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1.
The prostaglandin endoperoxide PGH2, HHT, HETE, thromboxane A2, and thromboxane B2, which are all products of arachidonic acid metabolites 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 thatn PHG2.  相似文献   

2.
The effect of human blood on prostaglandin metabolism in vitro was studied at 37°C and 4°C. Labeled prostaglandins were incubated for up to one hour in whole blood or plasma. After extraction, the prostaglandins were purified by LH-20 Sephadex chromatography. Appropriate 14C labeled compounds, when available, were used to correct for losses. Metabolism was determined by comparison of incubated samples with zero time controls. There was no reduction in isotopic recovery of prostaglandins B1, B2 and E1 after incubation with whole blood for up to one hour. In contrast, human whole blood, but not plasma, rapidly metabolized prostaglandins A1 and A2 at 37°C. The rate of metabolism was temperature dependent, but still continued at 4°C. The products of these reactions were not identified, but they appeared to remain in the aqueous solution after extraction with the neutral organic solvent.  相似文献   

3.
4.
In vitro experiments indicate that thromboxane A2 (TA2) is a potent platelet aggregator and vascular constrictor. However, it is unclear what roles these specific actions may contribute in the pathophysiology of myocardial ischemia. Carbocyclic thromboxane A2 (CTA2), a TA2 analog, constricts isolated perfused cat coronary arteries, but does not aggregate platelets, and thus appeared useful to clarify these separate actions of TA2. In anesthetized cats, radioactive labeled microspheres were injected into the left atrium for measurement of cardiac output and tissue blood flows. Compared to control measurements, CTA2 infusion (4.8 μg·kg?1·min?1 to 10 min) significantly decreased cardiac output from 347 ± 16 ml·min?1 to 248 ± 16 ml·min?1 (p<0.025). Furthermore, V7 CTA2 also significantly reduced blood flow to the left ventricle by 33 ± 7%, but did not alter heart rate or MABP in the intact cat. In cats subjected to left anterior descending coronary artery occlusion, infusion of CTA2 (1 μg·min?1 for 120 minutes) 30 min after ligation resulted in a significantly reduced myocardial cellular integrity as measured by myocardial creatine kinase activity (p<0.01) or percent bound myocardial cathepsin D (p<0.01). Thus, these data suggest that activation of vascular thromboxane receptors as well as direct cellular damage may play a role in the pathophysiology of myocardial ischemia.  相似文献   

5.
The binding characteristics of [3H]U46619 to washed human platelets were studied. [3H]U46619 binding to washed human platelets was saturable and displaceable. Kinetic studies yielded a Kd of 11 ± 4 nM (n=4). Scatchard analysis of equilibrium binding studies revealed one class of high affinity binding sites with a Kd of 20 ± 7nM and a Bmax of 9.1 ± 2.3 fmole/107 platelets (550 ± 141 binding sites per platelet) (n=4). A number of compounds that act as either agonists or antagonists of the TXA2/PGH2 receptor were tested for their ability to inhibit the binding of [3H]U46619 to washed human platelets. The Kds of the agonists and antagonists were similar to their potencies to induce or inhibit platelet aggregation. These data provide some evidence that [3H]U46619 binds to the putative human platelet TXA2/PGH2 receptor.  相似文献   

6.
Dog platelets challenged with arachidonic acid fail to aggregate but synthesize a substance which aggregates rabbit and human platelets, this aggregation being suppressed by dibutyryl cyclic AMP. The aggregating substance contracts strips of rabbit aorta and of coeliac and mesenteric arteries, is soluble in diethyl ether, has a half-life of about 40 seconds at 37°C and of 100 seconds at 22°C. Its generation is blocked by various inhibitors of prostaglandin biosynthesis. The thromboxane A2 synthetase inhibitor imidazole and its analogue benzimidazolamine also suppress generation of vessel contracting activity in incubates of dog platelets and prostaglandin H2. Since dog platelets also transform prostaglandin H2 into thromboxane A2 their failure to aggregate, when stimulated by arachidonic acid or by prostaglandin H2, is not due to lack of thromboxane synthesizing ability.  相似文献   

