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Sodium and potassium in the pathogenesis of hypertension

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Thenewenglandjournalofmedicine
reviewarticle
mechanismsofdisease
SodiumandPotassiuminthePathogenesis
ofHypertension
HoracioJ.Adrogué,M.D.,andNicolaosE.Madias,M.D.
FromtheDepartmentofMedicine,BaylorCollegeofMedicine;theDepartmentofMedicine,MethodistHospital;andtheRenalSection,VeteransAffairsMedicalCenter—allinHouston(H.J.A.;andtheDepartmentofMedicine,TuftsUniversitySchoolofMedicine,andtheDivisionofNephrology,CaritasSt.Elizabeth’sMedi-calCenter—bothinBoston(N.E.M..AddressreprintrequeststoDr.MadiasattheDepartmentofMedicine,CaritasSt.Elizabeth’sMedicalCenter,736Cam-bridgeSt.,Boston,MA02135,oratnicolaos.madias@caritaschristi.org.NEnglJMed2007;356:1966-78.
Copyright©2007MassachusettsMedicalSociety.
H
ypertensionaffectsapproximately25%oftheadultpopulationworldwide,anditsprevalenceispredictedtoincreaseby60%by2025,whenatotalof1.56billionpeoplemaybeaffected.1Itisthemajorrisk
factorforcardiovasculardiseaseandisresponsibleformostdeathsworldwide.2Primaryhypertension,alsoknownasessentialoridiopathichypertension,accountsforasmanyas95%ofallcasesofhypertension.3
Primaryhypertensionresultsfromtheinterplayofinternalderangements(pri-marilyinthekidneyandtheexternalenvironment.Sodium,themainextracellularcation,haslongbeenconsideredthepivotalenvironmentalfactorinthedisorder.Numerousstudiesshowanadverseeffectofasurfeitofsodiumonarterialpres-sure.4-7Bycontrast,potassium,themainintracellularcation,hasusuallybeenviewedasaminorfactorinthepathogenesisofhypertension.However,abundantevidenceindicatesthatapotassiumdeficithasacriticalroleinhypertensionanditscardiovascularsequelae.8-10Inthisreview,weexaminehowtheinterdependencyofsodiumandpotassiuminfluencesbloodpressure.Recentevidenceaswellasclassicstudiespointtotheinteractionofsodiumandpotassium,ascomparedwithanisolatedsurfeitofsodiumordeficitofpotassium,asthedominantenvironmentalfactorinthepathogenesisofprimaryhypertensionanditsassociatedcardiovascu-larrisk.OurreviewconcludeswithrecentrecommendationsfromtheInstituteofMedicineconcerningthedietaryintakeofsodiumandpotassium.
DietarySodiumandHypertension
Primaryhypertensionandage-relatedincreasesinbloodpressurearevirtuallyab-sentinpopulationsinwhichindividualconsumptionofsodiumchlorideislessthan50mmolperday;theseconditionsareobservedmainlyinpopulationsinwhichpeopleconsumemorethan100mmolofsodiumchlorideperday.3TheInterna-tionalStudyofSaltandBloodPressure(INTERSALT,whichincluded10,079sub-jectsfrom32countries,showedamedianurinarysodiumexcretionvalueof170mmolperday(approximately9.9gofsodiumchlorideperday.11Althoughindi-vidualsodiumintakeinmostpopulationsthroughouttheworldexceeds100mmolperday,mostpeopleremainnormotensive.Itappears,then,thatsodiumintakethatexceeds50to100mmolperdayisnecessarybutnotsufficientforthedevelop-mentofprimaryhypertension.
Inananalysisacrosspopulations,theINTERSALTresearchersestimatedanincreaseinbloodpressurewithageovera30-yearperiod(e.g.,from25to55yearsofage;meansystolicbloodpressurewas5mmHghigheranddiastolicbloodpressurewas3mmHghigherwhensodiumintakewasincreasedby50mmolperday.Inananalysiswithinsinglepopulations,apositivecorrelationbetweensodiumintakeandbloodpressurewasalsodetectedafteradjustmentforanumberofpotentiallyconfoundingvariables.11
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nengljmed356;19www.nejm.orgmay10,2007
Downloadedfromwww.nejm.orgonAugust8,2007.Copyright©2007MassachusettsMedicalSociety.Allrights
reserved.

