Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Thromboxane A2”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1995

Involvement of thromboxane A2-thromboxane A2 receptor system of the hepatic sinusoid in pathogenesis of cold preservation/reperfusion injury in the rat liver graft.

This study was designed to investigate the possible involvement of the thromboxane A2 (TXA2)-TXA2 receptor (TXA2R) system of the hepatic sinusoid in cold preservation/reperfusion injury in liver grafts. Rat livers were preserved in cold University of Wisconsin solution for either 6 or 24 hr. The number of TXA2Rs in sinusoidal endothelial cells isolated from 0-, 6-, and 24-hr preserved liver specimens was 22.50 +/- 1.80 x 10(3)/cell, 12.66 +/- 1.00 x 10(3)/cell, and 4.17 +/- 0.65 x 10(3)/cell, respectively. Kd and Bmax at 0 hr, 6 hr, and 24 hr of preservation were 8.54 +/- 1.26 nM and 37.34 +/- 3.01 fmol/10(6) cells, 7.08 +/- 1.14 nM and 12.66 +/- 1.00 fmol/10(6) cells, and 1.91 +/- 0.10 nM and 3.88 +/- 0.59 fmol/10(6) cells, respectively. The administration of OKY-046 (inhibitor of TXA2 synthesis) to the University of Wisconsin solution suppressed this reduction in TXA2R number. Furthermore, the concentration of TXA2 in hepatic sinusoid was decreased by OKY-046. In a reperfusion experiment, liver tissue preserved for 24 hr exhibited a higher reperfusion pressure, and effluent levels of both aspartate aminotransferase and lactate dehydrogenase were markedly elevated. The addition of OKY-046 to the preservation solution, however, prevented the rise in reperfusion pressure almost completely and the increase in effluent enzyme levels. This study showed that the TXA2Rs in sinusoidal endothelial cells were internalized through binding with TXA2 during cold preservation, causing activation of the TXA2-TXA2R system. This activation apparently induces an increase in reperfusion pressure, possibly due to sinusoidal contraction, resulting in microcirculatory disturbances.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Vasoconstrictor response of arterioles of the hamster cheek pouch to norepinephrine, prostaglandin H2, F2 alpha and carbocyclic thromboxane A2, a possible thromboxane A2 analogue.

Activated platelets produce thromboxane A2, a potent vasoconstrictor, which may play an important role in pathophysiological disturbances of microcirculation. Thromboxane A2 has a very short half life and has neither been isolated nor synthesized. Hence, the recently reported stable analogue, carbocyclic thromboxane A2 (CTA2), may become an interesting tool in pharmacological research. Its vasoconstrictor potency was compared in vivo with norepinephrine, prostaglandin H2 and F2 alpha using the following method: vessels of a hamster cheek pouch preparation were exposed to a superfusion to which the respective compounds were added to give 1 ng/ml to 0.1 mg/ml final concentrations. The decrease of vessel diameters was measured microscopically. Prostaglandin H2 was found to be the most potent vasoconstrictor followed by CTA2 and norepinephrine. Prostaglandin F2 alpha was least effective. The respective maximal vasoconstrictory responses did not differ significantly.

Animals↗
PubMed1998

Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2.

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.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMedDate not supplied

Molecular characterization of a dominantly inherited bleeding disorder with impaired platelet responses to thromboxane A2.

Thromboxane A2 (TXA2) is a major arachidonic acid metabolite of platelets and induces platelet functions by binding to specific receptors on the membrane. We have found patients with hemostatic defects due to impaired platelet responses to TXA2, and molecular characterization of the patients has been carried out. Platelets from these two unrelated patients showed impaired aggregation responses to TXA2 and its analogues despite the normal response to thrombin. Although the patients' platelets exhibited normal binding activities to TXA2 analogues, they showed decreased GTPase activity and second messenger formation when stimulated by STA2, a stable TXA2 agonist. To understand the molecular basis of this abnormality, we determined the cDNA sequence of the TXA2 receptor by reverse transcription-polymerase chain reaction (RT-PCR) from the patient's platelet RNA, and identified a single amino acid substitution (Arg60 for Leu) in the first cytoplasmic loop of the receptor. This mutation was found in both isoforms of the platelet TXA2 receptor which we have recently found: TXR alpha with the same structure as the placental TXA2 receptor and TXR beta with the same structure as the endothelial TXA2 receptor, and was detected exclusively in affected members of two unrelated families with the disorder. The mutant TXR alpha and TXR beta expressed in COS-m6 cells showed decreased agonist-induced phospholipase C activation despite their normal ligand binding affinities. These results suggest that the Arg60 for Leu mutation is responsible for the disorder and imply a critical role for the first cytoplasmic loop in the interaction of the TXA2 receptor with the G protein.