7.
When rat platelets are incubated with phospholipase A2, thromboxane A2-like activity and prostaglandins are formed. The amounts are approximately similar, whether aggregation is induced after the incubation or not. No aggregation is observed when the platelets are incubated with phospholinase A2. In the platelets of essential fatty acid deficient rats, only small amounts of thromboxane A2-like activity and prostaglandins are formed. No formation of these substances occurs when human and rabbit platelets are incubated with phospholipase A2.The results indicate that formation of thromboxane A2-like activity enhances aggregation in rat platelets, but that aggregation is not induced.  相似文献   

8.
The influence of hyperventilation on the spontaneous generation of prostacyclin and thromboxane A2 by isolated rat lungs was studied. Both prostacyclin and thromboxane A2, as measured by RIA of their stable end-products, 6-oxo-PGF and TXB2 respectively, were continuously released into the perfusate. However, the concentration of prostacyclin in the perfusate was higher than thromboxane A2. Under normal ventilation at a rate 40–50 breaths/min, the ratio between these two compounds was 5:1. Increasing the rate of respiration to 100 breaths/min preferentially stimulated the release of prostacyclin. During hyperventilation, the ratio between 6-oxo-PGF and TXB2 was 12:1. Aspirin and indomethacin suppressed both basal and hyperventilation-stimulated release of prostacyclin and thromboxane A2. Hydroperoxy-fatty acids and tranylcypromine inhibited only the release of prostacyclin but did not affect the generation of thromboxane A2. Our findings confirm that the lung generates prostacyclin predominantly, and provide direct evidence that respiratory movements are involved in generation of pulmonary prostacyclin and thromboxane A2.  相似文献   

9.
The influence of platelets and platelet membranes on the generation of prostacyclin (PGI2) and thromboxane A2(TXA2) by isolated rat lung and porcine aortic endothelial cell, as measured by RIA of their stable end-producs, 6-oxo-PGF and TXB2 respectively, was studied. After introduction of either aspirin-treated platelets or membranes from aspirin-treated platelets to the perfusate, 1 5-fold increase in the amount of 6-oxo-PGF and TXB2 in the perfusate was observed. Treatment of the lung with aspirin produced a 50% reduction in the platelet-stimulated release of PGI2 and TXA2. Treatment of the lung with the phospholipase inhibitor, mepacrine, significantly reduced the platelet-stimulated release of PGI2 and TXA2. Incubation of endothelial cells with untreated platelet membranes did not alter the generation of PGI2. These results suggest that platelet-stimulated release of PGI2 and TXA2 occurs via mechanical stimulation of phospholipase A2, liberating arachidonic acid.  相似文献   

10.
Histamine 2.5, 5, 10 or 20 μg/kg i.v. induce a pronounced bronchospasm in guinea-pigs, accompanied by a dose-related increase of TXA2 in arterial blood, as revealed by contraction of rabbit isolated aorta and by radioimmunoassay. Aspirin 10 mg/kg prevented formation of TXA2 like material without significantly modifying the severity of the bronchospasm. Bradykinin 0.5, 1 or 2 μg/kg i.v. acted similarly, except that pretreatment with aspirin blocked both the increased airway resistance and release of TXA2. Aspirin also blocked the increase in blood pressure and heart rate caused by histamine or bradykinin.  相似文献   

