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October2004URICACIDANDCARDIOVASCULARPROGNOSISANDTHEACTIONOFCARDIOVASCULARDRUGSONURICACIDArielJ.ReyesInst

ituteofCardiovascularTheory,Montevideo,Uruguay尿酸与心血管预后及心血管药物对尿酸的作用1ThesynthesisofuricacidTheantioxidantaction/functionofuricacidDoesuricaciddam

agetheheartandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAcetylsalicylic

acidThepurportoftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用2Uricacidisproducedinthepurinecatab

olicchainguanosineinosinehypoxanthinexanthineoxidoreductasexanthinexanthineoxidoreductaseuricacid尿酸与心血管预后及心血管药物对尿酸的作用3Xanthineoxidor

eductasesystemxanthinedehydrogenaselowoxygentensioninflammatorycytokineshormonesxanthineoxidase•XantinedehydrogenaseusesNAD+asanelectronacceptor•Xant

hineoxidaseusesO2asanelectronacceptorBerryCE,HareJM.JPhysiol2004;555:589–606.尿酸与心血管预后及心血管药物对尿酸的作用4Reactiveoxygenspeciesareco-ge

neratedwithxanthineandwithuricacidinreactionsmediatedbyxanthineoxidaseHypoxanthineXanthine+2O2+H2O+2O2+H2OxanthinexanthineoxidaseoxidaseXanth

ineUricacid+2O•-+2H++2O•-+2H+Four/twosuperoxideanionradicals(O•-)areformedpereachunitofinosine/guanosinecatabolisedthroughtheactionofxa

nthineoxidase尿酸与心血管预后及心血管药物对尿酸的作用5ThesynthesisofuricacidTheantioxidantaction/functionofuricacidDoesuricaciddam

agetheheartandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAce

tylsalicylicacidThepurportoftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用6Uricacidisan

antioxidant:itcan/appearstobeabletoscavengeseveralreactiveoxygenspecies:•peroxynitriteandperoxylradicals•hydroxylradical•hypochlorousacid

•nitrogendioxide,carbonateion–SquadritoGL,CuetoR,SplenserAE,etal.ArchBiochemBiophys2000;376:333–7.–RegoliF,WinstonGW.ToxicolAp

plPharmacol1999;156:96–105.–WhitemanM,KetsawatsakulU,HalliwellB.AnnNYAcadSci2002;962:242–259.–AugustoO,BoniniMG,AmansoAM,etal.FreeRadicBio

lMed2001;32:841–859.尿酸与心血管预后及心血管药物对尿酸的作用7Elevationsinserumuricacidentailincreasesinplasmaantioxidantcapacityinman–War

ingWS,WebbDJ,MaxwellSR.JCardiovascPharmacol2001;38:365–371.–WaringWS,ConveryA,MishraV,etal.ClinSci(Lond)2003;1

05:425-430.尿酸与心血管预后及心血管药物对尿酸的作用8ThesynthesisofuricacidTheantioxidantaction/functionofuricacidDoesuricaciddamagetheheartandvesse

lsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAcetylsalicylicacidThepurporto

ftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用9Acutehyperuricaemiadoesnotimpaircardiovascular

functioninhealthymanLocalforearmandsystemichyperuricaemiawereproducedbyinfusionofuricacid•Basalforearmbloodflowwas

notaffected•Theresponsesofforearmbloodflowtoacetylcholine,sodiumnitroprussideandL-NMMAwerenotaffected•Centralhaemody

namicvariables,baroreflexsensitivityandanindexoflargearterystiffnesswerenotaffectedWaringWS,AdwaniSH,BreukelsO,etal.He

art2004;90:155–159.尿酸与心血管预后及心血管药物对尿酸的作用10ThesynthesisofuricacidTheantioxidantaction/functionofuricacidDoesuricaciddamagetheh

eartandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAcetylsalicylicacidThepurporto

ftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用112/3ofalltheuri

cacidthatisproducedisexcretedbythekidneysinnormalmanRenalhandlingofuricacid•Totalamountfiltered:100%•Amountsecret

edintothenephronalproximaltubule:40%•Amountreabsorbedfromthenephronalproximaltubule:130%•Netproximaltubularreabsorption