Base Sequence↗
PubMed1983

The effect of long-term colchicine therapy in patients with recurrent polyserositis on the capacity of blood platelets to synthesize thromboxane A2.

Thromboxane B2 (TXB) production during platelet activation was measured in 13 patients with recurrent polyserositis on long-term colchicine therapy and 10 healthy controls. Plasma colchicine concentration in patients ranged between 0.8-7.8 ng/ml (2.0-19.5 X 10(-9) M). Thromboxane production induced during aggregation by arachidonic acid or collagen and serum TXB2 levels (clotted blood, 37 degrees C, 1 h) did not differ among patients and controls. Previous studies reporting platelet function defects including anomalous TXB2 production, were performed in vitro using colchicine concentrations markedly exceeding the therapeutic range.

Adolescent↗
PubMed1992

The expression of thromboxane A2 synthase and thromboxane A2 receptor gene in human uterus.

The expression of thromboxane (TX) A2 synthase and thromboxane A2 receptor gene in human uterus was investigated by immunoblotting, immunocytochemistry, Northern blot, in situ hybridization, and autoradiographic analyses. Human uterus contains a single immunoreactive protein of 55 kDa that corresponds to the molecular size of human TXA2 synthase. Human uterus also contains a single 2.8-kb TXA2 receptor mRNA transcript and a receptor protein that can bind TXA2 antagonist, 125I-PTA-OH. The immunoreactive TXA2 synthase, TXA2 receptor mRNA, and protein are present in endometrial glands, stromal cells, myometrial smooth muscle, and uterine blood vessels. The TXA2 synthase and TXA2 receptors in different uterine cells varied within as well as between various reproductive states. There were differences in the binding site numbers even between elongated and circular myometrial smooth muscle in all reproductive states except postmenopause. In summary, the data presented demonstrate for the first time that different human endometrial and myometrial cells and uterine blood vessels express TXA2 synthase as well as TXA2 receptor gene. The expression, as well as changes during various reproductive states, suggests that TXA2 could be an autocrine/paracrine regulator of human myometrial contractions, endometrial secretory functions, and intrauterine blood flow and could play a role in the initiation and/or progression of labor in women.

Autoradiography↗
PubMed1987

Overview of physiological and pathophysiological effects of thromboxane A2.

Thromboxane (Tx) A2 is a biologically potent and chemically unstable metabolite of prostaglandin endoperoxides. Recent developments in measurement techniques and the availability of both selective inhibitors of Tx synthetase and TxA2 receptor antagonists have facilitated the implication of TxA2 as a physiological modulator and as a mediator in thrombotic, vasospastic, and bronchospastic conditions. TxA2 is synthesized by platelets and contributes to platelet activation and irreversible platelet aggregation in physiological hemostasis and in thrombosis (e.g., unstable angina, stroke). TxA2 is also synthesized in intestinal, pulmonary, and renal tissues by cells other than platelets. Particularly in these tissues, TxA2 appears to act as a physiological modulator of changes in blood flow distribution and airway caliber. Strong stimuli for TxA2 release from these tissues may initiate ulcer, pulmonary hypertension, bronchoconstriction, and renal vasoconstriction. Evidence supports participation of TxA2 and/or TxA2 receptors in modulation of natural cytotoxic cell cytotoxicity, in tumor growth and metastasis, in complications of pregnancy (e.g., preeclampsia), and in the progression of ischemic injury after coronary artery occlusion. This evidence supports pivotal involvement of TxA2 in pathophysiology and provides a strong rationale for pursuing TxA2-blocking strategies in drug development.

