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(Circulation. 1995;91:1182-1188.)
© 1995 American Heart Association, Inc.

Articles

Administration of Wine and Grape Juice Inhibits In Vivo Platelet Activity and Thrombosis in Stenosed Canine Coronary Arteries

Heather S. Demrow, BS; Peter R. Slane, BS; John D. Folts, PhD

From the Cardiology Section, University of Wisconsin-Madison, Madison, Wisc.

Correspondence to John D. Folts, PhD, Professor of Medicine, Director, Coronary Thrombosis Research Laboratory, University of Wisconsin-Madison, Cardiology Section, Clinical Sciences Center H6/379, 600 Highland Ave, Madison, WI 53792.

	Abstract

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Background Moderate daily consumption of alcoholic beverages is a negative risk factor for the development of atherosclerosis and coronary artery disease (CAD), especially in France and other Mediterranean areas where red wine is regularly consumed with meals. Platelets contribute to the development of atherosclerosis, CAD, and acute arterial thrombus formation.

Methods and Results Anesthetized dogs were prepared with the Folts model of mechanically stenosed coronary arteries and intimal damage. Periodic acute platelet-mediated thrombus formation occurred, causing cyclic flow reductions (CFRs) in coronary blood flow. The CFRs were eliminated by the administration of 1.62±1.12 mL/kg red wine intravenously (IV) and 4.0 mL/kg intragastrically (IG). The CFRs were abolished by 2.04±1.42 mL/kg of grape juice IV and 10 mL/kg IG. White wine did not have significant results in eliminating the CFRs, either IV (2.0 mL/kg) or IG (4.0 mL/kg), decreasing the slopes of the CFRs only slightly.

Conclusions Pure ethanol has been shown to inhibit platelet aggregation in vitro, ex vivo, and in vivo, although a blood alcohol content (BAC) of 0.2 g/dL is usually required. The BAC of dogs administered the red wine–saline solution intravenously was 0.028 g/dL, much less than is usually necessary for platelet inhibition with pure ethanol. Because red wine and grape juice, but not white wine, abolished the CFRs, this suggests there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine. Wine and grape juice contain a wide variety of naturally occurring compounds, including fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones). These compounds have shown platelet inhibition in vitro by a variety of proposed mechanisms. Perhaps the biological activity of these compounds can explain the platelet-inhibitory properties of red wine and grape juice that are observed without high levels of ethanol.

Key Words: alcohol • thrombosis • platelets

	Introduction

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The French Paradox" (as it has been publicized by both the scientific and popular news media) deals with interesting yet confusing statistics regarding the lifestyle and rate of myocardial infarction of the French people. The French eat 3.8 times as much butter and 2.8 times as much lard as Americans, and they have higher serum cholesterol levels and higher blood pressure than Americans.¹ Other risk factors for cardiovascular disease, such as body mass index and cigarette smoking, are comparable, yet Americans have a 2.5-fold greater rate of death due to ischemic (coronary) heart disease than the French.²

A number of hypotheses have been proposed to account for this paradox. The "Mediterranean diet" may play a role in explaining this paradox. The French drink very little milk and eat a large amount of fresh vegetables, fruits, and wine.^{2 3}

Autopsy, geographic, case-control, cohort, clinical, and epidemiological studies have shown that there is an inverse relation between alcohol consumption and coronary artery disease (CAD).³ Moore and Pearson³ reviewed case-control and cohort studies showing that moderate alcohol consumption reduces the risk of CAD to 0.4% to 0.7% compared with nondrinkers. Since 1986, seven separate studies have corroborated the theory of decreased CAD risk with moderate alcohol consumption.^{3 4} Because wine⁵ and alcohol consumption^{6 7 8} have been shown to decrease platelet aggregation, the cardioprotective effects of alcohol may be in part related to platelet activity.

In the past 20 years, it has become apparent that platelets contribute to the rate of development of atherosclerosis and CAD through several mechanisms.⁹ In addition, platelet-mediated thrombus formation plays a key role in unstable angina, myocardial infarction, restenosis after angioplasty, and atherectomy.^{9 10 11} One way to study the platelet-inhibitory effects of various compounds in vivo is by using an in vivo model such as the Folts coronary thrombosis model of platelet aggregation and thrombus formation.^{12 13}

