TXB2 Production Research Articles

Oral nimodipine reduces prostaglandin and thromboxane production by arteries chronically exposed to a periarterial haematoma and the antifibrinolytic agent tranexamic acid.

The calcium antagonist nimodipine blocks the effects of many vasoconstrictors of cerebrovascular smooth muscle and may reduce the incidence of delayed cerebral ischaemia following subarachnoid haemorrhage though not necessarily by inhibiting the development of angiographic cerebral vasospasm. Post-haemorrhagic CSF contains abnormally large quantities of various eicosanoids that partly reflect enhanced production by cerebral arteries. Does nimodipine affect this process? The extra-arterial and intra-arterial production of PG6 keto-F1 alpha, PGE2, PGF2 alpha and TXB2 were measured in perfused common carotid arteries taken from rabbits in which the arteries had been ensheathed by blood clot in vivo for 7 days. All rabbits were given the antifibrinolytic agent tranexamic acid to retard resolution of the clot, and half were given oral nimodipine (2 mg/kg/day) for 10 days. Nimodipine significantly reduced the extra-arterial production of TXB2 during the third and fourth hours of perfusion and, less consistently, the production of PGF2 alpha, PGE2 and PG6 keto-F1 alpha. Lutrol, the solvent for nimodipine, had no such effect.

Evidence that renal prostaglandin and thromboxane production is stimulated in chronic cyclosporine nephrotoxicity.

Previous reports suggest that cyclosporine (CsA) may have direct effects on arachidonic acid (AA) metabolism in several different tissues. However, the effects of CsA on renal eicosanoid production are unclear. Furthermore, the potential role of changes in renal prostaglandin and thromboxane metabolism in mediating CsA nephrotoxicity is not known. Therefore, in this study, we evaluated the effects of CsA toxicity on the production of AA metabolites by the kidney. In a postischemic, denervated rat model, CsA (50 mg/kg/day) administered for 12-14 days resulted in significant nephrotoxicity with marked decreases in both glomerular filtration rate and renal blood flow. This reduction in renal function was associated with an increase in the renal production of TXB2, PGE2, and 6-PGF1 alpha in vitro. Arachidonic acid significantly stimulated renal eicosanoid production above control values. Increased urinary excretion of TXB2, 2,3-dinorTXB2 (a major TXB2 metabolite), and 6-keto-PGF1 alpha also occurred in rats with CsA nephrotoxicity and reflected the increase in renal production of these eicosanoid products. In contrast, urinary PGE2 excretion was not increased in CsA toxic rats. Thus, CsA nephrotoxicity is associated with specific alterations in renal AA metabolism. Furthermore, alterations in AA metabolism may be important in modulating renal hemodynamics and excretory function in this model. These studies suggest that specific inhibition of vasoconstrictor products of AA metabolism might ameliorate the nephrotoxic effects of CsA.

Postischemic production of eicosanoids in gerbil brain.

The postischemic production of PGE2, PGD2, 6-keto-PGF1 alpha, and TXB2 in brain tissue was studied in Mongolian gerbils using tissue extraction as well as a new ex vivo method. This new method permits the study of prostaglandin synthesis in slices from discrete areas of the brain (cortex, hippocampus, striatum, hypothalamus). Gerbils were sacrificed at 0, 5, and 30 minutes, and 4 and 24 hours after a 15-minute occlusion of both carotid arteries. Apart from 6-keto-PGF1 alpha, tissue prostaglandins determined by the extraction method were significantly increased 3 and 30 minutes after reperfusion. The most pronounced changes found by the ex vivo method were increased productions of PGD2 immediately after reperfusion (285% in cortex, 215% in hypothalamus) and PGE2 (350% in hippocampus, 320% in striatum) 4 hours after reperfusion. At 24 hours after reperfusion PGE2 and PGD2 synthesis were significantly decreased by 23-70% of the values obtained from sham-operated controls. Thromboxane increased slightly in all areas after recirculation and subsequently decreased to values below the control level in striatum. The results obtained by ex vivo incubation of tissue slices demonstrate that ischemia and subsequent recirculation cause site-, time-, and PG-specific changes of tissue eicosanoid production.

Thromboxane production in diabetes mellitus.