Animals↗
PubMed1980

Dissociation of vasoconstrictor and platelet aggregatory activities of thromboxane by carbocyclic thromboxane A2, a stable analog of thromboxane A2.

Carbocyclic thromboxane A2 [2 beta (Z),3 alpha- (1E,3R*)-3-(3-hydroxy(1-octenyl)-bicyclo[3.1.1]hept-2-yl-5-heptenoic acid], a stable analog of thromboxane A2, has been tested for its physiologic properties. Carbocyclic thromboxane A2 is a potent coronary vasoconstrictor, stimulating cornonary vascular smooth muscle at concentrations as low as 29 pM. At 1-5 micro M it is also an inhibitor of arachidonic-acid- and endoperoxide-induced aggregation of platelets. At 200 nM it stimulated the release of lysosomal hydrolases from large granule fractions of liver homogenate. It inhibited thromboxane synthesis in platelets, although it did not inhibit synthesis of prostacyclin in ram seminal vesicles. Thus, carbocyclic thromboxane A2, a molecule closely related to thromboxane A2, separates coronary vasoconstrictor from platelet-aggregating activity. The constrictor activity predominates in vivo; carbocyclic thromboxane A2 induces coronary vasoconstriction leading to myocardial ischemia and sudden death in rabbits in the absence of pulmonary or coronary thrombosis.

Animals↗
PubMed2002

Role of prostacyclin in the cardiovascular response to thromboxane A2.

Thromboxane (Tx) A2 is a vasoconstrictor and platelet agonist. Aspirin affords cardioprotection through inhibition of TxA2 formation by platelet cyclooxygenase (COX-1). Prostacyclin (PGI2) is a vasodilator that inhibits platelet function. Here we show that injury-induced vascular proliferation and platelet activation are enhanced in mice that are genetically deficient in the PGI2 receptor (IP) but are depressed in mice genetically deficient in the TxA2 receptor (TP) or treated with a TP antagonist. The augmented response to vascular injury was abolished in mice deficient in both receptors. Thus, PGI2 modulates platelet-vascular interactions in vivo and specifically limits the response to TxA2. This interplay may help explain the adverse cardiovascular effects associated with selective COX-2 inhibitors, which, unlike aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs), inhibit PGI2 but not TxA2.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

LPS exacerbates endothelin-1 induced activation of cytosolic phospholipase A2 and thromboxane A2 production from Kupffer cells of the prefibrotic rat liver.

BACKGROUND/AIMS: Thromboxane A2 (TXA2) has been suggested to play a significant role in the development of portal hypertension in fibrosis, and Kupffer cell (KC) derived TXA2 has been shown to mediate the hyperresponsiveness of the portal circulation to the vasoconstrictive actions of endothelin-1 (ET-1) during endotoxemia. The aim of this study was to determine whether the double stresses of prefibrotic changes and endotoxemia additively activate KC to increase release of TXA2 in response to ET-1, resulting in elevated portal resistance. METHODS: One week Bile duct ligation (BDL) rats and sham-operated controls were subjected to isolated liver perfusions following LPS or saline for 6h. In a separate experiment, KC were isolated from BDL or sham rats and incubated with LPS or saline for 6h before the ET-1 treatment. RESULTS: The double stresses of early fibrosis and LPS resulted in a greater sustained increase in portal pressure in response to ET-1 in BDL rats, and this increase correlated well with the much enhanced release of TXA2 in the perfusate. Media from the cultured KC showed significantly greater TXA2 release in response to ET-1 in BDL group than those in sham group, and LPS exacerbated this effect. Protein levels of cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2, and thromboxane synthase were also significantly elevated in KC from BDL rats. ET-1 produced a marked increase in cPLA2 activation as measured by the phosphorylation of cPLA2 in KC of both BDL and sham groups. LPS greatly exacerbated the activation of cPLA2. CONCLUSIONS: The data suggest that the double stresses additively activate KC with an upregulation of the key enzymes in the TXA2 biosynthesis and release increased amount of TXA2 via the augmented activation of cPLA2 in response to ET-1, which leads to the increased portal resistance and ultimately hepatic microcirculatory dysfunction.