Platelet-mediated thrombi periodically form in the stenosed coronary artery, followed by distal embolization. This produces cyclic reductions in measured coronary blood flow that are called cyclic flow reductions (CFRs). We have shown that the CFRs in mechanically stenosed canine arteries can be eliminated by platelet inhibitors such as aspirin or prostacyclin¹² and the nitric oxide donor sodium nitroprusside.¹⁴ We have also shown that 1.0 mL/kg of pure ethanol inhibits platelets in this model, producing an average blood alcohol content (BAC) of 0.24 g/dL.¹⁵ Preliminary studies suggested that red wine inhibited platelet activity and coronary thrombosis in vivo.¹⁶

To determine the antithrombotic, antiplatelet activity of wine, we decided to study the effectiveness of red and white wine in the Folts in vivo model. We also sought to determine if grape juice, a compound that is similar yet is without alcohol, would have a platelet-inhibitory effect. This would help to clarify the cardioprotective importance of the ethanol content of wine.

	Methods

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Forty-seven adult mongrel dogs of either sex were anesthetized as follows. We have previously shown that barbiturates, commonly used as anesthetic agents, inhibit platelet activity at plasma levels of 10^-4 mol/L.¹⁷ These levels are often achieved in animals administered 30 mg/kg of sodium pentobarbital.¹⁷ To minimize the circulating plasma levels of pentobarbital, we developed a new method of administering barbiturate anesthesia. The dogs were premedicated with 3 mg/kg morphine sulfate IM followed by 5 mg/kg of the short-acting dissociative anesthetic ketamine (Vetalar) administered intravenously. This allowed us to perform a cutdown on the brachial artery in the right front leg and advance a catheter into the brachiocephalic artery. In dogs, this artery supplies three fourths of the blood flow to the brain via the left vertebral artery. Sodium pentobarbital (5 mg/kg) given in this artery completely anesthetizes the brain and produces a plasma concentration of only 0.7 mg/dL. All subsequent pentobarbital is also given through this catheter. This produces a properly anesthetized brain but minimizes the depression of other organ systems by pentobarbital.¹⁸

After the dogs were properly anesthetized, a left thoracotomy was performed and the left circumflex coronary artery was dissected. An electromagnetic flow probe was placed around the artery to measure blood flow. The coronary artery was squeezed 2 to 3 mm distal to the flow probe with a special surgical clamp to produce intimal and medial damage. A plastic constricting occluder was then placed around the outside of that portion of the artery to produce a 70% stenosis. Blood pressure and the ECG of each animal were also monitored. When the instrumentation was in place, each dog was observed until CFRs due to platelet-mediated coronary artery occlusion were occurring at regular intervals (approximately 30 to 45 minutes).

Group 1: Red Wine
After the control period, 15 dogs were given an intravenous infusion of red wine diluted in saline. The red wine (1987 Chateauneuf-du-Pape) was 13% alcohol by volume. To determine how much red wine might be needed to eliminate the CFRs, 2 mL/kg of red wine was diluted in 200 mL of saline. The solution was then given intravenously at a rate of 20 drops per minute. The intravenous infusion was continued until all had been given or until the CFRs were abolished. When the CFRs were eliminated, the volume of the remaining wine–saline solution was measured and subtracted from the starting volume. This permitted calculation of the minimum effective intravenous dose of wine needed to abolish the CFRs as well as calculation of the exact amount of ethanol given in that amount of wine. A blood sample was taken when the CFRs were abolished or all of the wine–saline solution had been given to determine the BAC.

In addition, because wine is normally processed by the stomach after consumption, animals were instrumented as described above, except that the red wine was given directly through a gastric tube with the tip placed in the duodenum. Five dogs were administered 4 mL/kg of red wine IG. We anticipated an increase in time for gastrointestinal absorption in the anesthetized animals due to depressed gastric motility.

Group 2: White Wine
After the control period, seven dogs were administered an intravenous infusion of white wine diluted in saline. The white wine, (1990 Chateau Villotte Bordeaux) was 12% alcohol by volume. To determine how much white wine might be needed to eliminate the CFRs, 2 mL/kg of white wine was diluted in 200 mL of saline. The solution was then given intravenously at a rate of 20 drops per minute. The intravenous infusion was continued until all had been given or until the CFRs were abolished. The minimum effective dose was calculated as described for group 1. A blood sample was taken when the CFRs were abolished or all of the wine–saline solution had been given to determine the BAC.

To test the gastrointestinal absorption of white wine, five dogs were instrumented as described above and received 4 mL/kg of white wine IG.

