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At least 19 recordsLinked to original sources

PubMed1976

A method for measuring the unstable thromboxane A2: radioimmunoassay of the derived mono-O-methyl-thromboxane B2.

A radioimmunoassay was developed for a mono-O-methyl derivative of thromboxane B2. The antibodies showed high specificity for this compound and cross reacted only 1.2% with thromboxane B2 and less than 0.1% with prostaglandins and prostaglandin metabolites. The method had a sensitivity of 7 picog. The radioimmunoassay was employed in studies where thromboxane A2 was generated in human platelets and immediately converted into mono-O-methyl thromboxane B2 by treatment of the sample with a large volume of methanol. In some of the experiments, thromboxane B2 was simultaneously measured by a separate radioimmunoassay. Using these two assays it was demonstrated that thromboxane A2 could be detected only during the earlier stages of the platelet aggregation, whereas thromboxane B2 rapidly reached a constant level. In a separate experiment, the half-life of thromboxane A2 in buffer was found to be 32.5 + 2.5 (S.D.) sec at 37 degrees C; the compound was more stable at lower temperatures. The t1/2 for thromboxane A2 was also considerably longer in plasma.

Antibody Specificity↗

PubMed1977

Inhibition of PGE1-stimulated cAMP accumulation in human platelets by thromboxane a2.

The prostaglandin endoperoxide PGH2, HHT, HETE, thromboxane A2, and thromboxane B2, which are all products of arachidonic acid metabolism of human platelets, were tested for their ability to modulate platelet cyclic nucleotide levels. None of the compounds tested altered the basal level of cAMP or cGMP, and only PGH2 and thromboxane A2 inhibited PGE1-stimulated cAMP accumulation. Thromboxane A2 was found to be a more potent inhibitor of PGE1-stimulated cAMP accumulation and inducer of platelet aggregation than PGH2.

Blood Platelets↗

PubMed1976

On the formation and effects of thromboxane A2 in human platelets.

Incubation of arachidonic acid and prostaglandin G2 with a suspension of human platelets led to formation of an unstable (t1/2, 41+/-7 s) compound, thromboxane A2. Thromboxane A2 induced irreversible aggregation of washed platelets and of platelets in platelet-rich plasma and caused release of serotonin and ADP from platelets in platelet-rich plasma.

Adenosine Diphosphate↗

PubMed1977

Thromboxane A2: effects on airway and vascular smooth muscle.

Thromboxane A2, an unstable compound derived from prostaglandin G2, was generated by incubation of arachidonic acid with a suspension of human platelets. The activity of thromboxane A2 relative to that of prostaglandin H2 in causing contractions of a number of smooth muscle organs were as follows: rabbit aorta, 7-20; human umbilical artery, 9-60; and guinea pig trachea, 2-12. Intravenous injection of thromboxane A2 into anaesthetized quinea pigs was followed by a pronounced increase in the tracheal insufflation pressure, potency compared to prostaglandin H2, 31-45.

Animals↗

PubMed1977

Platelet rich plasma transforms exogenous prostaglandin endoperoxide H2 into thromboxane A2.

Platelet rich plasma transforms exogenous prostaglandin endoperoxide H2 into thromboxane A2 immediately prior to the initiation of irreversible aggregation. Selective thromboxane synthetase inhibitors block thromboxane A2 formation and aggregation. Thromboxane A2 formation appears to be essential during arachidonate mediated aggregation. The results presented reconcile the previously accepted paradoxical behavior of thromboxane synthetase in platelet rich plasma toward the prostaglandin endoperoxide H2 substrate.

Arachidonic Acids↗

PubMed1979

Synthesis and biological properties of pinane-thromboxane A2, a selective inhibitor of coronary artery constriction, platelet aggregation, and thromboxane formation.

Pinane-thromboxane A2 (PTA2, [1alpha,2 beta(Z),-3 alpha (1E,3R*),5 alpha]-7-(3-(3-hydroxy-1-octenyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl)-5-heptenoic acid) has been synthesized and tested for biological activity in systems responsive to thromboxane A2, stable prostaglandin endoperoxide (PGH2) analogs, and prostatacyclin (PGI2). At low concentrations, PTA2 inhibited cat coronary artery constriction induced by stable prostaglandin endoperoxide analogs, and it stabilized liver lysosomes. At slightly higher concentrations, it inhibited platelet aggregation. At still higher concentrations, PTA2 inhibited thromboxane synthetase, but it had no effect on prostacyclin synthetase. The analog also had no effect on the inhibition of platelet aggregation by PGI2 or prostaglandin D2. It is suggested that PTA2 has a suitable biochemical profile for use as an antithrombotic agent.

Animals↗

PubMed1978

Influence of agents which modulate thromboxane A2 synthesis or action on R3230AC mammary carcinoma.

The effects of agents which modulate thromboxane A2 synthesis or action, were tested in the R3230AC transplanted mammary tumour. Three different inhibitors of thromboxane A2 synthesis or action (copper, dipyridamole and diazepam) all caused an increase in tumour growth. Colchicine and melatonin, both stimulators of thromboxane A2 synthesis, inhibited the growth of the tumour significantly.