A correlation between increased platelet adhesiveness and aggregation and the development of angiopathy in diabetes mellitus can be made. Thromboxane produced by platelets represents a potent platelet aggregation factor. We studied the platelet TXB2 production during blood coagulation in carefully selected patients with type II diabetes mellitus in good metabolic control and the results were correlated with the presence or absence of microangiopathy, fasting blood glucose levels, type of therapy, age, duration of diabetes and the most important hematochemical parameters. No statistically significant differences were found between serum TXB2 concentrations in diabetic patients and control subjects, in diabetics with or without microangiopathy and in diabetics on insulin therapy or on oral hypoglycemic agents. We did not observe any correlation between TXB2 production and age, duration of diabetes, sex, basal blood glucose levels, total and HDL-cholesterol, triglycerides, blood creatinine and blood electrolytes. The thromboxane production may be a not important factor for determining the increased platelet aggregation which is at the origin of the angiopathy in diabetes mellitus.

Involvement of prostaglandins in the response of frog adrenocortical cells to muscarinic receptor activation

The role of prostaglandins (PGs) in the mechanism of action of acetylcholine (ACh) on frog adrenocortical cells has been examined. Administration of a single dose of ACh (5 × 10 −5 M) to perifused frog interrenal fragments, for 20 min, stimulated the production of corticosterone, aldosterone, PGE 2 and 6-keto-PGF 1α. In contrast ACh did not significantly alter TXB2 production. The effect of ACh could be mimicked by muscarine (10 −5 M). Conversely, nicotine (10 −6 to 10 −4 M) was totally inactive. The increase in PG biosynthesis preceded the peak of corticosteroid release. Repeated 20-min pulses of ACh (5 × 10 −5 M) or muscarine (10 −5 M) given at 130-min intervales induced a desensitization phenomenon. In presence of indomethacin (5 × 10 −6 M), the effect of ACh on PG and steroid secretion was totally abolished. In calcium-free medium, the effect of ACh on PG and corticosteroid production was completely blocked. These results indicated that, in the frog, ACh stimulates corticosteroid secretion through a PG-dependent mechanism.

Sex Difference in the Effect of Aspirin on Intracellular Ca2+ Mobilization and Thromboxane A2 Production in Rat Platelets

The intracellular Ca2+ mobilization in thrombin-stimulated platelets was greater in male rats than in female rats. Thromboxane (TX) B2 production in male platelets was greater than that in female platelets. Aspirin suppressed Ca2+ mobilization in rat platelets, but the inhibitory effect of aspirin was more efficient in males than that in females. Aspirin inhibited TXB2 production, and this inhibitory effect of aspirin was stronger in male platelets than in female platelets. Castration decreased Ca2+ mobilization and TXB2 production and weakened the effect of aspirin on them. It is suggested that the sex difference in the antiplatelet effect of aspirin results from the difference in the inhibition of Ca2+ mobilization via the inhibition of TXA2 production in thrombin-stimulated rat platelets.

The Effects of Modulation of Prostanoid Metabolism on the Thoracic Platelet Accumulation Induced by Intravenous Administration of Collagen in the Guinea-Pig

The effects of intravenously administered collagen on the circulatory platelet count, TxB2, 6-keto PGF1 alpha and 51Cr-labelled platelet accumulation in the thorax have been evaluated in the guinea-pig. Administration of collagen induced a dose-related peripheral thrombocytopenia and a concomitant increase in 51Cr-labelled platelets in the thorax. There was also a transient dose-related increase in plasma TxB2 but no change in plasma 6-keto PGF1 alpha levels. The thromboxane synthetase inhibitors tested, reduced the platelet accumulation, but only CGS 13080 significantly inhibited TxB2 production. In contrast all the cyclooxygenase inhibitors tested impaired the elevation of plasma TxB2 after collagen, but only diclofenac inhibited the 51Cr-labelled platelet accumulation. The greater effect of thromboxane synthetase inhibitors compared to cyclooxygenase inhibitors on platelet accumulation in this system cannot be completely explained by the changes measured in the circulating prostanoids.