Group 3: Grape Juice
After the control observation period, five dogs were administered an intravenous infusion of grape juice diluted in saline. The grape juice used was Welch's 100% natural purple grape juice with no sugar, artificial flavors, or colors added. To determine how much grape juice might be needed to eliminate the CFRs, 4 mL/kg of grape juice was diluted in 400 mL of saline. The solution was then given intravenously at a rate of 20 drops per minute. The intravenous infusion was continued until all had been given or until the CFRs were abolished. The minimum effective dose was then calculated as described for group 1.

In addition, animals were instrumented as described above, except that the grape juice was given intragastrically as in groups 1 and 2. Three doses of grape juice were administered: two dogs received 6 mL/kg, three dogs received 8 mL/kg, and five dogs received 10 mL/kg.

Whole-blood aggregation studies were performed on the five animals who received 10 mL/kg of grape juice by stomach tube. Blood was collected by a fresh puncture in the exposed left atrial appendage and placed in 1:10 vol of 3.2% sodium citrate. The blood was diluted 1:1 with saline and studied with a Chronolog Whole Blood Aggregometer.¹⁹ The aggregation response to collagen (Chrono-Par) before administration of the beverage was compared with the aggregation response to the same dose of collagen after the beverage.

High-Performance Liquid Chromatography Analysis
The red wine, white wine, and grape juice were analyzed by high-performance liquid chromatography analysis for two naturally occurring flavonoid compounds—quercetin and rutin—and we searched for the fungicide resveratrol by standard biochemical techniques.²⁰

All values are reported as mean±1 SD, and statistical significance expressed by P values was determined by Student's t test.

	Results

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Group 1: Red Wine
CFRs were observed during the initial observation period for all of the dogs. Elimination of the CFRs occurred in all animals with the infusion of the red wine–saline solution (Fig 1). The average time for elimination of the CFRs was 5.2±2.8 minutes. The average amount of red wine needed to inhibit platelet activity and abolish the CFRs was 1.62±1.12 mL/kg with an average alcohol content of 0.21±0.15 mL/kg. The BAC after elimination of the CFRs was 0.028±0.021 g/dL. The CFRs were abolished for approximately 1 hour, at which time the study was terminated.

View larger version (48K): [in this window] [in a new window]   Figure 1. Representative tracing of the hemodynamic effect of intravenous red wine. Top, Mean aortic blood pressure. Bottom, Blood flow in the stenosed left circumflex artery. Cyclic flow reductions were eliminated 12 minutes after the red wine–saline infusion was started. The amount of wine administered to this animal was 0.9 mL/kg.

In the five anesthetized dogs administered 4 mL/kg red wine by gastric tube, the CFRs were eliminated in all animals after an average of 113±32 minutes (Fig 2). The slopes of the CFRs during this time period decreased gradually. The average ethanol content of the red wine given was 0.52 mL/kg and produced an average BAC of 0.036±0.013 g/dL. The CFRs were abolished for approximately 1 hour, at which time the study was terminated.

View larger version (65K): [in this window] [in a new window]   Figure 2. Representative tracing of the hemodynamic effect of intragastric red wine. Top, Cyclic flow reductions before the red wine was given; shows mean aortic blood pressure and blood flow in the stenosed left circumflex artery. Bottom, Elimination of the cyclic flow reductions 90 minutes after administration of 4 mL/kg red wine; shows mean aortic blood pressure and blood flow in the stenosed left circumflex artery.

Group 2: White Wine
CFRs were observed during the initial observation period for all of the dogs. The intravenous white wine–saline infusion had an ethanol content of approximately 0.24 mL/kg and produced an average BAC of 0.020±0.006 g/dL. At this concentration, the white wine did not abolish the CFRs. The average slopes of the CFRs (in mL/min², calculated using the best-fit line through the CFR) decreased slightly from -18.96±4.95 mL/min² before the infusion to -16.26±4.13 ml/min² after the infusion, suggesting minimal inhibition of in vivo platelet activity (P=.16).

In the five dogs administered 4 mL/kg white wine by gastric tube, the CFRs were not eliminated in any of the animals (Fig 3). The average ethanol concentration of the wine–saline solution was 0.48 mL/kg and produced an average BAC of 0.024±0.015 g/dL after the administration. The slopes of the CFRs were not significantly different after intragastric administration of the white wine. The average slope of the CFRs was -18.47±3.56 mL/min² before the wine and -14.85±5.35 ml/min² (P=.09) after the intragastric administration of white wine.

