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(Circulation. 2002;105:e53.)
© 2002 American Heart Association, Inc.
Correspondence |
Synergism Among Flavonoids in Inhibiting Platelet Aggregation and H2O2 Production
Institute of Clinical Medicine I, University La Sapienza, Rome, Italy
Department of Experimental Medicine and Pathology, University La Sapienza, Rome, Italy
To the Editor:
In vitro and in vivo studies carried out by Freedman et1 demonstrated that purple grape juice inhibits platelet aggregation and production of superoxide anion and increases the platelet formation of nitric oxide. These findings are of potential relevance for explaining the cardioprotective effect of grape juice and red wine. The authors sought also to investigate the mechanism by which grape juice inhibits platelet function and observed a consistent difference in terms of platelet inhibition among the 5 fractions of grape twice containing flavonoids. We agree with the authors that flavonoids, which are constituent of both red wine and grape juice, contribute to inhibiting platelet activity, but there are some issues that merit consideration.
The first point is to determinate whether one or more flavonoids contribute to the antiplatelet effect of red wine or grape juice. Assuming that only one flavonoid inhibits platelet function is not realistic because the concentration of flavonoids in human circulation is low. Surprisingly, there are no data of flavonoids concentration in human circulation after assumption of red wine, but taking into account other sources, such as onions or tea, the plasma concentration would range from 0.6 to 13 µmol/L.2,3 Assuming a similar range of concentration after ingestion of red wine or grape juice, it is difficult to imagine that one flavonoid contributes to platelet inhibition. Indeed, Freedman’s study and others4 demonstrated in vitro that much higher concentrations, for instance of quercetin or resveratrol, are necessary for inhibiting platelet function.
On the basis of these considerations, we combined in vitro 2 flavonoids, namely quercetin and cathechin, and demonstrated that they are synergistic in reducing platelet formation of H2O2 and inhibiting platelet function by interfering with the activation of phospholipase C pathway.5 As this effect was observed with concentrations of quercetin and cathechin (5 µmol/L and 25 µmol/L, respectively) close to those potentially achievable in blood after wine assumption, we believe that the concept of synergism among the flavonoids could help explain the antiplatelet activity of red wine and grape juice in vivo. In this regard, it is crucial that future studies with red wine or grape juice provide information on flavonoid bioavailability and its relationship with antioxidant activity and platelet function.
References
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Freedman JE, Parker C3rd, Li L, et al. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. 2001; 103: 2792–2798.
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Janssen PLTMK, Mensink RP, Cox FJJ, et al. Effect of the flavonoids quercetin and apigenin on hemostasis in healthy volunteers: results from an in vitro and dietary supplement study. Am J Clin Nutr. 1998; 67: 255–262.[Abstract]
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Pietta P, Simonetti P, Gardana C, et al. Relationship between rate and extent of catechin absorption and plasma antioxidant status. Biochem Mol Biol Int. 1998; 46: 895–903.[Medline]
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Pace-Asciak CR, Hahn S, Diamandis EP, et al. The red wine phenolics trans-resveretrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta. 1995; 235: 207–219.[CrossRef][Medline]
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Pignatelli P, Pulcinelli FM, Celestini A, et al. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Am J Clin Nutr. 2000; 72: 1150–1155.
[Abstract/Free Full Text]
Response
Boston University School of Medicine, Boston, Mass
The findings from our study1 are in agreement with the main comments of Violi and colleagues. A central message of this study1 is that one isolated flavonoid is not responsible for the antioxidant and platelet inhibitory effects that we reported. This is clear from the failure of any single flavonoid group to cause the same effects as the purple grape juice either in vitro or ex vivo. As we were not sure what the relevant flavonoids were, it was difficult to measure specific flavonoids from the subjects who drank the juice. However, we do not believe that the quercetin or resveratrol are the main substances responsible for the platelet inhibitory or nitric oxide–releasing effects. Although previous studies have shown that, in vitro, flavonoids including quercetin, resveratrol, and catechin inhibit platelet aggregation,2 the physiological relevance of these findings has been questioned in humans because oral supplementation with quercetin causes markedly increased plasma levels but does not alter total, LDL, or HDL cholesterol levels or change thrombogenic markers including platelet aggregation and platelet thromboxane B2 production.3 However, Violi and colleagues are correct that flavonoid levels would have provided useful information especially as a point of comparison with the antioxidant levels measured from the plasma of subjects who consumed purple grape juice.
References
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Freedman JE, Parker C3rd, Li L, et al. Select flavonoids and whole juice from purple grapes inhibit platelet function and enhance nitric oxide release. Circulation. 2001; 103: 2792–2798.
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Pace-Asciak C, Hahn S, Diamandis E, et al. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: implications for protection against coronary heart disease. Clin Chim Acta. 1995; 235: 207–219.
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Conquer J, Maiani G, Azzini E, et al. Supplementation with quercetin markedly increases plasma quercetin concentrations without effect on selected risk factors for heart disease in healthy subjects. J Nutr. 1998; 128: 593–597.
[Abstract/Free Full Text]
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