Captopril enhances aminoglycoside nephrotoxicity in potassium-depleted rats

We demonstrated that potassium depletion significantly increased gentamicin nephrotoxicity in Sprague-Dawley rats (100 mg X kg-1 X day-1). To determine whether this enhanced toxicity was mediated by renin secretion, we evaluated the effect of a converting enzyme inhibitor in this model. When we administered the combination of captopril (100 mg X kg-1 X day-1) and gentamicin in potassium-depleted rats, we observed a surprising and significant adverse effect of this combination on the clearances of inulin (CIn) and PAH (CPAH) and renal blood flow (RBF). Pretreatment with indomethacin significantly improved CIn and CPAH, and potassium repletion abolished this effect entirely. In potassium-depleted animals that received both gentamicin and captopril, the intra-arterial administration of imidazole, a thromboxane synthetase inhibitor, significantly reduced urinary TXB2 excretion and significantly improved RBF and CIn in vivo. In the same group of animals, administration of the kallikrein antagonist aprotinin also significantly increased both RBF and CIn. To measure total renal thromboxane B2 production (TXB2), we perfused kidneys ex vivo with cell-free perfusate. Three groups of animals were studied: potassium-repleted control animals, potassium-depleted control animals, and potassium-depleted animals treated with gentamicin alone, captopril alone, or the combination of gentamicin and captopril. We measured TXB2 in renal venous effluent by radioimmunoassay. Ex vivo perfused kidneys from potassium-depleted control animals produced significantly more TXB2 than potassium-repleted controls. Kidneys from potassium-depleted animals that received both gentamicin and captopril produced significantly greater amounts of TXB2 than did kidneys from potassium-depleted animals treated with captopril alone, gentamicin alone, or control potassium-depleted kidneys. The administration of imidazole ex vivo at a rate equivalent to in vivo administration (10 microM/min) reduced TXB2 production by potassium-depleted kidneys that received the combination of gentamicin and captopril to that of potassium-repleted control kidneys. These results suggest that the deleterious effect of captopril in potassium-depleted rats that received gentamicin is due at least in part to kinin-stimulated renal TXB2 production.

Inhibition of platelet aggregation and thromboxane production by pinacidil

We examined the effects of pinacidil on in vitro platelet function and arachidonic acid metabolism. Pinacidil is an arterial vasodilator currently undergoing clinical trials. Although its mechanism of action is yet undetermined, there is evidence that the activity of other vasodilators may in part be mediated through their effects on arachidonic acid metabolism. Alterations in platelet function were investigated by measuring ADP-induced aggregation in aliquots of human platelet rich plasma that were preincubated with pinacidil. Changes in arachidonic acid metabolism were determined using washed platelets incubated with 14C labeled arachidonic acid after preincubation with pinacidil or indomethacin. The arachidonate metabolites formed were extracted, separated by thin layer chromatography and quantitated via liquid scintillation spectrometry. Pinacidil inhibited platelet aggregation in a concentration dependent manner with 94% inhibition at 0.005M pinacidil. Pinacidil also caused concentration dependent inhibition of TXB2 production (63% inhibition at 0.01M) with reciprocal increases in PGE 2 and PGF 2α production. There was no significant alteration in arachidonic acid utilization. Indomethacin (0.01M), as expected, inhibited TXB 2 as well as PGE 2 and PGF 2α synthesis. We conclude that, under the conditions of our assay, pinacidil inhibits platelet aggregation and specifically inhibits thromboxane synthetase, an action different from that of indomethacin. Alterations in the relative synthesis of vasodilating and vasoconstricting prostaglandins may be one mechanism whereby pinacidil exerts its antihypertensive activity.

Enhancement of the antiaggregatory activity of prostacyclin by propranolol in human platelets.

The beta-adrenergic antagonist propranolol has been found to inhibit platelet aggregation. We investigated the possibility that propranolol exerts this action by stimulating the synthesis or enhancing the antiaggregatory activity of prostaglandin (PG) I2. The media from cultures of human endothelial cells inhibited thrombin-induced platelet aggregation, an effect attributed to PGI2 production by the cells. When endothelial cells were incubated with dl- or d-propranolol, the media had two to three times the inhibitory activity of control media. However, this increased activity was not due to increased synthesis of PGI2 because control and propranolol-treated cultures synthesized similar amounts of the PGI2 metabolite, 6-keto-PGF1 alpha. Instead, propranolol enhanced the antiaggregatory activity of PGI2. Propranolol (1 microM) and PGI2 (0.05 nM), when tested separately, inhibited aggregation by 19% and 13%, respectively, whereas the combination inhibited aggregation by 51%. PGI2 inhibited platelet aggregation and thromboxane (Tx) B2 production but stimulated cyclic AMP formation. The adenyl cyclase inhibitor 2',5'-dideoxyadenosine (DDA) had no effect of its own on these parameters, but blocked the actions of PGI2. Propranolol inhibited aggregation and TxB2 synthesis without changing cyclic AMP levels. Unlike PGI2, propranolol's effects were not altered by DDA. While the combination of propranolol and PGI2 inhibited aggregation to a greater extent than either agent alone, this enhanced effect with the combination did not extend to TxB2 or cyclic AMP production. Propranolol, PGI2, and the combination inhibited TxB2 synthesis to a similar extent, and PGI2 produced a similar increase in cyclic AMP in the presence and absence of propranolol. These findings indicate that propranolol and PGI2 inhibit platelet aggregation through cyclic AMP-independent and dependent mechanisms, respectively. While propranolol does not alter the synthesis of PGI2, it enhances the inhibition of aggregation by PGI2, and this may contribute to its antiplatelet effect.