Animals↗
PubMed1982

Anti-thromboxane A2 actions of pinane thromboxane A2 derivatives.

Six pinane-thromboxane A2 analogs have been synthesized and tested for their ability to antagonize carbocyclic thromboxane A2 (CTA2) induced coronary vasoconstriction and prostaglandin endoperoxide analog induced platelet aggregation. Two of the derivatives, 5C-15S BPTA2 and 5T-15S BPTA2 and 5T-15S BPTA2 (1 microM) showed 76 +/- 3 and 72 +/- 9 percent inhibition of CTA2 (15 nM) induced vasoconstriction of cat coronary arteries respectively, while the other compounds showed between 15 and 50 percent inhibition at 1.0 and 2.0 microM. 5C-15S BPTA2 also antagonized prostaglandin-endoperoxide analog induced human platelet aggregation, although the other compounds showed little or no antagonism of aggregation in this system.

Animals↗
PubMed1997

Thromboxane A2 synthase inhibition and thromboxane A2 receptor blockade by 2-[(4-cyanophenyl)amino]-3-chloro-1,4-naphthalenedione (NQ-Y15) in rat platelets.

The effects of 2-[(4-acetylphenyl)amino]-3-chloro-1,4-naphthalenedione (NQ-Y15), a synthetic 1,4-naphthoquinone derivative, on platelet activity and its mechanism of action were investigated. NQ-Y15 caused a concentration-dependent inhibition of the aggregation induced by thrombin, collagen, arachidonic acid (AA), and A23187. The IC50 values of NQ-Y15 on thrombin (0.1 U/mL)-, collagen (10 microg/mL)-, AA (50 microM)-, and A23187 (2 microM)-induced aggregation were 36.2 +/- 1.5, 6.7 +/- 0.7, 35.4 +/- 1.7, and 93.1 +/- 1.4 microM, respectively. NQ-Y15 also inhibited thrombin-, collagen-, AA-, and A23187-stimulated serotonin secretion in a concentration-dependent manner. However, a high concentration (100 microM) of NQ-Y15 showed no significant inhibitory effect on ADP-induced primary aggregation, which is independent of thromboxane A2 (TXA2) production in rat platelets. In fura-2-loaded platelets, the elevation of intracellular free calcium concentration stimulated by AA, thrombin, and 4-bromo-A23187 was inhibited by NQ-Y15 in a concentration-dependent manner. The formation of TXA2 caused by AA, thrombin, and collagen was inhibited significantly by NQ-Y15. NQ-Y15 inhibited TXA2 synthase in intact rat platelets, since this agent reduced the conversion of prostaglandin (PG) H2 to TXA2. Similarly, NQ-Y15 selectively inhibited the TXA2 synthase activity in human platelet microsomes, whereas it had no effect on activity of phospholipase A2, cyclooxygenase, and PGI2 synthase in vitro. NQ-Y15 inhibited platelet aggregation induced by the endoperoxide analogue U46619 in human platelets, indicating TXA2 receptor antagonism, possibly of a competitive nature. These results suggest that the antiplatelet effect of NQ-Y15 is due to a combination of TXA2 synthase inhibition with TXA2 receptor blockade, and that it may be useful as an antithrombotic agent.

Animals↗
PubMed1996

Synthesis of [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives containing pyridyl or imidazolyl groups and their thromboxane A2 receptor antagonistic and thromboxane A2 synthase inhibitory activities.