11.
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.  相似文献   

12.
Soluble elastin, prepared from insoluble elastin by treatment with oxalic acid or elastase, was found to inhibit the formation of thromboxane B2 both from [1-14C]arachidonic acid added to washed platelets and from [1-14C]arachidonic acid in prelabeled platelets on stimulation with thrombin. In both systems, the formation of 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) was accelerated. Oxalic acid-treated soluble elastin st 1 and 10 mg/ml inhibited the formation of thromboxane B2 from exogenously supplied arachidonic acid 21 and 59%, respectively, and the formation of thromboxane B2 in prelabeled platelets stimulated by thrombin 44 and 94%, respectively. These concentrations of elastin increased the formation of 12-HETE from exogenously supplied arachidonic acid about 3.4- and 7.3-times, respectively. Almost all the added arachidonic acid was converted to metabolites. In prelabeled platelets, soluble elastin at 1 and 10 mg/ml increased the formation of 12-HETE stimulated by thrombin about 1.3- and 2.8-times, respectively, and inhibited the thrombin-induced total productions of thromboxane B2 (12-hydroxy-5,8,10-heptadecatrienoic acid (12-HETE) and free arachidonic acid by 26 and 25%, respectively. Elastase-treated digested elastin also inhibited the formation of thromboxane B2 and stimulated the formation of 12-HETE in prelabeled platelets stimulated by thrombin. This inhibitory action of elastin was not replaced by desmosine. The level of cAMP in platelets was not affected by soluble elastin. Soluble elastin was also found to inhibit platelet aggregation induced by thrombin. However, the inhibitory action of soluble elastin on platelet aggregation cannot be explained by inhibition of thromboxane B2 formation by the elastin.  相似文献   

13.
Experimental atherosclerosis in rabbits was associated with increased aggregation of their platelets to arachidonic acid, and with increased generation of thromboxane A2 by their platelet-rich plasma. A heightened susceptibility of platelets to the anti-aggregatory action of prostacyclin against the ADP-induced aggregation was also observed. It is concluded that in advanced atherosclerosis the platelet system is hypersensitive to biologically active metabolites of arachidonic acid.  相似文献   

14.
The production of vasodilatory, antiaggregatory prostacyclin (PGI2) and vasoconstrictory, proaggregatory thromboxane A2 (TxA2) by the placenta was studied in the cases of hypertensive pregnancy complications by superfusing pieces from maternal and fetal sides of placentae of 9 pre-eclamptic, 6 hypertensive and 11 healthy women and measuring the release of 6-keto-prostaglandin F (6-keto-PGF) and thromboxane B2 (TxB2), the breakdown products of PGI2 and TxA2 respectively, from the superfusate. Both sides of the placentae from the controls produced 6-keto-PGF (maternal side 0.5±0.1 ng/g/min dry weight of tissue, mean±SEM; fetal side 0.7±0.2 ng/g/min) and TxB2 (maternal side 2.5±0.4 ng/g/min; fetal side 2.7±0.5 ng/g/min with no correlation between the two. The 6-keto-PGF production was normal in hypertensive complications whereas the TxB2 production was increased on the fetal side of the placentae obtained from the pre-eclamptic (3.7±0.3 ng/g/min: p<0.05) and hypertensive women (4.1±0.4 ng/g/min; p<0.025). This may explain the occurrence of microthrombi and infarctions in placentae of hypertensive women.  相似文献   

15.
Effects of nitrogen dioxide (NO2) exposure on prostacyclin (PGIP2) synthesis in the rat lung and thromboxane A2 (TXA2) synthesis in the platelets were studied. Male Wistar rats were exposed to 10 ppm NO2 for 1, 3, 5, 7 and 14 days. PGI2 synthesizing activity of homogenized lung decreased. The damage of PGI2 synthesizing activity reaches its maximum at 3 days. At 14 days, PGI2 synthesizing activity returned to the normal level. The activity of PGI2 synthetase decreased significantly. The formation of lipid peroxides due to NO2 exposure may cause the depression of PGI2 synthesizing activity of lung. On the other hand, platelet TXA2 synthesizing activity increased. This increased TXA2 synthesizing activity lasted at least till 3 days. Then, it returned to the normal level. The counts of platelet were decreased significantly by 1, 3, 5 and 7 days NO2 exposure. Then the decreased counts of platelet returned to the normal level at 14 days NO2 exposure. These results indicate that the depression of PGI2 synthesizing activity lung by NO2 exposure cause an increase in TXA2 synthesizing activity of platelets. It may contribute to induce platelet aggregation and to the observed decrease in the number of platelets during NO2 exposure.  相似文献   

