Salicylic Acid in Wine as a Therapeutic Agentin Gard iovascular D isease

VanVelden, DPMB ChB (Stel), M Prax Med(Pret)Senior Lecturer, Department ofFamily Medicine and PrimaryCare, University of Stellenbosch.

Hundt, HKLPhD (Organic Chemistry)Professor, Department ofPharmacology, University of theOrange Free State.

Key wordscardiovascular disease, acetyl-salicylic acid, salicylic acid,wine,platelet aggregation, alcohol.

Address for correspondenceDr David P vanVeldenDepartment of Family Medicineand Primary CareUniversity of StellenboschPO Box 19063TYGERBERG, T5O5Tel: 02l-9389449Fax: 02 I -9389 | 53E-mai l: dpw@maties.sun.ac.za

In t roduct ion Epidemiologicalevidence consistently links moderatewine consumpt ion wi th reducedmortality, mostly due to reducedincidence of cardiovascular disease.Recent scientific reports indicatingthat a diet rich in fruit and vegeables,together with moderate amounts ofalcohol, but more specific red winein moderation, is protective againstva r i ous degene ra t i ve d i seases ,created a renewed interest in theconsumption of grapes and wine aspart of a healthy diet and lifestyle.Aims The aims of this investigationwere to de te rm ine f rom theavailable information whether thereare grounds for these claims. Thecardioprotective effects of wine maybe due to t he p resence o fpharmacological active ingredientssuch as acetyl-salicylic acid (aspirin)or salicylic acid.Methods In th is s tudy twelvedifferent South African wines wereanalyzed according to standardizedpharmacological methods for the

S A Fom Proct 2000;22(6): I 5-l 8

presence of salicylic acid and acetyl-salicylic acid.Results Our results indicate thatalthough all the red and white winesamples contain varying amounts ofsalicylic acid, it is noteworthy that noacetyl-salicylic acid could be detectedin any wine sample.Conclusions There is signi f icantep idemio log ica l and labora toryevidence to promote the consumptionof grapes and wine as part of abalanced diet and lifestyle for certainindividuals to prevent cardiovasculardisease. The presence of salicylic acidand other phenolic compounds mayprovide protection against plateletaggregation by altering eicosanoidmetabolism in favour of increasedpros tacyc l ine and decreasedthromboxane A, synthesis. Alcoholc o n s u m p t i o n g u i d e l i n e s s h o u l demphasize that it is inappropriate toindiscriminately advise non-drinkers,and for those people who should notdrink at all to take up alcohol for healthreasons.

Abstract

ntroduct ioResearch cons i s ten t l y show tha tregular moderate consumpt ion ofalcohol per si whether in the form ofw i n e , b e e r o r s p i r i t s , e x e r t s aprotective effect against coronaryhea r t d i sease . r -3 A l t hough heavya l coho l i n take i nc reases ove ra l lmor ta l i t y r ' a and mor ta l i t y due tocardiovascular diseases,s-5 moderateintake appears to have a protectiveeffect against coronary heart disease,as compared to drinking no alcohol.T-e

Evidence based on studies of diversep o p u l a t i o n s s u g g e s t s t h a t w i n e

consumers have a l ower r i sk f o rcoronary heart disease and death fromall causes. While red wine has beenconsidered healthier than white wine,both red and white wine users wereshown to have a lesser risk of dyingfrom coronar\/ artery disease than beeror l iquor drinkers.r0 More recendy anew set of data from the Copenhagenheart study revealed that wine drinkerswere the least l ikely to die during thel2-year study period.rr In this study,intake of spirits implies increased risk,whi le beer dr ink ing d id not af fectmortality. Light and moderate drinking

is associated with a dose dependantdecrease in mortality attributable tocardiovascular and cerebrovasculardisease as wel l as from other causes.Moderate consumption of wine isconsidered to be one to two glasses( 125 - 250 ml) per day for men, ando n e g l a s s p e r d a y f o r w o m e n ,corresponding to l0 - 30 I ethanolper day.

The French lifestyle includes risk fuctorsfor coronary heart disease (high fatc o n s u m p t i o n , h i g h f r e q u e n c y o fsmoking, lower exercise consciousness)

more than in North Americans, yet theyhave a lower incidence of this disease.Thishas appropriately been called the"FrenchParadox".r2'r3 lt has been postulated thatthe French are protected againstcoronary heart disease mortality by thela rge amoun t o f w ine they d r i nk ,pafticularly red wine.ra Red wines,whichhave undergone extended grape skincontact and oak maturation, containphenolic antioxidants, which inhibit l ipid

pe rox ida t i on , and cou ld p reven tatheromatous plaque formation. Whitewines have much lower concentrationsof these antioxidants than red winesr4-r7which would suppoft the view that redwine is more protect ive againstatheroscleros is and coronary hear tdisease than white wine.

Wine may have benefits due to thepresence of factors such as ethanol or

other non-alcoholic components, andeven other associated lifestyle factorsassociated wi th wine consumpt ion.E p i d e m i o l o g i c a l s t u d i e s a r e n o tcapable of determining the specificcauses for the observed effects,and itis therefore important to establishwhether or not there are identif iablemolecular mechanisms whereby winenutrients could affect cardiovasculard isease.