Experimental coronary artery thrombosis in the absence of thromboxane A2 synthesis: evidence for alternate pathways for coronary thrombosis.

The actions of the thromboxane synthetase inhibitor, U-63557A, were evaluated in vivo in anesthetized open-chest dogs by inducing left circumflex coronary artery (LCCA) thrombosis with low amperage electrical stimulation (100 microA for 6 h) of the intimal surface of the vessel, and ex vivo by assessing platelet aggregation and TXB2 production. U-63557A, 10 mg/kg + 5 mg/kg/h i.v., reduced ex vivo platelet aggregation in response to arachidonic acid (0.65 mM) by 93 +/- 2% (p less than 0.05, means +/- SEM), whereas the concurrent formation of TXB2 was decreased by 78 +/- 8% (p less than 0.05). TXB2 concentration also was reduced significantly in vivo as measured from coronary sinus blood samples; however, 6-keto-PGF1 alpha concentration was unchanged from predrug values. Despite the significant inhibition of platelet aggregation and TXB2 production, thrombus mass was not reduced: control, 32.0 +/- 5.9 mg (n = 7); U-63557A, 30.8 +/- 12.0 mg (n = 5, p = NS). These results suggest that U-63557A effectively inhibits TXA2 synthetase, but lacks antithrombotic activity in our experimental model. Therefore, substances other than TXA2 may be capable of mediating occlusive coronary artery thrombosis.

Immunoreactive thromboxane B 2 and 6-keto-prostaglandin F 1α in neonatal hyperbilirubinemia

To study the effects of hype rbilirubinemia on platelet thromboxane A 2 (TxA 2) and vascular prostacyclin (PGI 2) production in newborn infants, the stable metabolites of these prostanoids, thromboxane B 2 (TxB 2) and6-keto-prostaglandin F(6-keto-PGF 1α),respectively, were studied in 1α hyperbilirubinemic (serum total bilirubin concentrations between 100 and 320 μmol/1) term infants before and after phototherapy at the age of 2–10 days. The effect of bilirubin on platelet TxA 2 production was also determined in vitro . The production of TxB 2 during spontaneous clotting in infants with moderate hyperbilirubinemia (serum total bilirubin 171–250 μmol/1) was higher than that in infants with mild (serum bilirubin 100–170 μmol/1) or marked (serum bilirubin >250 μmol/1) jaundice. There was, in addition, an inverse correlation (r= −0.625, p<0.01, n=20) between TxB 2 formation and serum total bilirubin concentrations in infants with total bilirubin concentrations over 170 μmol/1. Platelet TxB 2 production was enhanced at low (200 pmol/1), but decreased at high (400–1600 μmol/1) concentrations of bilirubin in vitro . Although phototherapy reduced the serum bilirubin levels, it did not change the TxB 2 generation. Neither hyperbilirubinemia nor phototherapy had any effect on the plasma 6-keto-PGF 1α levels. The results indicate a dual effect of bilirubin on the TxA 2 production in neonatal platelets. This may contribute to the hemostatic disturbances in neonatal hyperbilirubinemia.

Production of prostacyclin (PGI2) and thromboxane A2 (TXA2) by vessels draining and not-draining benign and malignant tumours of the breast

The production of PGI2 (determined by bioassay) and TXB2 (determined by radioimmunoassay) was studied in the supernatant solutions obtained after incubation of vessel rings prepared from veins draining and not draining benign and malignant tumours of the breast. A significant increase (p < 0.01) was found in the production of PGI2 by vessels draining the malignant tumours as compared to those not draining such tumours or vessels draining benign tumours. The changes in PGI2, and the tendency for TXB2 to be higher in vessels draining malignant tumours, were in the same direction so that they balanced out when the ratio PGI2/TXB2 was calculated: in consequence no significant changes in this ratio were found in malignant tumours as compared to the benign. A significant difference (p < 0.01) was observed in the ratios of vessels draining tumours:vessels not draining tumours between malignant and benign tumours in relation to the production of PGI2. The present data demonstrate that the production of PGI2 by vessels draining malignant tumours of the breast is different to that obtained with vessels from patients with benign tumours, although the mechanism responsible for this difference is not known.