As part of our search for a dual inhibitor possessing both thromboxane A2 (TXA2) receptor antagonistic and TXA2 synthase inhibitory activities, some [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives possessing a pyridyl or imidazolyl group were synthesized. Their TXA2 receptor antagonistic and TXA2 synthase inhibitory activities were evaluated in terms of the inhibitory effects on U-46619-induced guinea-pig platelet aggregation and on thromboxane B2 (TXB2) production in human platelets, respectively. It was found that 3-[4-[2-(1-imidazolyl)-1-(4-chlorobenzenesulfonamido)ethyl]phenyl] propionic acid (22a), containing an imidazolyl group, is a well-balanced dual inhibitor having both TXA2 receptor antagonistic activity (IC50 = 0.31 microM) and TXA2 synthase inhibitory activity (IC50 = 0.39 microM).

Animals↗
PubMed1998

Effects of cysteinyl-leukotriene receptor antagonist, thromboxane A2 receptor antagonist, and thromboxane A2 synthetase inhibitor on antigen-induced bronchoconstriction in patients with asthma.

BACKGROUND: Leukotriene (LT) and thromboxane A2 (TXA2) receptor antagonists have been used in the treatment of asthma. OBJECTIVES: We examined the effects of an LT receptor antagonist, TXA2 receptor antagonist, and TXA2 synthetase inhibitor on bronchoprovocation test (BPT) in patients with mild-to-moderate atopic asthma. METHODS: BPT was performed four times in each of six asthmatics. Development of the immediate asthmatic reaction (IAR) and late asthmatic reaction (LAR) was confirmed on the first BPT (BPT1). After a 7-day washout period, an LT receptor antagonist (pranlukast, 450 mg/d), TXA2 receptor antagonist (seratrodast, 80 mg/d), or TXA2 synthetase inhibitor (ozagrel, 800 mg/d) was administered orally over 7 days at random using a cross-over method (BPT2-4). Blood levels of LTB4, LTC4, LTD4, 11-dehydrothromboxane B2, eosinophil cationic protein, and histamine were measured at reaction phases of pre-BPT, IAR, and LAR. RESULTS: Administration of pranlukast suppressed IAR by 80.5% (p < 0.0001) and LAR by 54.6% (p = 0.0391). Ozagrel significantly suppressed IAR by 39.5% (p = 0.0413), but the fall in FEV1 was >20% (21.56+/-4.173%). Seratrodast did not suppress IAR or LAR. Blood levels of chemical mediators did not correlate with the suppressive effects of the tested drugs. CONCLUSIONS: The LT receptor antagonist was considered to be the most effective. LT might play a more important role in the pathogenesis of asthma than TXA2. Our data showed that measurement of blood levels of chemical mediators is not useful in identifying the pathogenic mechanisms of asthma.

Administration, Oral↗
PubMed1980

Preservation of ischemic myocardium by pinane thromboxane A2.

Pinane thromboxane A2 (PTA2), a thromboxane A2 analog has been shown to antagonize the vasoconstriction and platelet aggregation induced by thromboxane A2, in addition to specifically inhibiting thromboxane synthetase. Because thromboxane A2 generation would be detrimental in acute myocardial ischemia (MI) by both decreasing coronary blood flow and increasing platelet aggregation, inhibition of thromboxane production and action may be beneficial in myocardial ischemia. In pentobarbital-anesthetized cats, the left anterior descending coronary artery was ligated, and PTA2 (0.5 mumol . kg-1 . h-1) or a Na2CO3 vehicle was infused 30 min post-MI for 270 min. Compared to vehicle-treated MI cats, PTA2 prevented the increase in plasma thromboxane levels seen at 2 through 5 h (P less than 0.005 at 2 through 5 h) and prevented the large increase in plasma CK activities at 4 and 5 h (P less than 0.025). In addition, PTA2 treatment abolished the differences in myocardial CK activities between ischemic and nonischemic regions and prevented the decrease in percent-bound cathepsin D in the ischemic region. Moreover, ECG analysis revealed a decreased incidence of premature beats in PTA2-treated MI cats as compared to MI-vehicle cats. In summary, these data indicate that PTA2 protects the ischemic myocardium and provide further evidence that inhibition of thromboxane formation, in addition to antagonism of its activity, is beneficial during the early stages of acute myocardial ischemia.

Animals↗