© 1995 American Heart Association, Inc.
Articles |
Platelet Rebound Effect of Alcohol Withdrawal and Wine Drinking in Rats
Relation to Tannins and Lipid Peroxidation
From the INSERM, Unit 63, Lyon-Bron (J.-C.R., S.R.), and SICAREX, Villefranche/Saône, (J.-L.B.), France.
Correspondence to Serge C. Renaud, INSERM, Unit 63, 22, Ave Doyen Lépine, Case 18, 69675 Bron Cedex, France.
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Abstract |
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Abstract We investigated in rats fed a purified diet for 2 and 4 months whether wine drinking was associated with the rebound effect on thrombin-induced platelet aggregation observed after alcohol withdrawal. With 6% ethanol drinking or its equivalent in red or white wine, platelet aggregation was reduced similarly by 70% when the animals drank the alcoholic beverages up to the venipuncture. Depriving the rats of alcoholic beverages for 18 hours was associated with an increase in the platelet response of 124% in those receiving 6% ethanol, of 46% with white wine but a decrease of 59% in those with red wine. The protective effect of red wine on platelets could be reproduced by tannins (procyanidins) extracted from grape seeds or red wine and added to 6% ethanol, but not by glycerol or wine without alcohol. That was related to inhibition of the alcohol-induced lipid peroxidation as shown by the lowering of conjugated dienes, lipid peroxides, and the increase in vitamin E in plasma. Owing to tannins, the platelets of rats drinking red wine did not exhibit the rebound effect observed hours after alcohol drinking, eventually associated with sudden death and stroke in humans.
Key Words: alcohol • lipid peroxidation • platelet aggregation • tannins • wine
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Introduction |
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Alcoholic beverages have been associated with protective effects against coronary heart disease (CHD) in a large number of ecological, case-control, and prospective studies.1 St Leger et al2 have postulated that this protective effect could be due essentially to wine. It has been further confirmed that wine drinking may eventually explain at least part of the French paradox, ie, a low mortality rate from CHD despite a high consumption of saturated fat3 and smoking habits similar to those of other countries.4 In a recent large prospective study, it has been shown that wine preference was associated with a 30% to 40% lower risk for CHD death compared with liquor or beer.5 Perhaps even more surprising, for oropharyngeal cancers6 a moderate intake of wine in both men and women was related to a protective effect of 20% to 50% that was not shared by other alcoholic beverages.
Wine, in addition to alcohol, contains glycerol and tannins. In tannins, there are powerful antioxidants such as resveratrol and polyphenols (procyanidins).7 The phenolic substances have been shown recently to protect low-density lipoprotein (LDL) from peroxidation in vitro more effectively than vitamin E.8 Because peroxidized lipoproteins could be the main atherogenic lipoproteins,9 the antioxidant effects of wine combined with the high-density lipoprotein (HDL) cholesterol–promoting effect of alcohol10 may offer an explanation for the apparent advantages of wine.
In addition to its effect on lipoproteins, alcohol has been shown to impede all tests of platelet aggregation after infusion or ingestion in humans,11 especially secondary aggregation to ADP.12 13 In a recent study on 1600 subjects in Caerphilly,14 primary and secondary aggregation to ADP were inhibited in a dose-related manner, to the same degree and by the same level of alcohol consumption3 known to protect against CHD.15 By contrast, there was a 1.5-fold to threefold increase in thrombin-induced aggregation, depending on the level of alcohol and fat consumption.14 Although the primary effect of alcohol is to decrease aggregation to thrombin, as shown in humans11 and in rats,16 the alcohol-withdrawal rebound effect has been described in alcoholic subjects17 and is associated with increased risk of thrombosis, sudden death, and stroke.18 The subjects from Caerphilly14 were not alcoholics but were consumers of primarily beer and spirits who had been deprived of food and alcohol for at least 12 hours when platelet reactivity was examined. Because the rebound effect on thrombin-induced aggregation was not observed in French farmers19 who drank primarily wine, the purpose of the present study in rats was to determine whether wine drinking was associated with the rebound effect on thrombin-induced aggregation that has been observed with alcohol drinking. Our results showed that enhanced platelet aggregation was not observed in rats drinking wine, after withdrawal. This protection of wine against the platelet rebound effect associated with alcohol drinking seems to be due essentially to the tannins it contains, which counteract the lipid peroxidation associated with alcohol drinking.
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Methods |
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Animals
A total of 144 male Sprague-Dawley rats (Charles River, Cléon, France) of an initial body weight of 150 to 175 g was used for these studies. The animals were housed two per cage in a room with controlled temperature (23°C to 24°C). The animals were maintained in compliance with the INSERM policy on animal care and use, which is similar to the policy expressed in the National Research Council guidelines (NRC 1985).
