Several agents inhibit thromboxane synthesis in platelets so might be expected to modulate the arachidonate- induced platelet release reaction and the platelet aggregation that accompanies it. Such agents include the nonsteroidal anti-inflammatory agents (NSAIAs) that inhibit cyclo-oxygenase activity, the selective inhibitor of thromboxane synthetase UK-34787, and dipyridamole. We have assessed their influence on the ability of platelets to convert arachidonate to malondialdehyde (MDA, a marker of thromboxane synthesis) and on the arachidonate-induced release reaction (release of 14C-serotonin from labelled platelets. Platelets from different individuals respond differently to some of these agents. Whereas similar concentrations of each of acetylsalicylic acid, indomethacin, flurbiprofen and tolmetin were required to inhibit MDA production in platelets from different donors, higher concentrations of these NSAIAs were sometimes required to inhibit the arachidonate-induced release reaction in platelets from some donors than were required in platelets from others. UK-34787 inhibited both MDA production and the release reaction in platelets from some donors, but in platelets from others it had little effect on release despite inhibiting MDA generation. Dipyridamole was more effective as an inhibitor of the platelet release reaction in platelets that were responsive to UK-34787 than in platelets that were not. These different effects of agents on platelets from different individuals might be relevant to their effectiveness in thromboembolic disease. Perhaps participants in clinical trials should be stratified according to the responsiveness of their platelets to the particular drugs under scrutiny.
1. Drugs that cause vasodilatation tend to inhibit platelet behaviour whereas compounds that cause vasoconstriction stimulate platelet behaviour. Thus there appears to be a similarity between platelet behaviour and vascular tone. To investigate this relationship we have compared the maximum vasoconstrictor response in the forearm induced by cold stimulation with some aspects of platelet behaviour. 2. In 26 normal volunteers there was a close correlation between the maximum vasoconstrictor response to cold and the threshold concentration of sodium arachidonate that was needed to induce platelets from each individual to aggregate and to undergo a release reaction (r = 0.774, P<0.001). 3. Infusion of epoprostenol (prostacyclin) in five volunteers altered both the maximum vasoconstrictor response to cold and the threshold concentration of sodium arachidonate needed to induce platelet aggregation in a manner parallel to this relationship.
1. The intracellular free calcium concentration ([Ca2+]i) in washed human platelets was measured using the fluorescent indicator, fura-2, in a cross-sectional study of 36 normotensive, primigravid volunteers, 12 in each trimester of pregnancy and a further 12 at 6 weeks post partum. The results were compared with those obtained from 30 normal female volunteers not using oral contraception. 2. The mean basal [Ca2+]i in the platelets of the pregnant women in the first two trimesters (115.6 ± 6.7 and 120.1 ± 5.7 nmol/l, respectively) was not shown to differ significantly from that of normal non-pregnant volunteers (112.3 ± 2.9 nmol/l). However, during the third trimester a significant increase in [Ca2+]i was noted (134.0 ± 4.9 nmol/l; P < 0.05), with a return to normal values in the post-partum period (108.2 ± 6.1 nmol/l). 3. [Ca2+]i was also measured in the platelets of a group of 12 primigravid pregnant women in the third trimester whose pregnancies were complicated by gestational hypertension (pregnancy-induced hypertension and preeclampsia). A significant rise in basal [Ca2+]i was noted in the platelets of primigravidae whose pregnancies were complicated by pre-eclampsia (163.6 ± 8.8 nmol/l) as compared with normotensive, third-trimester primigravidae (P < 0.02). However, no correlation could be demonstrated between [Ca2+]i and systemic blood pressure.
The effects of different regimens of 40 mg aspirin on platelet thromboxane A2 synthesis and vascular prostacyclin synthesis were determined in patients who were undergoing elective surgery for removal of varicose veins. Aspirin 40 mg taken at intervals of 48 hours consistently reduced platelet thromboxane A2 synthesis to a level at which it failed to support platelet aggregation and the associated release reaction. This effect lasted for at least 36 hours. In contrast, aspirin 40 mg every 72 hours did not have the same consistent effect. Both dose regimens led to a reduction in vascular prostacyclin synthesis 12 hours after the last dose, but 36 or 72 hours after the last dose prostacyclin synthesis was not reduced; thus the inhibition of prostacyclin synthesis was short lived. If the balance between platelet thromboxane A2 and vascular prostacyclin synthesis is important in thrombosis 40 mg aspirin every 48 hours may have the maximum antithrombotic effect.