View larger version (62K): [in this window] [in a new window]   Figure 3. Representative tracing of the hemodynamic effect of intragastric white wine. Top, Cyclic flow reductions before the white wine was given; shows mean aortic blood pressure and blood flow in the stenosed left circumflex artery. Bottom, Continuation of the cyclic flow reductions 90 minutes after administration of 4 mL/kg of white wine; shows mean aortic blood pressure and blood flow in the stenosed left circumflex artery.

Group 3: Grape Juice
CFRs were observed during the initial observation period for all dogs. Elimination of the CFRs occurred in 4 of the 5 animals administered the intravenous infusion of the grape juice–saline solution (Fig 4). The remaining dog showed a decrease in the slopes of the CFRs (P<.03), and spontaneous embolizations of thrombi were observed. The average time for elimination of the CFRs was 15.3±9.0 minutes. The average amount of grape juice needed to abolish the CFRs was 2.04±1.42 mL/kg. The inhibitory effect of the intravenous grape juice lasted approximately 45 minutes, and then the experiment was terminated.

View larger version (46K): [in this window] [in a new window]   Figure 4. Representative tracing of the hemodynamic effect of intravenous grape juice. Top, Mean aortic blood pressure. Bottom, Blood flow in the stenosed left circumflex artery. Cyclic flow reductions were eliminated 10 minutes after the grape juice–saline infusion was started. The amount of grape juice administered to this animal was 0.6 mL/kg.

The dogs administered 6 or 8 mL/kg of grape juice IG showed platelet inhibition by a decrease in the slopes of the CFRs and spontaneous embolizations of thrombi, yet the CFRs were not completely eliminated in every animal at a given dose. The CFRs in the five dogs administered 10 mL/kg were completely abolished after an average of 95±33 minutes. The amount of intragastric grape juice necessary to abolish the CFRs was 2.5-fold greater than the amount of intragastric red wine administered. The aggregation response to collagen before the grape juice administration was compared with the response when the CFRs were eliminated (Fig 5). The studies showed a 67.6±19.7% decrease in aggregation in response to the same concentration of collagen (P<.01).

View larger version (28K): [in this window] [in a new window]   Figure 5. Top: Representative tracing of the hemodynamic effects of intragastric grape juice. X denotes a spontaneous platelet thrombus embolization that did not require the manual shaking of the occluding cylinder. Bottom, Whole-blood aggregation tracings from the animal in the top tracing. Sample 1 was taken before the animal was given the grape juice, and sample 2 was taken when the cyclic flow reductions were eliminated. The decrease in aggregation to collagen corresponds to the decrease of the slopes of cyclic flow reductions. The two whole-blood aggregation tracings on the left are duplicates, as are the two tracings on the right. Diminished response shown on the right indicates significant inhibition of ex vivo aggregation by the administered grape juice.

High-Performance Liquid Chromatography Analysis
The red wine used in this study contained 119 mg/L of quercetin, 76 mg/L of rutin, and nondetectable levels of the fungicide resveratrol. The white wine we used contained 25 mg/L of quercetin, 14 mg/L of rutin, and 9 mg/L of resveratrol. The grape juice we used contained 86 mg/L of quercetin, 82 mg/L of rutin, and nondetectable levels of resveratrol. The total high-performance liquid chromatography absorbance counts of the three standards tested and unidentified compounds (possible flavonoids) in the red wine were 2.7-fold greater than those in the grape juice.

	Discussion

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Many epidemiological studies have investigated the relative cardioprotective benefits of different types of alcoholic beverages.^{2 3 4} Renaud and DeLogeril,²¹ Nanji,²² and St Leger et al²³ have suggested that wine consumption is responsible for the low levels of CAD mortality in countries with high wine consumption. Both Nanji and St Leger et al found an inverse association between CAD mortality and wine consumption (r=-.75 and -.65, respectively) but reported a positive correlation between CAD mortality and beer consumption (r=.60 and .27). In case-control studies, Hennekens et al²⁴ give the relative risk of CAD mortality for light to moderate drinkers (2 oz of ethanol per day) as 0.3 for those consuming beer or wine and 0.2 for those consuming liquor. Klatsky and Armstrong²⁵ give the relative risk as 0.7 for those preferring beer or wine but calculates the relative risk as 1.0 to 1.1 for those preferring liquor.

Numerous studies have attributed the observed cardioprotective effects of alcohol consumption to an increase in plasma HDL cholesterol levels,^{4 26} yet some scientists believe that a higher HDL cholesterol level does not fully explain the cardioprotective effects of moderate alcohol consumption.^{27 28} Seigneur et al⁵ studied platelet aggregation and lipid levels of human volunteers who consumed red wine or white wine for a 15-day study period. The consumption of either red or white wine increased HDL levels and the consumption of red wine decreased ADP-induced platelet aggregation.