Animals↗

PubMed1976

Thromboxane A2 and prostaglandin H2: potent stimulators of the swine coronary artery.

Thromboxane A2 was generated by incubation of arachidonic acid with a suspension of human platelets. The filtrate contained 266 +/- 46 ng/ml (n=10) of thromboxane A2 and 25 ng/ml or less of prostaglandin endoperoxides (prostaglandins G2+H2). Thromboxane A2 was 2-10 times more potent than prostaglandin H2 and 9-102 times and 26-308 times more potent than prostaglandins E2 and F2alpha, respectively, in causing contractions of the superfused swine coronary artery.

Animals↗

PubMed1979

Prostacyclin, thromboxane A2 interactions in haemostasis and thrombosis.

Prostacyclin and thromboxane A2 are products of arachidonic acid which play a role in the regulation of haemostatic plug and thrombus formation. Aspirin inhibits the synthesis of both compounds but is more active in blocking TXA2 formation; based on this, aspirin is suggested to have an anti-thrombotic effect. Other possible approaches to the development of anti-thrombotic drugs are discussed.

Animals↗

PubMed1977

Diversion of prostaglandin endoperoxide metabolism by selective inhibition of thromboxane A2 biosynthesis in lung, spleen or platelets.

Infusion of arachidonic acid through the guinea pig lung or the cat spleen causes a release of thromboxane A2 and prostaglandins, as measured by bioassay. After incubation of human platelets with arachidonate similar metabolites are formed, as demonstrated chromatographically. Infusion of imidazole (50-75 microgram/ml) through the lung or spleen specifically inhibits thromboxane A2 production and diverts the pathway to the prostaglandins, mainly prostaglandin F2alpha. In human platelets imidazole causes a dose-dependent inhibition of thromboxane A2 formation (ID50 5.5 X 10(-4) M). This inhibition is accompanied by a dose-dependent increase in prostaglandin F2alpha. Since thromboxane A2 induces platelet aggregation and is a potent vasoconstrictor, diversion of pathways to prostaglandins with opposite or less potent action might be of relevance in the treatment of cardiovascular diseases.

Animals↗

PubMedDate not supplied

Cerebral arterial smooth muscle contraction by thromboxane A2.

The contractile effects of thromboxane A2 (TxA2), a labile arachidonic acid metabolite, were studied in arterial smooth muscle strips. TxA2 was generated upon the addition of 255 nM prostaglandin cyclic endoperoxide H2 to human platelet particles in the muscle bath. Using the isometric contaction produced by 40 mM K+ in isotonic saline as the reference contraction, bovine middle cerebral artery strips contracted to 153 +/- 14% of the reference response while bovine coronary and porcine coronary, renal and common carotid strips contracted to 47 +/- 3, 26 +/- 5, 43 +/- 2 and 2 +/- 1% of reference, respectively. The cerebral artery response to the TxA2 generating system was as great as the maximum response to prostaglandin F2alpha and two times the maximum response to 5-hydroxytryptamine. Because TxA2 is formed by brain tissue and released from aggregating platelets, it may be important in the pathogenesis of spasm associated with injured brain tissue or pathologic changes leading to platelet aggregation.

Animals↗

PubMed1978

Biosynthesis and biological properties of prostaglandin endoperoxides and thromboxane A2.

Two prostaglandin endoperoxides, i. e. PGG2 and PGH2 were detected and isolated. They were unstable in aqueous medium (t1/2 at 37 degrees C about 5 min) and were converted to PGF2alpha by mild reducing agents. Human platelets as well as guinea pig lung and spleen converted the endoperoxides into thromboxane A2, an unstable (t1/2 at 37 degrees C about 30 s) oxetane/oxane derivative. Thromboxane A2 was converted into a stable hemiacetal derivative, thromboxane B2, by addition of 1 H2O. The two prostaglandin endoperoxides as well as thromboxane A2 caused platelet aggregation and the platelet release reaction. In addition they were potent stimulators of vascular and airway smooth muscle in vitro and in vivo.

Animals↗

PubMed1978

A possible role of thromboxane A2 (TXA2) and prostacyclin (PGI2) in circulation.

Recently two local hormones, thromboxane A2 (TXA2) and prostacyclin (PGI2) have been discovered. These hormones are labile metabolites of arachidonic acid. TXA2 is generated by blood platelets, while PGI2 is produced by vascular endothelium. TXA2 is a potent vasoconstrictor. It also initiates the release reaction, followed by platelet aggregation. PGI2 is a vasodilator, especially potent in coronary circulation. It also inhibits platelet aggregation by virtue of stimulation of platelet adenyl cyclase. Common precursors for both hormones are cyclic endoperoxides PGG2 and PGH2, being formed by cyclooxygenation of arachidonic acid. This last enzymic reaction is more efficient in platelets than in vascular endothelium, and therefore the generation of PGI2 by vasuclar wall is accelerated by an interaction between platelets and endothelial cells. During this interaction platelets supply the endothelial PGI2 synthetase with their cyclic endoperoxides. The newly formed PGI2 repels the platelets from the intima. When PGI2 synthetase is irreversibly inactivated by low concentration of lipid peroxides, then the platelets are not rejected but stick to the endothelium, generate TXA2 and mature thrombi are formed. A balance between formation and release of PGI2, TXA2 and/or cyclic endoperoxides in circulation is of utmost importance for the control of intra-arterial thrombi formation and possibly plays a role in the pathogenesis of atherosclerosis.