:88–94%Renalfractionalexcretionofuricacid(%ofthefilteredamountthatisexcretedinurine):6–12%尿酸与心血管预后及心血管药

物对尿酸的作用12Eventhemoderatereductionsinsodiumintakeprescribedtopatientswithhypertensionorheartfailureresultins

ignificantincreasesinserumuricacidconcentration•Randomised,placebo-controlled,anddouble-blindcrossoverstudy•Seventeenhyperten

sivepatientsaged65–79Mean24-hnatriuresis(mmol)30495Meanserumuricacid(mol.L-1)277174FotherbyMD,PotterJF.JHumHy

pertens1997;11:361–366.尿酸与心血管预后及心血管药物对尿酸的作用13ThesynthesisofuricacidTheantioxidantaction/functionofuricaci

dDoesuricaciddamagetheheartandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAcetylsalic

ylicacidThepurportoftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用14ThesynthesisofuricacidTheant

ioxidantaction/functionofuricacidDoesuricaciddamagetheheartandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidA

llopurinolDiureticsAcetylsalicylicacidThepurportoftheincreasesinserumuricacidthatarecausedbycardiovascula

rdrugsinman尿酸与心血管预后及心血管药物对尿酸的作用15Allopurinolanditsmetaboliteoxypurinolareinhibitorsofxanthineoxidasehypoxan

thineorxanthine+2O2+H2Oallopurinolxanthineoxidaseoxypurinolxanthineoruricacid+2O2•-+2H+尿酸与心血管预后及心血管药物对尿酸的作用16Inadditiontothei

ractiononxanthineoxidase,allopurinolanditsmetaboliteoxypurinolscavengefreeradicalsdirectly–MoorhousePC,GrootveldM,HalliwellB,etal.FEBSLe

tt1987;213:23–28.–DasDK,EngelmanRM,ClementR,etal.BiochemBiophysResCommun1987;148:314–319.–HoeyBM,ButlerJ,HalliwellB.FreeRadicResComm

un1988;4:259–263.–RicardoSD,BertramJF,RyanGB.ExpNephrol1995;3:270–279.尿酸与心血管预后及心血管药物对尿酸的作用17Relevantact

ionsofallopurinol•Itimprovedperipheralvasodilationcapacityinheartfailure–DoehnerW,etal.Circulation2002;105:2619–2624.–FarquharsonCA,etal.Circu

lation2002;106:221–226.•ItdecreasedtheserumconcentrationofoxidisedLDLautoantibodiesinpatientswithgout,whereastheuricosuricbenzbromaroned

idnot–TsutsumiZ,MoriwakiY,TakahashiS,etal.ClinChimActa2004;339:117–122.尿酸与心血管预后及心血管药物对尿酸的作用18ThesynthesisofuricacidTheantioxidantaction

/functionofuricacidDoesuricaciddamagetheheartandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovascul

ardrugsonuricacidAllopurinolDiureticsAcetylsalicylicacidThepurportoftheincreasesinserumuricacidthatarecausedbycardiovasc

ulardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用19Allloopdiuretics,mostthiazide-typediureticsandallpotassium-retainingdiuretics•enhanc

ethereabsorptionofuricacidintheproximaltubuleofthenephron•reducetherenalexcretionofuricacid•elevateserumuricaci

dconcentration尿酸与心血管预后及心血管药物对尿酸的作用20ThesynthesisofuricacidTheantioxidantaction/functionofuricacidDoesuricaciddamagethehear

tandvesselsinman?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAcetylsalicylicacidThep

urportoftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用21•Acet

ylsalicylicacidatadailydoseof500mgorhigherraisesuricosuriaandreducesserumuricacid•Acetylsalicylicacidat60or325mgoncedailyreducedtherenal

fractionalexcretionofuricacidinhealthysubjectsLouthrenooW,KasitanonN,WichainunR,etal.JClinRheumatol2002;8:299–304.•Acetylsalicylicacid

at75or100mgoncedailyreducedtherenalclearanceofuricacidandincreaseduricaemia–CaspiD,LubartE,GraffE,et

al.ArthritisRheum2000;43:103–108.–SegalR,LubartE,LeibovitzA,etal.AmJMed2003;115:462–466.尿酸与心血管预后及心血管药物对尿酸的作用22Acetylsalicylicacid100mgonced

ailywasfoundtoincreaseserumantioxidantcapacityinhealthysubjectsRistimaeT,etal.CardiovascDrugsTher1999;13:485–490.尿酸与心血管预后及