Ｅｌａｓｔａｓｅの血小板凝集および血小板アラキドン酸代謝に及ぼす影響について

We studied ex vivo and in vitro effects of elastase on platelet aggregation and its arachidonic acid (AA) metabolism in normal aubjects. Aggregation of platelets in citrated plasma (PRP aggregation) and of washed platelets were nephelometrically studied and whole blood aggregation by the impedance method was also determined. Elastase showed the significant inhibitory effects on PRP aggregation induced by collagen (0.5μg/ml) and AA (increase in its threshold concentration) as well as on whole blood aggregation by collagen (2.0μg/ml) after its oral administration of 10, 800 units per day for a week in 8 volunteers. Plasma prostacyclin-regenerating activities were not affected throughout. In in vitro experiments, elastase inhibited washed platelet aggregation induced by AA, collagen and thrombin, and PRP aggregation induced by ADP, epinephrine and STA2 (a stable analog of thromboxane A2) was also inhibited. Elastase decreased TX B2 production by platelets incubated with collagen or thrombin as measured by a radioimmunoassay, but failed to inhibit its production by exogenous AA.Thus, it was demonstrated that elastase inhibited platelet aggregation in certain conditions ex vivo as well as in vitro and its mechanism seemed to be due to some inhibitory effects on the platelet membrane rather than through the inhibition of cyclo-oxygenase activities.

Platelet Suruival and Function in Rats with Enhanced Thrombotic Tendency

We have investigated the relevance of some laboratory tests of platelet function in predicting conditions of thrombotic tendency. For this purpose, we studied platelet survival, platelet aggregation in response to different stimuli, TxB2 and 6-keto-PGF1 alpha production in serum of rats bearing a nephrotic syndrome induced by adriamycin. These animals show a heavy predisposition to the development of both arterial and venous thrombosis. The mean survival time was normal in nephrotic rats in comparison to controls. As to aggregation tests, a lower aggregating response was found in ADR-treated rats using ADP or collagen as stimulating agents. With arachidonic acid (AA) we observed similar aggregating responses at lower AA concentrations, whereas at higher AA concentrations a significantly lower response was found in nephrotic rats, despite their higher TxB2 production. Also TxB2 and 6-keto-PGF1 alpha levels in serum of nephrotic rats were significantly higher than in controls. No consistent differences were found in PGI2-activity generated by vessels of control or nephrotic rats. These data show that platelet function may appear normal or even impaired in rats with a markedly increased thrombotic tendency. On the other hand, the significance of high TxB2 levels in connection with mechanisms leading to thrombus formation remains a controversial issue.

Studies on ovarian prostaglandin production in relation to ovulation in the rat.

Prostaglandin (PG) and thromboxane (TX) synthesizing capacities of the rat ovary were measured at 4-h intervals during the 4-day oestrous cycle of the rat. Production of PGE-2, PGF-2 alpha, 6-oxo-PGF-1 alpha and TXB-2 increased 5-fold, 1.6-fold, 1.7-fold and 1.7-fold, respectively, between 18:00 h on the day of pro-oestrus and 02:00 h at oestrus. This preferential stimulation of ovarian PGE-2 production, after the ovulatory surge of LH before ovulation, provides further evidence for the involvement of ovarian PGE-2 in ovulation in the rat. These increases in ovarian PG production were not due to differences in arachidonic acid availability, PG metabolism, or the interconversion of PGE-2 and PGF-2 alpha. In addition, the greater stimulation of PGE-2 synthesis was not due to an increase in PGH-2 to PGE-2 synthetase activity. It is concluded that the ovulatory LH surge late in the afternoon of pro-oestrus in the rat causes an increase in ovarian cyclo-oxygenase (PGH-2 synthetase) activity with the majority of the PGH-2 synthesized being directed into the PGE-2-forming pathway.

Studies on the control of prostaglandin production by the hypothalamus in relation to LH release in the rat.

