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Imbalance of endogenous homocysteine and hydrogen sulfide metabolic pathway in essential hypertensive children

By Bill Gordon,2014-06-02 02:16
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Imbalance of endogenous homocysteine and hydrogen sulfide metabolic pathway in essential hypertensive childrenImbala

    Imbalance of endogenous homocysteine and

    hydrogen sulfide metabolic pathway in

    essential hypertensive children ChineseMedicalJournal200120(5):389393389

    Originalarticle

    Imbalanceofendogenoushomocysineandhydrogensulfide

    metabolicpathwayinessentialhypertensivechildren

    CHENLi,INGRIDSumou,DINGYaguang,LIUYing,QIJianguang,TANGChao

    shuandDUJun-bao

    Keywor~:homocysteine;hydrogensulfide;hypertension;systolicbloodpressure BackgroundHypertensionisacommondiseaseofthecardiovascularsystem.Sofar,thepathogenesisofpdma~

    hypertensionremainsunclear.Theelaborationofitspathogenesisisanimportanttopicinthefieldwhichcallsforurgent

    resolution.Theaimofthisstudywastoprobeintothemetabolicimbalanceofhomocysteine(Hcy)andhydrogensulfide

    (H2S)inchildrenwithessentialhypertension,anditssignificanceinthepathogenesisofessentialhypertension.

    MelhodsTwent,,-fivechildrenwithessentiaIhypertensionand30healthychildrenwithnormaIbloodpressurewere

    enrolledinthestudy.ThemedicaIhistorywasinvestigatedandaphysicalexaminationwasconductedonthesubjects.

    PlasmaHcycontentwasexaminedbyfluorescencepolarizationimmunoassayfFPIA).TheplasmaH2SIeve1was

    detectedbyamodifiedmethodwithasulfideelectrode.Datawerepresentedasmean?

    standarddeviation.Thettest

    wasappliedtothemeanvaluesofbothgroups.PearsonIinearcorrelationanalysiswasappliedtotheplasmaHcyand

    H2SaswelIastothesystolicpressureagainsttheplasmaH2S/Hcyratio. ResultsPlasmaHcy,anintermittentmetaboliteoftheendogenousmethioninepathway,wasmarkedlyincreasedbut

    plasmaH2S.afinaIproductofthispathwaywassignificantlydecreasedinhypertensivecaseswhencomparedwith

    normalsuNe~s((Hcy:(12.68-t-9.69)pmol/LMS(6.62?

    4.79)pmol/L(t=-2.996,P<0.01):H2S:(51.93?6.01)pmol/LMS

    (65.70?5.50)pmol/L)(t=-

    8.670,P<0.01)).TheratioofplasmaH2S/Hcyinchildrenwithhypertensionwas5.83?

    2.91,

    whilethatofthecontroIgroupwas11.60?

    3.30.andthedifferenceissignificantwithat---6.610andP<0.01.Anegative correlationexistedbetweenplasmaHcyandH2Sconcentrations,,_-

    0.379.P<0.05.Andanegativecorrelationwas

    foundbetweensystolicbloodpressureandtheplasmaH2S/Hcyratio,仁一0.687.P<0.05.

    ConclusionTherewasametabolicimbalanceofhomocysteineandhydrogensulfideinessentialhypertensive

    children.

    ChinMedJ2007:120(5):389393

    H(Hcy)isasulfuraminoacidwhichismetabolicbyproductinthemethionine cycleaswellasanindependentriskfactorinthe

    pathogenesisofatherosclerosis.acutemyocardial

    infarction,cerebralapoplexy,coronaryarterialdisease,

    andperipheralvasculardisease.Thereisanassociation

    betweentheelevationofplasmaHcylevelandthe

    pathogenesisofhypertension..However,thepathogenesis

    ofhypertensionisnotfullyexplainedbythepresenceof

    Hcy.

    Hydrogensulfide(H2S)isarecentlydiscoverednew gasotransmitterinthemodulationofcardiovascular function.H2Scanbesynthesizedthroughtheinvivo methioninemetabolicpathway,withthecatalysisby cystathionineBsynthetase(CBS)andcystathionineY

    lyase(CSE)ofHcy.ThemodulatingfunctionsofH2Son vasodilationandsmoothmusclecellproliferation, resemblestoagreatextent,althoughnotidenticaltothe essentialbiologicalcharacteristicsofnitricoxide(N0) andcarbonmonoxide(CO).