Diet and Beverages
Rats were offered free access to their beverage and diet. After
being equally distributed according to body weight into four groups
(series 1 and 2) or three groups (series 3 and 4), they were given the
following purified diet ad libitum: (grams per 100 g/body wt) casein
23, vitamin diet mixture (US Biochemical Corporation [USB]) 2, salt
mixture Wesson (modification USB) 1.5, sawdust 6, sucrose 23, glucose
23, butter 21.5. This diet contained only a saturated fat because
previous studies had shown that the effect of alcohol on platelet
aggregation was observed primarily in animals16 and
men14 on a diet high in saturated fat.
In series 1 (12 rats per group, except group 4 with only 6 rats), group 1 received commercial mineral water (Volvic; [mg/L] Ca 9.9, Mg 6.1, Na 9.4, K 5.7, HCO3 65.3) only, which was also used for diluting alcohol or wine. Group 2 received a 6% ethanol solution in the same water as group 1; group 3, a red wine solution in water to obtain a 6% ethanol content; and group 4, white wine, also diluted to 6% ethanol.
In series 2 (12 rats per group), group 1 received a 6% ethanol solution in the mineral water used in series 1; group 2, red wine diluted to 6% alcohol; group 3, a 6% ethanol solution containing 0.4% glycerol; and group 4, a 6% ethanol solution containing 0.025% of a grape-seed extract.
In series 3 (6 rats per group), group 1 received a 6% ethanol solution as in series 2; group 2, a red wine solution diluted to 6% alcohol; and group 3, a phenolic extract (0.03%) of the wine used in group 2 added to a 6% ethanol solution.
In series 4 (12 rats per group), group 1 received only the mineral water; group 2, red wine diluted to 6% alcohol adjusted for its content in glycerol to the level of the wine without alcohol; and group 3, wine without alcohol diluted to the same extent as the wine with alcohol of group 2. For preservation of the wine without alcohol, a higher level of glycerol was required.
To confirm the similarity of the tannin content (polyphenol) of the red wines used and of the alcohol solutions, spectrophotometry analysis of the samples was performed at 280 nm; concentration was adjusted to obtain the same optical density of the total phenols.
Wine with and without alcohol and wine extracts, which contained the phenolic compounds of the same wine used in series 3 and 4, were obtained from Institut National de Recherche Agronomique (Pech rouge, Narbonne, France). These wines were produced from Cabernet-Sauvignon vines.
Grape-seed extracts were obtained from Centre d'Experimentation Pharmaceutique (Leognan, France; Professor J. Masquelier) using the following technique. In brief, the polyphenols (procyanidins) from white grape seeds were extracted by acetone in water (30:70, vol/vol), with the water phase saturated by NaCl to remove high-molecular tannins. After filtration, the procyanidins were extracted by ethyl acetate, precipitated by chloroform, and dried in a vacuum.
Collection of Samples
After series 1, venipuncture was performed in animals not
deprived and, 2 weeks later, in the same animals deprived of alcoholic
beverages for 18 hours but given water. All animals were in a fasting
condition. In series 2 to 4, the studies were performed only in animals
that had alcoholic beverages withdrawn for 18 hours before blood
removal and replaced by water.
Platelet Aggregation
Platelet aggregation was studied in platelet-rich plasma (PRP)
adjusted to 600 000 platelets per microliter with platelet-poor plasma
as previously described.20 Only aggregation to thrombin
(from human plasma, Sigma Chemical Co) was performed by adding 100 µL
of thrombin (0.08 U/mL PRP, final concentration) to 400 µL of PRP
diluted to 500 µL, 1 minute before adding thrombin, by incomplete
tyrode containing 148.9 mmol/L sodium chloride, 5.5 mmol/L glucose, 9.5
mmol/L sodium hydrogen carbonate, 2.7 mmol/L potassium chloride, 0.5
mmol/L sodium dihydrogen orthophosphate, and distilled water to 1000
mL, adjusted to pH 7.4, immediately before use.
Vitamin Determinations
Vitamins A and E were analyzed in plasma by high-performance
liquid chromatography (Thermo Separation Products) on a spherisorb ODS2
(100x4.6 mm) column with a 3-µm particle size (Interchim). Serum
levels of vitamin A and E were determined by a modification of the
method of Vuilleumier et al.21 Serum proteins were
precipitated by ethanol containing the internal standard (tocopherol
acetate), and serum lipids were extracted by heptane. The lipid extract
was evaporated under nitrogen, dissolved in methanol, and eluted by
methanol with a flow rate of 1.5 mL/min. Response factors were
calculated by external standardization with a mixture containing
retinol, 
-tocopherol, and tocopherol acetate standards.
