In basilar arteries with endothelium and treated with ketanserin, the thromboxane A2 receptor antagonist, ICI 192605 (1 microM), significantly decreased the responsiveness to 5-HT and the dose-response curve for 5-HT became monophasic. ICI 192605 and the thromboxane A2 synthase inhibitor, ridogrel (10 microM), both suppressed the first phase of the dose-response curve to 5-CT. These data indicate that both endothelial 5-HT1 and smooth muscle 5-HT2 receptors participate in the contractions caused by 5-HT in the rat basilar artery.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelial thromboxane production plays a role in the contraction caused by 5-hydroxytryptamine in rat basilar arteries. 827 69

1. The thromboxane A2 synthase (TXS) inhibitory activity and the thromboxane A2 (TP)-receptor blocking action of ZD1542 (4(Z)-6-[2S,4S,5R)-2-[1-methyl-1-(2-nitro-4-tolyloxy)ethyl]-4-(3- pyridyl)-1,3-dioxan-5-yl]hex-4-enoic acid) has been evaluated in vitro on platelets and whole blood from a range of species including man. Antagonist activity has also been investigated in vascular and pulmonary smooth muscle preparations in vitro. 2. ZD1542 caused concentration-dependent inhibition of human platelet microsomal thromboxane B2 (TXB2) production in vitro (IC50 = 0.016 microM); this inhibition was associated with an increase in prostaglandin E2 (PGE2) and PGF2 alpha formation. 3. ZD1542 also inhibited collagen-stimulated TXS in human, rat and dog whole blood giving IC50 values of 0.018, 0.009 and 0.049 microM respectively. The drug did not modify platelet cyclo-oxygenase activity as inhibition of TXB2 formation was associated with a concomitant increase in the levels of PGD2, PGE2 and PGF2 alpha. ZD1542 had little if any effect against cultured human umbilical vein endothelial cell (HUVEC) cyclo-oxygenase (IC50 > 100 microM) and prostacyclin (PGI2) synthase (IC50 = 18.0 +/- 8.6 microM). 4. ZD1542 caused concentration-dependent inhibition of U46619-induced aggregation responses of human, rat and dog platelets yielding apparent pA2 values of 8.3, 8.5 and 9.1 respectively. The drug was selective as, at concentrations up to 100 microM, it did not modify 5-hydroxytryptamine (5-HT) or the primary phases of adenosine diphosphate (ADP) and adrenaline-induced aggregation. Furthermore, ZD1542 (100 microM) modified only weakly the platelet effects of PGD2, PGE1 and PGI2. 5. ZD1542 also caused concentration-dependent inhibition of U46619-mediated contractions of rat thoracic aorta, guinea-pig trachea and lung parenchyma preparations giving apparent pA2 values of 8.6,8.3 and 8.5 respectively. At concentrations approaching three orders of magnitude greater than those required to block U46619-mediated contractions, the drug did not affect the actions of non-prostanoid agonists or exhibit agonist activity in any of the smooth muscle preparations employed; neither did it interact at EP- or FP-receptors.6. In conclusion, the present study demonstrates that ZD1542 is a drug that exhibits both potent,selective TXS inhibition and TXA2 receptor antagonism.
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PMID:ZD1542, a potent thromboxane A2 synthase inhibitor and receptor antagonist in vitro. 830 7