Adenylyl Cyclases↗

PubMed1979

9,11-Iminoepoxyprosta-5,13-dienoic acid is a selective thromboxane A2 synthetase inhibitor.

9,11-Iminoepoxyprosta-5,13-dienoic acid inhibits the thromboxane A2 synthetase in platelet and lung microsomal enzyme preparations and in intact platelets. It does not inhibit the protaglandin I2 synthetase in aorta or lung microsomes and intact Balb 3T3 fibroblasts. In lung microsomes, which contain both enzymes, 9,11-iminoepoxyprosta-5,13-dienoic acid inhibits only thromboxane A2 formation and augments prostaglandin I2 formation. This inhibitor is more selective than other reported prostaglandin endoperoxide analogs which inhibit the platelet thromboxane synthetase.

Animals↗

PubMed1978

Coronary vasospastic action of thromboxane A2 in isolated, working guinea pig hearts.

The effects of thromboxane A2 (TXA2) on isolated, working guinea pig heart and left ventricular papillary muscle preparations were investigated. TXA2 was generated by the enzymatic conversion of prostaglandin H2 (PGH2) with indomethacin-treated horse platelet microsomes (IPM). TXA2 caused dose-dependently a considerable decrease in the coronary flow, left ventricular systolic pressure and left ventricular dp/dt in the perfused heart, while the similar effects of PGH2 were transient and weaker than those of TXA2. These effects of TXA2 disappeared after the TXA2-generating system was left standing at 37 degree C for 3 min. When IPM in the TXA2-generating system was pretreated with a TXA2 synthetase inhibitor, L-8027, the enhanced cardiac responses induced by the mixture of IPM and PGH2 disappeared. TXA2 had no direct effect on the contractile force of the papillary muscle. These results suggest that TXA2 has a specific coronary vasopastic action without a direct inotropic effect.

Animals↗

PubMed1978

Impairment of platelet thromboxane A2 generation and of the platelet release reaction in two patients with congenital deficiency of platelet cyclo-oxygenase.

Two cases of thrombocytopathia with congenital deficiency of platelet cyclo-oxygenase were investigated. The platelet release reaction was impaired. There was a marked decrease of aggregation with collagen and with adrenalin and a total absence of aggregation with sodium arachidonate. The platelet response to labile aggregation stimulating substance (LASS, mostly thromboxane A2) was normal. There was no biosynthesis of prostaglandin cyclic endoperoxides or of thromboxane A2 from arachidonic acid. Basal levels of platelet PGE1 were lowered although plasma levels were normal. Thrombin decreased the cyclic AMP content of patients' platelets and also that of control platelets pretreated with aspirin. The patients platelets showed no ultrastructural difference when compared with control platelets, except for a slight decrease of granule volume, but, in contrast to control platelets, thrombin (0.02 U/ml) did not provoke contraction of the patients' platelets.

Adult↗

PubMed1978

Salicylic acid fails to inhibit generation of thromboxane A2 activity in platelets after in vivo administration to the rat.

Arachidonic acid-induced aggregation of rat platelets and the accompanying generation of thromboxane A2 activity were inhibited by aspirin, whereas 20 times higher doses of salicylic, gentisic and salicyluric acids were inactive. Salicylic acid administered to the rats before aspirin prevented the inhibition of the cyclo-oxygenase-mediated effects of arachidonic acid. These results do not support the hypothesis that the anti-inflammatory activity of salicylic acid is due to inhibition of prostaglandin systhetase (cyclo-oxygenase) by an unknown metabolite and indicate that salicylic acid displays an anti-inflammatory activity independent inhibition of prostaglandin biosynthesis.

Animals↗

PubMed1977

Experimental ischemic heart disease induced by thromboxane A2 in rabbits.

How an acute ischemic attack is induced in a patient with coronary atherosclerosis is unknown and we carried out studies using thromboxane A2 (TXA2) to determine if acute myocardial ischemia and necrosis could be induced in rabbits. TXA2 was perfused through the coronary artery for 5 seconds by means of a Swan-Ganz catheter through the right common carotid artery. Significant serial changes of ST-T on ECG and hypotension were observed from 1 minute to more than 1 day after the perfusion in all 22 rabbits. The TXA2 that was composed of both aggregated platelets and prostaglandin H2 induced the same response, and such was dose dependent. The inactivated TXA2 was without effect. Seventeen of the experimental rabbits were autopsied. Histological studies of the hearts showed focal myocardial ischemia and necrosis in all rabbits except one autopsided 10 minutes after the perfusion. TXA2 is apparently capable of inducing acute myocardial ischemia and necrosis.

Acute Disease↗