The influence of antioxidant nutrients on platelet function in healthy volunteers
Introduction
Blood platelets are important contributors to thrombosis and possibly to the development of atherosclerosis 1, 2. Once the endothelium is injured, the earliest event is the adhesion of circulating platelets to the subendothelium followed by platelet aggregation and secretion of the granule contents. During platelet activation, arachidonic acid (AA) is released from membrane phospholipids and oxygenated into different biologically active metabolites including thromboxane A2 (TXA2), a potent aggregating agent [3]. Other vasoactive molecules are released such as 5-hydroxytryptamine (serotonin), noradrenaline, ADP and ATP from the dense granules, whereas β-thromboglobulin and platelet-derived growth factor (PDGF), a mitogenic factor, are released from the α-granules. Free radicals have been involved in processes regulating platelet function 4, 5. In particular, low concentrations of lipid hydroperoxides stimulate cyclooxygenase [6]thereby leading to an increased formation of the pro-aggregatory metabolite, TXA2. On the contrary, lipid peroxides inhibit prostacyclin synthase [7], an enzyme mainly present in endothelial cells which catalyses the formation of prostacyclin (PGI2), an inhibitor of platelet aggregation [8].
The outcome of the Physicians' Health Study was that 12 years of supplementation with β-carotene produced neither benefit nor harm in terms of cardiovascular disease [9]. There is increasing evidence for the role of dietary antioxidant nutrients (namely vitamin E and vitamin C) in the prevention of initiation and development of atherosclerosis (reviewed in 10, 11, 12). However, their mechanisms of action are still under current investigation. Besides the protection of low-density lipoprotein from oxidation (reviewed in 13, 14), antioxidants act at the cellular level and may modulate some thrombotic events such as platelet aggregation. In particular, antioxidants, via their ability to reduce the formation of lipid peroxides, may decrease levels of TXA2 relative to PGI2 and thus platelet hyperactivation. It is recognised that antioxidants (namely vitamin E and vitamin C) decrease platelet aggregation in vitro 15, 16. Although supplementation of patients with vitamin E decreases platelet aggregation 17, 18, the effect of antioxidant nutrient supplementation of normal healthy subjects on platelet function is controversial.
The aim of the present study was to determine whether supplementation of healthy volunteers with either vitamin E, vitamin C or β-carotene for 56 days influence platelet function assessed by platelet aggregation induced by varying concentrations of specific agonists (ADP, collagen, arachidonic acid), platelet responsiveness to the inhibitor PGE1, β-thromboglobulin release and ATP secretion. In particular, the relationship between the levels of antioxidant nutrients and the tendency for platelets to aggregate was investigated.
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Subjects
40 healthy volunteers (24 men, 16 women) aged between 20 and 50 years (mean±S.D., 31.2±8.8) participated in the study. There were no significant differences between the four groups with respect to age, body mass index (mean±S.D., 23.6±3.7 kg/m2) and lipid profiles. Exclusion criteria included smoking, heavy drinking, consumption of antioxidant and mineral supplements, oral contraceptives, taking aspirin or specified drugs interfering with platelet functions for two weeks before the study and
Results
As previously reported [19], supplementation with 300 mg vitamin E resulted in a significant increase of plasma α-tocopherol (+69%, 20.6±1.7→34.9±3.3 μM, P<0.001) or α-tocopherol/cholesterol ratio (4.25±0.43→7.60±0.89 μM, P=0.001) compared with placebo. Vitamin C supplementation (250 mg) led to a 26% increase of plasma mean ascorbic acid level (65.2±6.3→81.8±4.2 μM, P=0.001) whereas ingestion of 15 mg β-carotene increased plasma β-carotene by 253% (0.84±0.12→3.07±0.35 μM, P<0.001). There were
Discussion
Although it is well established that vitamin E inhibits platelet aggregation in vitro 15, 25, 26, 27, 28, platelet adhesion in vivo [29]and also the platelet release reaction [30], reports on the effect of vitamin E supplementation on normal healthy subjects on platelet function in vivo, have been controversial and at best variable. The results of this double-blind, randomised, placebo-controlled trial with detailed examination of platelet responses to agonists and an antagonist provide
Acknowledgements
The authors thank the Ministry of Agriculture, Fisheries and Food for financial support for this project. The authors gratefully acknowledge Roche Nicholas, Geneva for providing the supplements and Roche Nicholas, Welwyn for monitoring the trial. We are grateful to the participants for their cooperation and to Dr Vimala Gopinathan and Ms Sally Brett for clinical assistance.
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Present address: INSERM U 352 (affiliated to CNRS), Biochimie et Pharmacologie, INSA-Lyon, Villeurbanne, France.