Evaluation of Peroxidative Status
Serum peroxidative status was assessed by measuring
4-hydroxyalkenals and conjugated dienes.
4-Hydroxyalkenals were determined using a new kit from Bioxytech. It has been recognized that measurement of such aldehydes provides a satisfactory index of lipid peroxides. The method combines one molecule of 4-hydroxyalkenal with two molecules of reagent, yielding a stable chromophore with maximal absorbance at 586 nm.
Conjugated dienes were evaluated according to the methods of Quintanilha and Packer22 in citrated plasma and kept at -40°C for a few days until analysis.
Plasma Lipids
Plasma lipid levels were determined in citrated plasma samples
using enzymatic kits from BioMérieux for total and HDL
cholesterol, an enzymatic kit from Merck (Merckotest) for
triglycerides, and an enzymatic kit from Sigma for glycerol.
Statistical Analysis
The data were analyzed using STATVIEW 512 (Brain
Power Inc) computer program. Results are mean±SE. One-way ANOVA was
used to examine the significance assigned to P<.05.
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Results |
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At the level of 6% alcohol, all alcoholic beverages were consumed by the rats in exactly the same amount as water alone after the switch from water to alcohol even in the first 24 hours. This indicates that the animals were not reluctant to consume the alcoholic beverages they were offered.
All determinations were performed after 2 and 4 months of diet and beverage consumption. Because the results were very similar, they have been pooled in the corresponding graphs and tables.
Series 1: Effects of Drinking Alcohol and Wine
As shown in Fig 1
, when the fasted animals were not
deprived of their alcoholic beverage, thrombin-induced aggregation was
reduced at about the same rate by alcohol, red wine, and white wine. By
contrast, when the same fasted animals were deprived of their alcoholic
beverage for 18 hours, a marked rebound effect (124% increase in
response) was observed with alcohol, a moderate effect (46% increase)
with white wine, but no rebound at all with red wine because the
aggregation was still reduced by 59% compared with water.
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Concerning the plasmatic variables (Table 1),
triglycerides were significantly increased with wine but only in
animals not deprived of the alcoholic beverages, and the level of
vitamin E decreased only with drinking alcohol compared with red wine.
Conjugated dienes were significantly higher in the group drinking
alcohol.
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Series 2: Comparative Effects of Glycerol and Grape-Seed Extracts
Added to Alcohol
The main two components of red wine in addition to alcohol are
glycerol and tannins. In the present study, the tannins used were
extracted from grape seed and added to alcohol (0.025%) at
approximately the level contained in red wine as determined by
spectrophotometry. Glycerol was also added to alcohol (0.4%).
Fig 2 indicates that the inhibitory effect of red wine
on thrombin-induced aggregation can be completely reproduced by adding
the tannins extracted from grape seed to alcohol. Glycerol added to
alcohol did not appear to change the response of platelets to
aggregation observed with alcohol alone.
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Nevertheless, addition of glycerol to alcohol decreased the level of
lipid peroxides (Table 2) and increased the ratio of
vitamin E to triglycerides to about the same extent as red wine or
tannins added to alcohol. In addition, only red wine and grape-seed
extracts added to alcohol were significantly associated with a lower
level of conjugated dienes.
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Series 3: Comparative Effects of Red Wine and Wine Extracts Added
to Alcohol
The purpose of this series was to determine whether the tannins
directly extracted from wine had a similar effect in our study as the
tannins extracted from grape seeds. The results in Fig 3
indicate that tannins extracted from wine had at least the same
protective effect on platelets as the tannins from grape seeds. As
shown in Table 3, both the red wine and the wine
extracts (added to alcohol) similarly reduced the level of lipid
peroxides and conjugated dienes compared with alcohol alone.
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Series 4: Comparative Effects of Red Wine With and Without Alcohol
The aim of this study was to determine whether wine without
alcohol could have inhibitory effects on platelet reactivity and
beneficial effects on peroxidation. As shown in Fig 4,
only the wine with alcohol was associated with a decrease in platelet
aggregation compared with water. In contrast, the wine without alcohol
increased the response of platelets to aggregation, a result
significant only when compared with results of wine with alcohol.
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The only blood level variable that was different in this series (Table 4) was cholesterol, which was significantly lower in the
group receiving wine without alcohol.