心血管药物对尿酸的作用23ThesynthesisofuricacidTheantioxidantaction/functionofuricacidDoesuricaciddamagetheheartandvesselsinman

?TherenalexcretionofuricacidTheeffectsofcardiovasculardrugsonuricacidAllopurinolDiureticsAcetylsalicyli

cacidThepurportoftheincreasesinserumuricacidthatarecausedbycardiovasculardrugsinman尿酸与心血管预后及心血管药物对尿酸的作用24Incr

easesinserumuricacidperse•entailincreasesintotalplasmaantioxidantcapacityandtherefore•arebeneficialtotheheartandvesselsHowever,thepurportofthei

ncreasesinserumuricacidthatoccurinmandependsupondefiniteprocess(s)andontheircombinations尿酸与心血管预后及心血管药物对尿酸

的作用251.Whenthesynthesisofuricacidmediatedbyxanthineoxidaseaugments,theconsequentincreaseinserumuricaciddenotes:•anelevation

inplasmaantioxidantcapacity•theoccurrenceoflocal(e.g.endothelial)oxidativestress(likely)Xanthineoxidaseinhibitionwithallopurinoloroxypurinolmaybeofv

alueincardiovascularprophylaxisandtherapyCont.尿酸与心血管预后及心血管药物对尿酸的作用26Cont.2.Whentherenalexcretionofuricaciddiminishes,theaccompa

nyingincreaseinserumuricaciddenotes:•anelevationinplasmaantioxidantcapacity•thatoxidativestressmightcoexist(?)compen

satorymechanismhypothesis*Increasesinserumuricacidduetodiminishedrenalexcretion,ascausedby•low-sodiumdiets•diuretics•low-doseacetylsalicylicacidaret

obeconstruedasbeneficialtocardiovascularprognosis*KirschbaumB.MedHypotheses2001;56:625–629.尿酸与心血管预后及心血管药物对尿酸的作用27AhypothesisTheincrease

inserumuricacidcausedbydiureticsisnotaccompaniedbyariseinreactiveoxygenspeciesandthereforeconveysareductioninoxidativestress;hence,itshouldbecon

struedasbeneficialThiscouldpartlyexplainthepositiveactionofdiureticsoncardiovascularprognosisfoundintheALLHATan

dotherstudies–ReyesAJ,LearyWP.CardiovascDrugsTher2002;16:485–487.–ReyesAJ,LearyWP.Hypertension2003;21:1775–1777.尿酸与心血管预后及心血管药物对尿

酸的作用28InstituteofCardiovascularTheoryMontevideo,Uruguay尿酸与心血管预后及心血管药物对尿酸的作用29ThepublishedsubanalysisoftheSHEPresultsdealing

withuricacidlackscogency尿酸与心血管预后及心血管药物对尿酸的作用30Introduction•Uricacidisanantioxidant.Thus,theincreaseinser

umuricacidcausedbydiureticsislikelytobenefittheheartandthevessels[1,2].•Chlorthalidone-inducedelevationsinserumuricacidhigherthan0.06mmol/L(abo

ut1mg/dL)werefoundtobluntthepositiveactionofbloodpressurereductionwithchlorthalidoneontheriskofcoronaryheartdiseaseinacommerciallysponsor

edsubanalysisoftheSHEPresultsthatwaspublishedin2000[3].尿酸与心血管预后及心血管药物对尿酸的作用31ObjectiveofthepresentundertakingToreappraisethequestionofwhetherth

echangesinserumuricacidthatwereinducedbychlorthalidoneHadabearingoncardiovascularprognosisintheSHEP.尿酸与心血管预后及