Ten patients with psoriasis resistant to conventional topical treatment were given dietary supplements of fish oil, providing approximately 12 g of eicosapentaenoic acid daily for a period of at least 6 weeks. In eight patients there was a modest improvement in their psoriasis, the principal effects being a diminution of erythema and scaling. The dietary treatment resulted in a substantial inhibition of leukotriene B4 production by the peripheral blood polymorphonuclear leukocytes in vitro. The discrepancy between the high degree of inhibition of leukotriene B4 synthesis and the modest therapeutic effect suggests that leukotriene B4 is not the only mediator involved in the development of the psoriatic lesion. Furthermore, the in vivo cutaneous levels of leukotriene B4 might not have been inhibited to the same extent as the polymorphonuclear leukocyte levels in vitro. Further studies on the use of fish oil supplements, both on their own and in conjunction with other forms of treatment in psoriasis are warranted. It will also be important to determine whether the altered profile of 5-lipoxygcnase products found in the blood is also seen in the skin.
1 A quantitative comparison has been made of the abilities of acetylsalicylic acid, flurbiprofen and indomethacin to inhibit the adenosine diphosphate (ADP)-induced platelet release reaction and to inhibit the synthesis of prostaglandins from arachidonic acid. 2 Experiments were carried out on human platelets that had been incubated with the agents in vitro and on platelets obtained from volunteers who had ingested standard doses of the drugs. 3 The results obtained for acetylsalicylic acid show that there is a close relation between the release reaction and the synthesis of prostaglandins in platelets. 4 Flurbiprofen and indomethacin appear to inhibit the release reaction rather more effectively than they inhibit the synthesis of prostaglandins. It is possible that these agents inhibit the release reaction by another mechanism.
Abstract Blood platelet behaviour was studied in six patients during infusion of an Intralipid-based intravenous feeding mixture. Lower concentrations of sodium arachidonate were required to induce platelets to aggregate and to undergo a release reaction during intravenous feeding than were required before or after intravenous feeding. This change was not due to a change in serum albumin level. The platelet behaviour that was induced by adenosine diphosphate or by adrenaline remained unchanged during intravenous feeding.
This study vas undertaken to determine if there was a dose of oral aspirin that would inhibit platelet cyclooxygenase but that had no effect on venous cyclo-oxygenase. Varicose veins were surgically removed from 68 patients of whom 21 had taken no medicines pre-operatively. Three groups of patients took aspirin 300 mg 14 hours (n=10), 24 hours (n=10) and 48 hours (n=9) pre-operatively. Two other groups took 40.5 mg (n=9) and 81 mg (n=9) 14 hours preoperatively. Two 6 mm discs of venous tissue were incubated with plasma that contained 1 mM sodium arachidonate (NaAA) and the anti-aggregatory activity of the plasma was compared with that of synthetic PGI2 in aspirinised citrated PRP challenged with ADP. PGI2 production in this procedure was confirmed by specific radio-immunoassay for 6-keto PGF1α. All doses of aspirin except 40.5 mg markedly inhibited PGI2 synthesis. Little recovery was seen with 300 mg at 48 hour post-drug. Five normal volunteers took aspirin 300 mg and 5 others 40.5 mg. Citrated PRP was prepared immediately before, 2, 24, 48, 96 and 192 hours after ingesting the drug. The amount of malondialdehyde (MDA, a marker for thromboxane synthesis) that was produced when 1 mM NaAA was added, was markedly reduced compared to the control at 2 and 24 hours by both 40.5 mg and 300 mg and thereafter it returned slowly to control values. This study indicates that 40.5 mg of aspirin inhibits platelet cyclo-oxygenase but not vessel wall cyclo-oxygenase.
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