The Folts coronary thrombosis model is an on-line in vivo bioassay for platelet activity producing CFRs in coronary blood flow.¹¹ The CFRs were abolished by both the red wine and the grape juice when administered intravenously and intragastrically. Administration of the white wine did not produce significant results in eliminating the CFRs, either intravenously or intragastrically and only slightly decreased the slope of the CFRs. These results suggest that there are compounds present in red wine and grape juice that are not present or are present in a lower concentration in white wine that may be antithrombotic and platelet inhibitory.

Red wine and grape juice were also effective as antiplatelet, antithrombotic compounds when administered intragastrically, suggesting that the active ingredients are absorbed and transported to the bloodstream. Many investigators have used the Folts cyclic flow model to study platelet inhibitors given intravenously.^{29 30 31} Torr et al³² were the first to study a drug in the Folts model given by stomach tube. Because the CFRs will continue for 3 to 4 hours if no antiplatelet agent is given,^{29 30 31} it is reasonable to study drugs (or foods) given by stomach tube.

Pure ethanol has been shown to inhibit platelet aggregation in vitro, ex vivo, and in vivo, although a BAC of 0.2 g/dL is required.^{6 15} We previously demonstrated in this model that an average of 1.0 mL/kg of pure ethanol dissolved in saline and administered intravenously eliminates the CFRs, producing an average peak BAC of 0.24 g/dL.²⁴ The BAC of the dogs that received the red wine–saline solution intravenously was 0.028 g/dL, 12% of the BAC of the dogs that received pure ethanol.

Because the amount of ethanol necessary to eliminate the CFRs is greatly reduced when red wine rather than pure ethanol was given, there must be active platelet inhibitors in the red wine in addition to the ethanol. These compounds may be the same antiplatelet compounds that provide the antithrombotic activity of grape juice.

It has been proposed that the protective effects of wine, specifically red wine, may be due to a large number of naturally occurring constituents in the beverage. Wine contains a wide variety of compounds, including naturally occurring fungicides, tannins, anthocyanins, and phenolic flavonoids (including flavonols and flavones).³³ Frankel et al³⁴ have shown that phenolic substances in red wine inhibit the oxidation of human LDL cholesterol. The bioflavonoid quercetin found in red wine also exhibits antioxidant capabilities and is more potent than vitamin E.³⁴

The naturally occurring flavonoids found in wine, grape juice, and other foods have been shown to decrease platelet aggregation in vitro,^{35 36 37} inhibit platelet aggregation on blood-superfused collagen strips in vivo,³⁸ and cause platelet disaggregation of preformed platelet thrombi in vitro.³⁸ Our group has shown that the flavonoids quercetin (given intravenously or intragastrically) and rutin (given intravenously) inhibit platelet activity, eliminating the CFRs in the Folts in vivo model.³⁹

There also is evidence that flavonoids inhibit the production of thromboxane A₂,³⁷ perhaps by inhibiting platelet cyclooxygenase activity.^{35 37} Especially interesting are the studies demonstrating that quercetin increases platelet cAMP levels⁴⁰ and that quercetin^{35 40} potentiates the increase in cAMP induced by prostaglandin I₂. Flavonoids (particularly quercetin, kaempferol, apigenin, and amentoflavone) have been shown to inhibit cAMP and cGMP phosphodiesterases.^{41 42} The inhibition of cAMP or cGMP phosphodiesterases would raise the platelet levels of cAMP or cGMP. This in turn would lower platelet cystolic calcium levels and decrease the level of in vivo platelet activity.⁴³

It is therefore possible to speculate that the cardioprotective effects of red wine consumption observed in the French and other populations may be attributed in part to the ethanol content of the wine and in part to the antioxidant and platelet-inhibitory properties of other naturally occurring compounds in the wine. Because platelet adhesion to damaged endothelium and subsequent platelet aggregation are major steps in both thrombosis and atherogenesis, the long-term inhibition of platelet activity by the consumption of flavonoid-containing foods and beverages may retard atherogenesis and prevent thrombosis on a daily basis. The potentially beneficial effects of alcoholic beverages and fruit juices on CAD warrants further study.

	Acknowledgments

 
This work was supported by the Nutricia Research Foundation (The Hague, Netherlands) and the Rennebohm Foundation.

Received July 6, 1994; revision received September 6, 1994; accepted September 28, 1994.

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