心血管药物对尿酸的作用32TheSystolicHypertensionintheElderlyProgram(SHEP)4327patientswithisolatedsystolichypertensionwererandomlyallocatedto

treatmentwith•placebo•chlorthalidone12.5–25mg/day,plusanotheragentifnecessaryandobservedfor5years.Chlorthalidonetreatment•reducedse

rumpotassium[4];•elevatedserumuricacid[4].TwosubanalysesoftheSHEPresultswerepublishedin2003:•asubana

lysisoftherelationshipbetweenserumuricacidandcardiovascularoutcomes[3];•asubanalysisoftherelationshipbetweenhypokalaemiaandcardiovascularou

tcomes[5].尿酸与心血管预后及心血管药物对尿酸的作用33Firstofthetwoyear-2000papersontheSHEP:Uricacidandcardiovascularprognosis[3].•Therisksofca

rdiovascularevents,strokeorcoronaryheartdisease(myocardialinfarction,coronaryproceduresandcardiacdeath)werel

owerinchlorthalidone-treatedpatients.•Despitetheprecedinggeneralfinding,elevationsinserumuricacidof0.06mmol/

L(about1mg/dL)orhighernullifiedthedecreaseinriskofcoronaryheartdiseaseassociatedwithchlorthalidonetreatment.Thelatterconclusionresultedfromamultivar

iateanalysisinwhichthedatawereadjustedforseverallikelyconfounders,butnotforserumpotassium(Table1).尿酸与心

血管预后及心血管药物对尿酸的作用34Secondofthetwoyear-2000papersontheSHEP:Serumpotassiumandcardiovascularprognosis[5]Patientswhopresentedhypoka

laemiaduringactivetreatment•presentedameanserumuricacidof0.41mmol/Lat1year(itwas0.37mmol/Linpatientswithouthypokalaemia,P<0.001);•hadasimilarrisk

ofanycardiovascularevent,strokeorcoronaryheartdiseaseasthoseintheplacebogroup.Thelatterconclusionresultedfromamultivariateanalysisi

nwhichthedatawereadjustedforseverallikelyconfounders,includingserumuricacid(Table1).尿酸与心血管预后及心血管药物对尿酸的作用35Table1.Likelyconfo

undersincludedinthesubanalysesPossibleconfounderK[5]UA[3]•AgeYesYes•SexYesYes•RaceYesYes•BodymassindexYesYes•AlcoholconsumptionYesNo•SmokingYesNo

•Historyofheartattack,strokeordiabetesYesYes•BaselineserumpotassiumYesNo•Year-1serumpotassiumIgnored•BaselineserumuricacidNoY

es•Year-1serumuricacidYes•Year-1serumcreatinineYesYes•Year-1serumglucoseYesYes•Year-1serumcholesterolYesYes•Year-1serumtriglyce

ridesYesYes•Year-1HDL-cholesterolYesYes•StudydrugdoseYesYes尿酸与心血管预后及心血管药物对尿酸的作用36Discussionandconclusions.I.

•Theunfavourableeffectattributedtomarkedincreasesinserumuricacidcouldhavebeenduetoassociatedlowserumpotassiumlevels,w

hichdefinitelyimpaircardiovascularprognosis[6].•Diuretic-inducedincreasesinserumuricacidareunlikelytodamagetheheartorvesselssinc

e•nomechanismwherebythiscouldhappenhasbeendescribedinman;•uricacidinfusionshavebeenfoundnottoaffectendothelialfunction,arterialcomplianceorcentralh

aemodynamicvariablesinhealthysubjects[7].尿酸与心血管预后及心血管药物对尿酸的作用37Discussionandconclusions.II.•Oxidativestressseemingly

hasabearingonthepathogenesisandprogressofhypertensionandassociatedcardiovascularconditions;thus,theriseintheserumleveloftheantioxi

danturicacidcausedbydiureticscouldbebeneficialtocardiovascularprognosis.Diureticsincreaseserumuricacidbyloweringtherenalexc

retionofthisetabolite;iftherisesinserumuricacidexceeding0.06mmol/Linthechlorthalidonegroupwerepartlyduetoincreasedsynthesismediated

byxanthineoxidase,theywoulddenotetheexistenceofoxidativedamagethatcouldaddtothehypokalaemia-relatedbluntingofsomeofthebene

fitofactivetreatment[8].尿酸与心血管预后及心血管药物对尿酸的作用38References[1]ReyesAJ,LearyWP.CardiovascDrugsTher2002;16:485–487.[2]ReyesAJ,Le

aryWP.JHypertens2003;21:1775–1777.[3]FranseLV,PahorM,DiBariM,etal.JHypertens2000;18:1149–1154.[4]SavagePJ,PresselSL,CurbJD,etal.ArchInternMed1