Capsular type-specific polysaccharide is thought to be an important pathogenetic factor in Group B streptococcus (GBS) sepsis. To determine the effects of capsular type-specific polysaccharide on GBS-induced hemodynamic responses, anesthetized infant piglets were infused for 3 h with three related GBS Type lb strains that express different amounts of capsular type-specific polysaccharide. A larger capsule strain and a smaller capsule strain were isolated from an infected infant and its mother, respectively. A capsule-deficient mutant was then made from the larger capsule strain by transposon insertion mutagenesis. The smaller capsule strain and capsule-deficient mutant caused similar elevations in mean pulmonary artery pressure and pulmonary vascular resistance index and reductions in cardiac index. The larger capsule strain caused moderate pulmonary hypertension, but this response was smaller than for the other two GBS strains. Further comparisons in responses between the large capsule strain and its capsule-deficient mutant were then performed using unanesthetized piglets. The mutant caused significantly greater pulmonary hypertension and arterial plasma thromboxane B2 levels than the large capsule strain. The pulmonary hypertension induced by both strains was reversed by dazmegrel, a thromboxane A2 synthase inhibitor. These results suggest that (1) capsular type-specific polysaccharide is not an essential component in the generation of acute hemodynamic responses; (2) expression of large amounts of capsular type-specific polysaccharide on the organism surface partially inhibits GBS-induced pulmonary hypertension; and (3) the inhibition of the pulmonary responses is due to reduced thromboxane A2 release.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Capsular type-specific polysaccharide partially inhibits group B Streptococcus-induced pulmonary hypertension. 831 91

The effects of CS-518 (sodium 2-(1-imidazolylmethyl)-4,5-dihydrobenzo [b]thiophene-6-carboxylate), a thromboxane A2 synthase inhibitor, on changes in arachidonic acid metabolism were investigated in the lung of actively sensitized guinea pigs. Antigen challenge enhanced the production of thromboxane A2 as well as histamine and peptide leukotrienes in lung fragments. Exogenous leukotriene D4 also stimulated significant thromboxane A2 production in the non-sensitized lung in vitro. CS-518 was effective in preventing the thromboxane A2 production induced by either antigen or leukotriene D4, and the IC50 values were 90 and 7.5 ng/ml (320 and 27 nM), respectively. CS-518 markedly potentiated the production of prostaglandin E2 and I2 with slight inhibition of leukotriene formation, but indomethacin significantly stimulated leukotriene production. When CS-518 was administered orally, it induced long-lasting inhibition of thromboxane A2 production and potentiation of prostaglandin I2 production in guinea pig lung. Thus, CS-518 not only inhibited thromboxane production but also improved the change in arachidonic acid metabolism in the guinea pig bronchoalveolar tissue during allergic reaction in vivo as well as in vitro, which suggests amelioration of the asthmatic condition.
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PMID:Alteration of eicosanoid production in the sensitized guinea pig lung by CS-518. 836 52

The effects of CS-518, a thromboxane A2 synthase inhibitor, on antigen-induced dual bronchial responses, airway hyperresponsiveness (AHR) and airway eosinophilia were investigated in an experimental guinea pig model of the late asthmatic response. Oral CS-518 (1 and 10 mg/kg) inhibited immediate and late asthmatic responses dose-dependently. It also inhibited AHR and eosinophil accumulation after antigen challenge. Therefore, thromboxane A2 is possibly involved in development of the late asthmatic response and AHR, and CS-518 was inferred to inhibit these via inhibition of eosinophil accumulation and thromboxane production.
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PMID:Effects of a thromboxane synthase inhibitor (CS-518) on the eosinophil-dependent late asthmatic response and airway hyperresponsiveness in guinea pigs. 852 55

In the present study we tested the effects of different antithrombotic interventions on platelet deposition in experimentally-stenotic rabbit carotid arteries with endothelial injury. Platelet deposition, quantitated by labeling autologous platelets with 111In-oxine, was significantly reduced compared to control animals by all interventions tested, i.e., R 68070, a drug with thromboxane A2 synthase and receptor blocking properties, BN 52021, a PAF receptor antagonist, aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (Gp) Ib/von Willebrand factor (vWf) interaction, AZ-1, a monoclonal antibody against rabbit GP IIb/IIIa, the platelet receptor for fibrinogen, and AP-1, a monoclonal antibody against rabbit tissue factor. ATA was significantly more effective than all the other interventions in reducing platelet deposition in the stenotic vessels. We conclude that inhibition of Gp Ib/vWf interaction may be a more suitable target for antithrombotic therapy under conditions of high shear stress, like those produced in this model.
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PMID:Aurintricarboxylic acid reduces platelet deposition in stenosed and endothelially injured rabbit carotid arteries more effectively than other antiplatelet interventions. 857 32


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