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Discussion |
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The main findings of the present study in rats are that the drinking of red wine, when compared with alcohol, is not associated with the rebound effect on platelet reactivity that has been observed by several investigators in humans who drink spirits or beer.13 14 17 In humans, the platelet rebound effect in alcoholics has been attributed to parallel changes in the ratio of LDL cholesterol to HDL cholesterol.17 In the present study in rats, with somewhat moderate drinking, there was no change in the level of HDL or cholesterol, except in the group given wine without alcohol. The protective effect of red wine appears to be essentially associated with tannins (polyphenols) extracted either from grape seeds or from wine itself. This protection was related to an inhibition of the known increased lipid peroxidation observed with alcohol drinking,23 as shown here by the higher level of lipid peroxides and conjugated dienes in animals drinking alcohol compared with that of those drinking water. By contrast, the animals drinking red wine exhibited levels of lipid peroxides, conjugated dienes, and vitamin E similar to those of the animals drinking water. Nevertheless, with red wine (or tannins added to alcohol), the inhibitory effect of alcohol on platelet reactivity observed after alcohol drinking was preserved for a much longer time. This may explain why in certain studies in humans deprived of alcohol for 24 hours, only red wine was associated with inhibition of platelet reactivity.24
The present study demonstrates also that in vivo, in animals, the tannins from grapes and red wine exert antioxidant properties. Nevertheless, the sparing effect of tannins on the plasma level of vitamin E, also observed recently in France25 mostly in moderate wine drinkers, was not noted in rats drinking red wine without alcohol. In addition, the wine without alcohol was associated with a significant increase in platelet aggregability, which was not explained in the present study by the variables determined. Whether the tannins were not absorbed in the absence of alcohol, or whether the wine was altered by the process that removed alcohol, has to be investigated in further studies.
The evaluation of white wine in our study was done for only six animals and one sample of white wine. Thus, additional studies are required to evaluate more extensively the potential effect of white wine. In the present study, its effect was intermediate between that of alcohol and of red wine.
Further studies are needed also to determine which substances in tannins are responsible for their antioxidant properties. Procyanidins preserved in the extraction process used here have been shown to exert oxygen free radical scavenger capacities26 and seem to be good candidates.
The present study, if reproduced in humans, could explain at least part of the long-term advantage of red wine over other alcoholic beverages. Because higher responses of platelets to thrombin and ADP-induced aggregation have been associated with prevalent cases of myocardial infarction,27 the rebound effect associated with alcohol drinking might be related to the increased risk of binge drinkers for CHD, sudden death,28 29 and stroke.18
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Acknowledgments |
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We wish to thank Professor J. Masquelier for supplying grape-seed extract and Professors S. Brun and M. Bourzeix for the supply of wine extracts and the wine with and without alcohol used in series 3 and 4 of the present study.
Received August 9, 1994; accepted October 31, 1994.
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References |
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1. Renaud S, Criqui MH, Farchi G, Veenstra J. Alcohol drinking and coronary heart disease. In: Verschuren PV, ed. Health Issues Related to Alcohol Consumption. Washington, DC: ILSI Press; 1993:81-124.
2. St Leger AS, Cochrane AL, Moore F. Factors associated with cardiac mortality in developed countries with particular reference to the consumption of wine. Lancet. 1979;1:1017-1020. [Medline] [Order article via Infotrieve]
3. Renaud S, de Lorgeril M. Wine alcohol, platelets and the French paradox for coronary heart disease. Lancet. 1992;339:1523-1526. [Medline] [Order article via Infotrieve]
4. Renaud S, de Lorgeril M. The French paradox: diet factors and cigarette smoking-related health risks. Ann N Y Acad Sci. 1993;686:299-309. [Medline] [Order article via Infotrieve]
5. Klatsky AL, Armstrong MA, Friedman GD. Alcohol and mortality. Ann Intern Med. 1992;117:646-654.
6.
Blot WJ, McLaughlin K, Winn DM, Austin DF, Greenberg RS,
Preston-Martin S, Bernstein L, Schoenberg JB, Stemhagen A, Fraumani JF
Jr. Smoking and drinking in relation to oral and pharyngeal cancer.
Cancer Res. 1988;48:3282-3287.
7. Sharp D. Coronary disease: when wine is red. Lancet. 1993;343:27-28.
8. Frankel EN, Kanner J, German JB, Parks E, Kinsella JE. Inhibition of oxidation of human low-density lipoprotein by phenolic substances in red wine. Lancet. 1993;341:454-457. [Medline] [Order article via Infotrieve]
9. Esterbauer H, Gebicki J, Puhl H, Jürgens G. The role of lipid peroxidation and antioxidants in oxidative modification of low density lipoproteins. Free Radic Biol Med. 1992;13:341-390. [Medline] [Order article via Infotrieve]
10. Suh IL, Shaten BJ, Cutler JA, Kuller LH. Alcohol use and mortality from coronary heart disease: the role of high-density lipoprotein cholesterol. Ann Intern Med. 1992;116:881-887.