AimsOur interest is directed towards therole of phytochemicals in plant foodsa n d w i n e i n r e d u c i n g p l a t e l e taggregation and thrombosis. Plateletaggregat ion is largely mediated bythromboxane A' a compound formedby enzymatic conversion of arachidonicacid via cyclo-oxygenase to PGH, andthen to thromboxaneA' a potent pro-aggregatory agent.rs're The synthesis ofthese compounds by cyclo-oxygenaseis enhanced by l ipid hydroperoxides.2oThese hydroperoxides are readi lygenerated in response to tissue injuryand during inflammatory reactions, inthe presence of activated macrophagesand platelets.2r'22

Acety l -sa l icy l ic ac id (aspi r in) inh ib i tscyc lo -oxygenase and reduces thethrombotic tendency of platelets.23-26 Invivo, aspirin is quickly de-acetylated tosalicylate. Both the salicylate and theace ta te i ons i n to wh i ch asp i r i n i sconverted, contributes to the overallactivity of aspirin. Furthermore,in a high

We decided to analyse l2 different highq u a l i t y w i n e s a m p l e s f r o m t h eS t e l l e n b o s c h r e g i o n . T h e s a m p l eincluded 5 red wines,and 7 white wineswith high concentrations of phenolicacids and antioxidants according toprevious analysis.rT

An assay for quant i ta t ing SA andA S A t o d e t e r m i n e t h e v a l u e s i nw i n e s a m p l e s w a s d e v e l o p e d . Am i n o r m o d i f i c a t i o n o f a m e t h o dw a s p r e v i o u s l y d e v e l o p e d f o r

dose , sa l i cy la te comp le te l y i nh ib i t sasp i r i n ' s (ASA) e f f ec t on p la te le tcyclooxygenase activity.2T Accordi ng tothese authors, platelet and/or vascularcyc looxygenase m igh t be spa redacetylation by acetyl salicylic acid if theplasma levels of salicylate is carefullybalanced with the plasma level of acetylsalicylate. The salicylate moiety may alsointer fere wi th the p late let and/orleukocyte lipo-oxygenase pathway ofarachidonic acid metabolism, preventinghydroperoxide formation.

B o t h r e d a n d w h i t e w i n e s a r eexcel lent sources of sa l icy l ic ac id andi ts metabol i tes 2,3 d ihydrobenzoicacid and 2,5 d ihydrobenzoic ac id,28 a l lo f which have vasodi la tor and ant i -inflammatory activit ies. Many plantsother than grapes produce sal icy l icac id. Sal icy l ic ac id is postu lated tobe a p lant hormone.2e

South Africa has one of the highestincidences of myocardial infarction in the

Materials and Methodsquan t i f i ca t i on o f SA and ASA inhuman p lasma . A known quan t i t yo f w i n e w a s d i l u t e d w i t hconcen t ra ted oe rch lo r i c ac id . andin jected onto the HPLC column. Tode te rm ine the re ten t i on t imes o fASA and SA , and to ca l cu la te t heconcentrat ion of ASA and SA in thew i n e , t h e s a m e v o l u m e o fp e r c h l o r i c t r e a t e d w i n e s a m p l e swere spiked with a known quantityof ASA and SA. To obtain a solutionofASA equivalent to 206 ng/ml in the

world. Serious consideration should begiven to prevent th is epidemic ofdisabling disease that affects the youngeconomical ly act ive sector of ourcountry. Since South Africa producesgood wines,we have decided to analysevarious South African wine cultivars forthe presence of salicylic acid and acetyl-salicylic acid (aspirin).

A thorough literature search to identifa n y a p p l i c a b l e d a t a a n d o t h e rinformation concerning the presenceof salicylic acid (SA) and acetyl-salicylicacid (ASA) or aspirin in wine and theirpossible role in the prevention andmanagement of coronary heart diseasewas carried out.

Available international data maydift r from SouthAfrican conditions;therefore comparative studies arenecessary. Our aim was thereforeto detect anti-platelet factors suchas SA and ASA in twelve SouthAfrican wine cultivars.

wine and SA equivalent to 826 ng/ml ( the standard addi t ion method).

Thereafter the samples were analysedagain. The retention times were 10. Im inu tes f o r sa l i cy l i c ac id and | 1 .6minutes for acetyl-salicylic acid. Thelower limit of quantification for the assayduring the study was set at the lowestacceptable calibration standard usedconsistently during the assay ofthe studysamples: 33. I ng/ml for acetyl-salicylicacid and 133 ng/ml for salicylic acid.

The results of the acetylsalicylic acid

and the salicylic acid determinations arepresented inTable l.

The analysis of the SouthAfrican wines

for salicylic acid (SA) and acetyl-salicylic

acid (ASA) revealed interesting results.