998;158:741–751.[5]FranseLV,PahorM,DiBariM,etal.Hypertension2000;35:1025–1030.[6]SiscovickDS,RaghunathanTE,PsatyBM,etal.NEnglJMed1994;330:1852–185

7.[7]WaringWS,AdwaniSH,BreukelsO,etal.Heart2004;90:155–159.[8]ReyesAJ.CardiovascDrugsTher2003;17:397–41

4.尿酸与心血管预后及心血管药物对尿酸的作用39Table2.Serumuricacid(mmol/L)accordingtothestateofserumpotassium(K)atyear1(mmol/L)–Mean(SD)[5]ActivePlacebotrea

tmentBaselineK>=3.5n=1951n=20030.32(0.08)0.32(0.08)K<3.5n=151n=210.32(0.08)0.33(0.08)NSvsK>=3.5NSvsK>=3.51yearK>=3.5n=1951n=20030.37(0.10)

0.33(0.09)K<3.5n=151n=210.41(0.11)0.42(0.09)P<0.001vsK>=3.5P<0.001vsK>=3.5尿酸与心血管预后及心血管药物对尿酸的作用40Losartan,serumuricacidandser

umpotassiuminLIFEstudy:anindependentundertaking尿酸与心血管预后及心血管药物对尿酸的作用41IntroductionUricacidisanantioxidant;thus,theuricos

uriceffectoflosartanandtheattendantfallinserumuricacidaretobeconsidereddetrimentaltotheheartandvessels.Theauthor

softheLIFEstudy[1]analysedthecontributionoftheactionoflosartanonserumuricacidtothetherapeuticeffectofthisagentandconcludedthatitwasbenefi

cial[2].TheLIFEStudy[1]•Patients:high-riskhypertensivesaged55–80.•Design:double-masked,randomised,parallel-groupstudy.•Patientswereassignedtolosartan

-oratenolol-basedanti-hypertensivetherapyfor4yearsoruntil1040patientshadacardiovascularevent(death,myocardialinfarctionorstroke).尿

酸与心血管预后及心血管药物对尿酸的作用42ResultsoftheLIFEstudy•Theprimaryendpoint(cardiovasculardeath,strokeandmyocardialinfarction)

was•11.0%inthelosartangroup,•12.8%intheatenololgroup(P=0.021)[1].•Meanserumuricacidincreasedduringtreatment•17.0μ

mol.L-1inthelosartangroup,•44.4μmol.L-1intheatenololgroup(P<0.001)[2].•85and86%ofpatientsinthelosartanandatenololgro

upswerealsotakinghydrochlorothiazideatendofstudy[2].•Theauthorsaffirmthatserumpotassiumdidnotchangesubstanti

allyduringtreatmentineithergroup[2].尿酸与心血管预后及心血管药物对尿酸的作用43Endofstudybiochemicalvariablesasreportedin[1]and[2].Meanvalues(SD).Losartan(n=

4605)Atenolol(n=4588)Ref.BaselineYear4,5ChangeBaselineYear4,5ChangePotassium(mmol/L)4.2(0.4)4.1(0.4)0.0(0.4)4

.2(0.4)4.1(0.4)-0.1(0.5)[1]4.1414.109-0.0324.1434.025-0.118[2]Uricacid(μmol/L)328.2(76.9)347.7(90.0)19.5(72.2)328.8(77.1)375.9(93.1)47.2(76.8)[