11. Haut MJ, Cowan DH. The effect of ethanol on hemostatic properties of human blood platelets. Am J Med. 1974;56:22-33. [Medline] [Order article via Infotrieve]
12. Meade TW, Vickers MV, Thompson SG, Stirling Y, Haines AP, Miller GJ. Epidemiological characteristics of platelet aggregability. Br Med J. 1985;290:428-432.
13. Mikhailidis DP, Barradas MA, Jeremy JY. The effect of ethanol on platelet function and vascular prostanoids. Alcohol. 1990;7:171-180. [Medline] [Order article via Infotrieve]
14.
Renaud S, Beswick AD, Fehily AM, Sharp DS, Elwood PC. Alcohol
and platelet aggregation: the Caerphilly prospective heart disease
study. Am J Clin Nutr. 1992;55:1012-1017.
15. Rimm EB, Giovannucci FL, Willett WC, Colditz GA, Ascherio A, Rosner B, Stampfer M. Prospective study of alcohol consumption and risk of coronary disease in men. Lancet. 1991;338:464-486. [Medline] [Order article via Infotrieve]
16. McGregor L, Renaud S. Inhibitory effect of alcohol on platelet functions of rats fed saturated fats. Thromb Res. 1981;22:221-225. [Medline] [Order article via Infotrieve]
17. Desai K, Owen JS, Wilson DT, Hutton RA. Platelet aggregation and plasma lipoproteins in alcoholics during alcohol withdrawal. Thromb Haemost. 1986;56:173-177.
18. Hillbom ME. What supports the role of alcohol as a risk factor for stroke? Acta Med Scand. 1987;717(suppl):93-106.
19. Renaud S, Dumont E, Godsey F, Supplisson A, Thevenon C. Platelet functions in relation to dietary fats in farmers from two regions of France. Thromb Haemost. 1978;40:518-531.
20. Davenas E, Ciavatti M, Nordoy A, Renaud S. Effects of dietary lipids on behaviour, lipid biosynthesis and lipid composition in rat platelets. Biochim Biophys Acta. 1984;793:278-286. [Medline] [Order article via Infotrieve]
21. Vuilleumier JP, Keller HE, Gysel D, Hunziker F. Clinical chemical methods for the routine assessment of the vitamin status in human population, I: the fat soluble vitamins A and E, and beta-carotene. Int J Vitam Nutr Res. 1983;53:265-272. [Medline] [Order article via Infotrieve]
22. Quintanilha AT, Packer L. Membrane effects of vitamin E deficiency bioenergetic and surface charge density studies of skeletal muscle and liver mitochondria. Ann N Y Acad Sci. 1982;393:32-47. [Medline] [Order article via Infotrieve]
23. Cederbaum AI. Introduction: role of lipid peroxidation and oxidative stress in alcohol toxicity. Free Radic Biol Med. 1989;7:537-539. [Medline] [Order article via Infotrieve]
24. Seigneur M, Bonnet J, Dorian B, Benchimol D, Drouillet F, Gouverneur G, Larrue J, Crockett R, Boisseau MR, Ribereau-Gayon P, Bricaud H. Effect of the consumption of alcohol, white wine and red wine on platelet function and serum lipids. J Appl Cardiol. 1990;5:215-222.
25. Leconte E, Herbeth B, Pirollet P, Chancerelle Y, Arnaud J, Musse N, Paille F, Siest G, Artur Y. Effect of alcohol consumption on blood antioxidant nutrients and oxidative stress indicators. Am J Clin Nutr. 1994:60:255-261.
26. Ricardo Da Silva JM, Darmon N, Fernandez Y, Mitjavila S. Oxygen free radical scavenger capacity in aqueous models of different procyanidins from grape seeds. J Agric Food Chem. 1991;39:1549-1552.
27.
Elwood PC, Renaud S, Sharp DS, Beswick AD, O'Brien J,
Yarnell
JWG. Ischaemic heart disease and platelet aggregation: the Caerphilly
collaborative heart disease study. Circulation. 1991;83:38-44.
28. Suhonen O, Aromas A, Reunanen A, Kneckt P. Alcohol consumption and sudden coronary death in middle-aged Finnish men. Acta Med Scand. 1987;221:335-341. [Medline] [Order article via Infotrieve]
29.
Peterson B. Analysis of the role of alcohol in mortality,
particularly sudden unwitnessed death, in middle-aged men in
Malmö, Sweden. Alcohol Alcohol. 1988;23:259-263.
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