None of the wine samples analysed

contained ASA, whilst SA was present

in a l l the samples in concentrat ions

ranging from 126 to 383 ng/ml (Table

l). These values differ significantly from

concentrations in several Californian

wines 28 where concentrations of SA

values of | | 100-2 | 000 ng/ml were

found . wh i ch a re two o rde rs o f

magn i tude h ighe r t han the l eve l s

detected in the South African wines.

This d iscrepancy is not expl icable.

Howeve[ researchers from Pennsylvania,

reporced an average value of 660 ng/ml

in seven Vidal blanc wines 30 which is

more comparable to our results.

Results

Table l:Acetylsolicylic and Solicylic Acid content of oserection of South Africon wines.

DiscussionO u r r e s u l t s i n d i c a t e t h a t t h e

concentrat ion of SA is on average

300ug /L wh i ch equa tes t o l 00x

l e s s t h a n t h e p r o p o s e d 3 0 m g

a s p i r i n p e r d a y f o r p r o t e c t i v e

e f fec t . 3 rThe re fo re w ine does no thave suf f ic ient ant i -p late let ef fect

to protect against card iovascular

d isease. We suggest that because

w i n e i s u s u a l l y t a k e n w i t h a

ba lanced mea l , t he add i t i ve e f f ec t

o f t h e w i n e - a n d t h e f o o d

s a l i c y l a t e s m a y p r o v i d e t h e

necessary Protect ion. The intake

of sa l icy lates in foods may have

c o n t r i b u t e d t o t h e d e c l i n e i n

ca rd iovascu la r mor ta l i t y i n t he

Uni ted States .32

The amoun ts o f sa l i cy la tes i n a

var iety of d iets are ev ident ly low;

i n an ana l ys i s o f r ed w ine , 0 ,7 mg

sa l i cy l i c ac id pe r l i t r e bu t a l so no

ace ty l - sa l i cy l i c ac id was found .33

T h i s i s p r o b a b l y i n s u f f i c i e n t t o

a f f e c t d i s e a s e r i s k . 3 a I n w i n e ,

howeve r , sa l i cy l i c ac id and o the r

ant iox idants co-exis t wi th ethanoland the synergis t ic ef fects between

t h e s e s u b s t a n c e s m a y h a v e ab e n e f i c i a l r o l e i n c a r d i o v a s c u l a r

we l l be ing .

Sa l i cy l i c ac id and i t s me tabo l i t es ,

2 ,3 -d ihyd robenzo i c ac id , and 2 ,5 -

d i h y d r o b e n z o i c a c i d h a v e

vasodi la tory and ant i - in f lammatory

act iv i t ies. Thei r combined ef fect in

wine is not equivalent to the ef fecto f t he recommended da i l y dose o f

3 0 m g a c e t y l - s a l i c y l i c a c i d t omainta in card iovascular wel l being

as a p la te le t i nh ib i t o r . 31

The p resence o f sa l i cy l i c ac id i n

w i n e m a y , i n p a r t , e x p l a i n t h e

cardioprotect ive ef fect of wine. In

w ine , sa l i cy l i c ac id co -ex i s t s w i t h

ethanol that may have a synergis t ic

ef fect for card iovascular wel l being.

A l t hough a t ab le t o f asp i r i n a daymay be benef ic ia l ly associated wi th

a regu la r da i l y use o f a coup le o fg lasses o f r ed w ine , t he poss ib i l i t y

o f an i nc reased haemor rhag i c r i sk

o f c o n c o m i t a n t c o n s u m p t i o n o f

a s p i r i n a n d w i n e s h o u l d b econs ide red .

T h e r e i s s i g n i f i c a n t e v i d e n c e t opromote the use of grapes and wine

in moderat ion as par t of a balanceddiet . l f sa l icy lates and ant iox idantsplay a ro le in the prevent ion andm a n a g e m e n t o f c a r d i o v a s c u l a r

d isease, i t is possib le that grapes

a n d w i n e c a n m a k e a p o s i t i v e

contr ibut ion in th is regard. Fur ther

i nves t i ga t i ons shou ld be done to

clarify the situation with regard to

the protect ive ef fects of wine on

the hea r t .

Wine(ng/ml)

Acetylsalicylic acid(mg/ml)

Salicylic acid(ng/ml)

Sauvignon Blanc'96

Merlot '93

Chardonnay'95

Pinotage'93

Cabernet Sauvignon'92

Tassenberg Red

Ros6

Rhine Riesl ing'96

Sauvignon/Chardonnay'95

Special Late Harvest'96

Noble Late Harvest'90

Chardonnay'93

none

none

none

none

none

none

none

none

none

none

none

none

3 t8

277

t26

277

232

348

234

154

t75

207

383

t32

We are greatly indebted to Prof Erna

PG Mansvelt, head of the Department

of Haematology (Pathology) of the

Faculty of Medicine of the University

Acknowledgements

o f S t e l l e n b o s c h , f o r h e r v a l u a b l e

c r i t i c i s m a n d s u g g e s t i o n s i n t h e

compiling of this report.

Gront Supporil Foundation for Research

DevelopmencTH Rl P (Technology and

H u m a n R e s o u r c e s f o r I n d u s t r yProgramme) award; contract THRIP

GUN 2038s30.

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