Prostaglandin (PG) and thromboxane (TX) synthesis by homogenates of the hypothalamus of rats has been measured in relation to the preovulatory surge of LH. Prostaglandin and TX production by the median eminence (ME) was five to ten times higher than that by the anterior hypothalamus/preoptic area (AH-POA). Prostaglandin E2 and PGF2 alpha were the major prostaglandins synthesized by the ME and AH-POA respectively. During the 4-day oestrous cycle, the PG- and TX-synthesizing capacity of the ME showed daily changes, being high at 06.00 and 22.00 h and, with the exception of pro-oestrus, low at 18.00 h. There was an additional peak of PGE2 production by the ME at 18.00 h on pro-oestrus coincident with the preovulatory LH surge. Progesterone treatment stimulated PGE2 synthesis by the ME of long-term ovariectomized, oestradiol-primed rats but not by the ME of acutely ovariectomized, oestradiol-primed rats. 2-Hydroxyoestradiol had no effect on PG and TX production by the ME at 18.00 h on dioestrus or 18.00 h on pro-oestrus. Noradrenaline stimulated PG and TX synthesis by the ME at the former time but not at the latter time. Prostaglandin F2 alpha-synthesizing capacity of the AH-POA peaked at 22.00 h on each day of the 4-day cycle. There was also an additional peak at 14.00 h on each day except dioestrus. Similar peaks occurred in the production of PGE2 and TXB2, except on pro-oestrus when the production of each compound remained low. There was no association between increased PGE2 production by the AH-POA and the preovulatory surge of LH. Noradrenaline, but not 2-hydroxyoestradiol, stimulated PG and TX production by the AH-POA at 18.00 h on both dioestrus and pro-oestrus. Progesterone stimulated PGE2, PGF2 alpha and 6-oxo-PGF1 alpha production by the AH-POA of acute, ovariectomized, oestradiol-primed rats but not of long-term ovariectomized, oestradiol-primed rats. Flurbiprofen, a cyclo-oxygenase inhibitor, prevented the preovulatory LH surge in two rats and delayed the LH surge by 2 h in four rats. It also reduced PG and TX production by the ME and AH-POA. Overall, the present studies show that there is an increase in PGE2-synthesizing capacity of the ME at the time of the preovulatory LH surge in the rat, and that the administration of an inhibitor of prostaglandin synthesis interferes with the timing of the LH surge.

Production of prostacyclin, 6-keto-PGF1α and thromboxane B2 by incubated samples of umbilical vessels: A comparison of methods for expressing the reults on dry weight, wet weight, protein or DNA bases

The production of PG12 (determined by abioassay), and of 6-keto-PGF1α and TXB2 (determined by radioummunoassay) by samples of human umbilical vessels have been measured. The results have been calculated on four bases: dry weigt, wet weight, protein and DNA. There was a higher production of PG12 and 6-keto-PGF1α by umbilical veins than by umbilical arteries; no significant difference in TXB2 production was observed between umbilical veins and arteries. The ratio of 6-keto-PGF1α: TXB2 production was about 100 for the samples of veins and about a40 for the samples of arteries. The best methods of expressing the results were on the bases of protein and DNA, the latter basis being marginally the best. The least satisfactory method for expressing the results was that based on dry weight. The physiological and practical implications of the results are discussed.

Production of prostaglandins and thromboxane by isolated cells from intracranial tumours.

Tumour cell-rich platelet-free preparations were isolated from 21 fresh samples of human intracranial tumours using enzymic digestion, followed by discontinuous density gradient centrifugation on Percoll and (14 preparations) adherence on plastic. Of the disaggregated cells 79.8 to 97.7% (mean 86.2%) were tumour cells, and mean cell viability was 82.6%. All the tumours produced prostaglandin (PG), E2, F2 alpha, 6 oxo F1 alpha and Thromboxane B2 during 16 hours of incubation but the amount varied widely. Highest production of PGE2 and TXB2 per 10(5) cells was by the eight meningiomas in which the prostanoid profile closely resembled that of circulating monocytes.

Activation of platelet prostaglandin biosynthesis pathway during neoplastic cell-induced platelet aggregation.

In a previous study we found a correlation between metastatic potential and platelet aggregating activity in sublines of a benzopyrene-induced murine fibrosarcoma ( mFS6 ); the purpose of the present work was to elucidate the role of thromboxane biosynthesis by platelets and/or by neoplastic cells in the activation of platelets in this system. The cells of the more malignant subline induced higher aggregation and TxB2 production than those of the non metastasizing one. The supernatants of aggregating cell suspensions contained very few TxB2; furthermore, preincubation of platelets with ASA or Apyrase resulted in inhibition of aggregation and TxB2 production, while preincubation of the cells was ineffective; these results suggest the platelet origin of the measured TxB2 and indicate that platelet-derived ADP plays an important role in their activation, while the production of ADP by the cells does not seem to be relevant in this model. The involvement of platelet prostaglandin biosynthesis pathway in neoplastic cell induced platelet activation could play an important role in the development of platelet-dependent tumour metastasis.