1]17.0(69.8)44.4(72.5)[2]尿酸与心血管预后及心血管药物对尿酸的作用44ConclusionbytheauthorsoftheLIFEstudy“Theincreaseinserumuricacidwasatte

nuatedbylosartancomparedwithatenololtreatment,appearingtoexplain29%ofthetreatmenteffectontheprimarycompositee

ndpoint”[2].OurmainobjectiontotheconclusionbytheauthorsoftheLIFEstudy:Serumpotassiumwasdisregardedasapotentialconfou

ndingfactorinthemultivariateanalysisthatgroundsthisconclusion,despitethefactthatpatientswithdiuretic-inducedhypokalaemiatendtohavehi

gherserumuricacidlevelsthansubjectswhodonotpresenthypokalaemia[3].尿酸与心血管预后及心血管药物对尿酸的作用45Objectivesofthepresentundertaking•toevaluatewhetherther

esponsesofserumpotassiumtolosartanandtoatenololintheLIFEstudydiffered;•todiscussthepossiblebearingofserumuricacidonth

edifferentialeffectoflosartanontheprimaryoutcome.MethodsofthepresentundertakingTocomparetheresponsesofserumpotassiumtolosar

tanandtoatenolol,weusedthenumberofpatientswhotookeachmedicationquotedbytheauthorsaccordingtotheirintent-to-treatanalysis,theme

anvaluesreportedinthesubanalysisonuricacid[2]sincetheyaremoreprecisethanthosereportedin[1](seethetableabove),andtheSDvaluesquotedintheprimerep

ort[1]sincenoscatterestimatesarereportedin[2](seethetableabove).尿酸与心血管预后及心血管药物对尿酸的作用46ResultsofthepresentundertakingSerumpota

ssiumwashigherinthelosartanthanintheatenololgroupatendofstudyandtheincidenceofhypokalaemiawashigherintheatenololgroup•Meanserumpotassiu

mwashigherinthelosartan(4.109mmol.L-1)thanintheatenololgroup(4.025mmol.L-1)atendofstudy(P<0.0001)–evaluatedbytheunpairedttest.•6.4%a

nd9.4%ofpatientsinthelosartanandatenololgroupsrespectivelypresentedhypokalaemiaatendofstudy(P<0.0001)–the

sepercentageswereevaluatedbytheintegralofthestandardisednormalcurvebetweenminusinfinityand3.499,mmol/L,whileusingtheSDvaluesquotedin[1]and

assumingthatserumpotassiumatendofstudyconformedtoaGaussiandistributioninbothgroups.尿酸与心血管预后及心血管药物对尿酸的作用47ConclusionsLosartan,uricacida

ndcardiovascularriskintheLIFEstudy•TheLIFEstudyauthorsignoredserumpotassiumintheirmultivariateanalysis;thisvariable,whichisknowntoass

ociatenegativelywithserumuricacidindiuretic-treatedpatients,waslowerintheatenololthaninthelosartangroupatendofstudy.•TheLIFEstudyauthorsma

intainthatthelowerlevelsofserumuricacidinthelosartangroupentailedanimprovedcardiovascularprognosis;thiscontent

ionisunscientific.Losartan-inducedfallsinserumuricacidmaywelldetractfromthepositivecardiovascularactionsofthisagent,giventhaturicaci

disapowerfulantioxidantinman[5].Intheabsenceoffurtheranalysesrefutingourobjections,theLIFEstudyauthors’analysisan

dconclusion[2]lackcogency.尿酸与心血管预后及心血管药物对尿酸的作用48Basisoftheoldstanceondiuretics,uricacidandcardiovascularrisk

•Selectedepidemiologicalstudieshavedisclosedthathighlevelsofserumuricacidimpaircardiovascularprognosis•Thecontrolofh

ighbloodpressurewithdiureticsfailstoimprovecardiovascularprognosiswhenitelevatesserumuricacidmarkedly•Theincreasein

uricosuriaandreductioninuricaemiacausedbylosartanimprovecardiovascularprognosis•Raisedlevelsofserumuricacidcauseren

aldamageandtriggerthedevelopmentofhypertensionintheratSrinivasTR,Herrera-AcostaJ,FeigGIetal.JHypertens2004;22:inpress.尿酸与心血管预后

及心血管药物对尿酸的作用49