16.
Platelets from vitamin E-deficient and vitamin E-supplemented rats generate the same amount fo thromboxane A2 (TxA2) when they are incubated with unesterified arachidonic acid. Platelets from vitamin E-deficient rats produce more TxA2 than platelets from vitamin E-supplemented rats when the platelets are challenged with collagen. Arterial tissue from vitamin E-deficient rats generates less prostacyclin (PGI2) than arterial tissue from vitamin E-supplemented rats. The vitamin E effect with arterial tissue is observed when the tissue is incubated with and without added unesterified arachidonic acid. These data show that arterial prostacyclin synthesis is diminished in vitamin E-deficient rats. Vitamin E, invivo, inhibits platelet aggregation both by lowering platelet TxA2 and by raising arterial PGI2.  相似文献   

17.
GA12-aldehyde obtained from mevalonate via ent-kaurene, ent-kaurenol, ent-kaurenoic acid and ent-7α-hydroxykaurenoic acid in a cell-free system from immature seeds of Cucurbita maxima was converted to GA12 by the same system. When Mn2+ was omitted from the system GA12-aldehyde and GA12 were converted further to several products. Among these GA15, GA24, GA36 and GA37 were conclusively identified by GC-MS. With the exception of GA37 these GAs have not previously been found in higher plants. Another biosynthetic pathway led from ent-7α-hydroxykaurenoic acid to very polar products via what was tentatively identified as ent-6α, 7α-dihydroxykaurenoic acid. An unidentified component with an MS resembling that of a dihydroxykaurenolide was also obtained from incubations with mevalonate.  相似文献   

18.
Phospholipase A2, an enzyme which may regulate the formation of polyunsaturated fatty acids utilized for prostaglandin synthesis, was found to have significant higher activity in decidual than in myometrial tissue. The major part of phospholipase A2 in the decidua had an acid pH optimum, which indicates that most of the enzyme is stored in the lysosomes of this tissue. These findings, together with previous observations, lend further support to the view that lysosomal phospholipase A2 released within decidual cells might be a trigger of abortion and parturition.  相似文献   

19.
Intervillous blood was collected from term placentae at delivery, and sera were tested for phospholipase A2 under various experimental conditions. Enzyme activity was found to develop upon extended storage in the cold or at 37°C. The enzyme is reversibly inhibited by dithiothreitol, requires Ca++ ions for activity, and tolerates various detergents. The apparent molecular weight is 42 kDa. In all these parameters the serum enzyme behaves similar to the 42 kDa phospholipase A2 which we recently purified to homogeneity from thoroughly washed placental tissue. Serum phospholipase A2 appears to be generated by proteolytic processing from a slightly larger inactive precursor which was detected immunochemically. Most likely this protein originates from fetal cells and may be released by membrane damage. We conclude that both placental serum and tissue harbour a novel type of phospholipase A2 which is distinct from cytosolic and secretory phospholipases A2. Preference for arachidonate containing substrate suggests a role in eicosanoid production within gestational tissues.  相似文献   

20.
S-145 (5Z-7-(3-endo-phenylsulfonylamino-(2.2.1.)-bicyclohept -2-exo-yl) heptenoic acid) is a potent and selective antagonist for thromboxane A2/prostaglandin H2 receptor. Using this compound as an immobilized ligand for affinity chromatography and [3H]S-145 as a radioligand, we have purified the thromboxane A2/prostaglandin H2 receptor from the membranes of human blood platelets. The purification procedures consisted of solubilization of the receptor with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), affinity chromatographies on columns of S-145 affinity gel, wheat germ agglutinin agarose and red agarose, and repeated gel filtration high performance liquid chromatography on a TSK gel G-3000SW column. On the second gel filtration high performance liquid chromatography, the [3H]S-145 binding activity was eluted as a symmetrical peak which overlapped exactly with a peak of ultraviolet absorption at 280 nm. By these procedures, the receptor was purified about 8700-fold from the solubilized extract with a recovery of 6%. The final preparation showed a broad protein band at Mr 57,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and maximally bound 19.2 nmol of [3H]S-145/mg protein with a Kd of 29.8 nM. The [3H]S-145 binding to the purified receptor was specifically displaced by several thromboxane A2/prostaglandin H2 analogues.  相似文献   

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