MechanismsofDisease
Humansshare98.4%geneticidentitywithencesintheprevalenceofhypertensionamongchimpanzees,andalandmarkinterventionalthesepopulationshaveusuallybeenattributedtostudyinchimpanzeesshowedthataddinguptodifferencesintheamountsofdietarysodium15gofsodiumchloridetothedietperdayin-consumed,buttheycouldalsoreflectdifferencescreasedsystolicbloodpressureby33mmHgandinpotassiumintake.Themovementofisolateddiastolicbloodpressureby10mmHg;thein-populationsintomoreurbanareasisconsistent-creaseswerereversedafterwithdrawalofthelyassociatedwithage-relatedincreasesinbloodsodiumchloridesupplement.12IntheDietarypressureandariseintheprevalenceofhyper-ApproachestoStopHypertension(DASHsodiumtensionasthedietarypotassium:sodiumratiostudy,areductioninsodiumintakecausedstep-decreasesinthenewlocation.15,16
wisedecreasesinbloodpressure.Levelsofsodi-umintakestudiedinrandomorderwereapproxi-mately150mmolperday,100mmolperday,andVascularEffectsofPotassium
50mmolperday.13Ameta-analysisofrandom-Depletionizedcontrolledtrialslastingatleast4weekscon-Earlyreportsofthevasodilatoryorblood-pres-cludedthatreducingsodiumintakeby50mmolsure–loweringpropertiesofbothpotassiumde-perdaydecreasessystolicbloodpressurebyanpletionandpotassiumsupplementation17,18de-averageof4.0mmHganddiastolicbloodpres-layedrecognitionoftheeffectsofpotassiumsurebyanaverageof2.5mmHginhypertensivedepletionthataretoxictothebloodvessels.subjectsanddecreasessystolicbloodpressurebyThesestudiesoftheeffectsofalowintakeofanaverageof2.0mmHganddiastolicbloodpotassiumonbloodpressure,performedmostlypressurebyanaverageof1.0mmHginnormo-inyoungrats,alsoinvolvedalowintakeofsodi-tensivesubjects.14
umandchloride.PotassiumrestrictioncausesadeficitincellularpotassiumthattriggerscellstogainsodiuminordertomaintaintheirtonicityofSodium-RPotassiumContentichDiets
andvolume.19Thedeficitsofpotassium,sodium,andchlorideinthebodyimposedbythoseearlyAscomparedwithdietsbasedonnaturalfoods,studiescontractedboththeintracellularandex-dietsbasedonprocessedfoodsarehighinsodiumtracellularcompartments,therebyengenderingaandlowinpotassium.3,10Forexample,twoslicesdecreaseinbloodpressure.18,20Subsequentstud-ofham(57gcontain32.0mmolofsodiumandiesinratsshowedthatthepressoreffectofpotas-4.0mmolofpotassium,andacupofcannedsiumdepletionrequiresabundantconsumptionchickennoodlesoupcontains48.0mmolofso-ofsodiumchloride(e.g.,4.5gofsodiumchloridediumand1.4mmolofpotassium.Conversely,per100.0gofdietaryintake.21
dietscontainingabundantfruitsandvegetablesPopulationstudieshaveshownaninversearesodium-poorandpotassium-rich.3,10Forexam-relationofpotassiumintaketobloodpressure,ple,anorange(131gcontainsnosodiumandtheprevalenceofhypertension,ortheriskof6.0mmolofpotassium,andacupofboiledpeasstroke.8,22-25Afteradjustingforpotentiallycon-contains0.3mmolofsodiumand9.8mmoloffoundingvariables,theINTERSALTresearcherspotassium.Isolatedpopulationsthateatnaturalestimatedthatadecreaseinpotassiumexcretionfoodshaveanindividualpotassiumintakethatby50mmolperdaywasassociatedwithanin-exceeds150mmolperdayandasodiumintakecreaseinsystolicpressureof3.4mmHgandanofonly20to40mmolperday(theratioofdietaryincreaseindiastolicpressureof1.9mmHg.Thepotassiumtosodiumis>3andusuallyclosertourinarypotassium:sodiumratiointheINTERSALT10.6,8,10Bycontrast,peopleinindustrializedna-studyhadasignificant,inverserelationwithtionseatmanyprocessedfoodsandtherebyingestbloodpressure.Thisratioboreastrongerstatis-30to70mmolofpotassiumperdayandasmuchticalrelationshiptobloodpressurethandidei-as100to400mmolofsodiumperday(theusualthersodiumorpotassiumexcretionalone.11Asdietarypotassium:sodiumratiois<0.4.3,10
comparedwithwhites,blackshaveahigherprev-Hypertensionaffectslessthan1%ofpeoplealenceofhypertensionandlowerpotassiumin-inisolatedsocietiesbutapproximatelyonethirdtake;sodiumintakeamongwhitesandblacksisofadultsinindustrializedcountries.3,10Differ-
similar.10,23Forexample,intheEvansCounty
nengljmed356;19www.nejm.orgmay10,2007
Downloadedfromwww.nejm.orgonAugust8,2007.Copyright©2007MassachusettsMedicalSociety.Allrights
reserved.
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