    Inrecentyears,researches9'lorevealedthatthereduction oftheintrinsicH2Slevelinratswasanimportantfactor leadingtospontaneoushypertension.SinceHcyandH2S coexistinthesameinvivometabolicpathwaywithCSE, whatwouldbethealterativeconnectionbetweenH2Sand Hcyinthepathogenesisofprimaryhypertension?This studywasaimedtoinvestigatethesignificanceoftheir metabolicimbalanceinthepathogenesisofhypertension throughdetectingthealterationsoftheircorresponding plasmaconcentrationinchildrenwithprimary hypertension.

    DepartmentofBediattics,PelingUniversityFirstHospital,Beijing 100034,China(ChenL,IngridS,DingYGLiuQiJGandDIl JB)

    InstituteofCardiovascularDiseases.PelingUniversityFirst

    Hospital,Beijingl00o34,China(TangCS)

    KeyLab,MolecularCardiovascularDiseases,Ministryof Education,Beijingl0DO34,China(DuJBandTaIlgCS) Correspondenceto:Prof.DUJun-bao,DepartmentofPediatrics, PekingUniversityFirstHospital,Beijingl00o34.Cllina(Tel:

86.10.6655l122ext3238.Fax:86l0.66134261.Emall:

    j~baedu@ht.ro1.cn.net)

    CHENLiandDGRI)Sumoucontributedequallytothispaper. Thisworkwassupportedbygrantsfrom?leKeyScienceand

    Techno1ogYProgramofBeiiing(No.H030930030530andNo. H030930030031),NationalNaturalScienceFoundationofChina (No.30425010andNo.3063o031),andMajorBasicResearch ProjectofChina(No.2006CB50380"/1.

390ChinMedJ2007;120(5):389393

    MTHoDS

    Subjects

    Atotalof55childrenwereenrolledinthestudy.Ofthem, 25children(1lboys,14girls)withanaverageageof (10.48?3.23)yearswhowerediagnosedwithprimary hypertensioninthePekingUniverityFirstHospitalwere assignedtothehypertensivegroup.Inthehypertensive group,20caseswereobesechildren,and7caseshada familialhypertensivehistory.TIleother30children(19 boys.1lgirls)withanaverageageof(10.57?0.73)

    yearswithnormalbloodpressurewereassignedtothe controlgroup.Amongthechildrenincontrolgroup,6 caseswereobesechildren,and2caseshadafamilial hypertensivehistory

    Thediagnosticcriteriaofhypertensionwasbasedonthe definitionwhichwasestablishedbythe2ndConference oftheAmericanChildrenandAdolescentsBlood PressureControlW_orkshopin1996.Hypertensionwas definedasameansystolicbloodpressureand/ormean diastolicbloodpressurebeiIlgequaltooroverthatofthe

    95thpercentileofchildrenandadolescentsofthesanle age.gendeLandheight."TIlemedicalhistorywas investigatedandaphysicalexaminationandlaboratory testswereperformedforthetwogroupstoexcludeother diseasesconcerningthecardiopulmonary,urinary,and endocrinesystems.Aninformedconsentwasobtained fromtheparentsofthechildrenandthestudyprotocol wasapprovedbythecalCommitteeofPeking

    UniversityFirstHospita1.C|lina.

    Demographicinformationincludingthepatient'sname, gendeaagewascollectedandadetailedphysical examinationwasconducted.estandardhydrargyric

    cafjfsphygmomanometer,whichmetthequantitative criteria,wasadoptedtodetectbloodpressure.The environmentfordetectionwasquiet,withanoptimum roomtemperatureof18.C22.C.Anyvigorous

    exercises,eatinganddrinking(exceptdrinkingwater)and theintakeofanymedicinethatmightaffectblood pressurewereavoidedatleastonehourbeforethetesting. Clothingwaslooseandfight.TIlechirldrenrestedfor15 minutes,seatedquietly.

    Therightbrachialarterialbloodpressurewasdetected, withtherightupperlimbatthesamehorizontallevelas theheart.Thewidthofthecuffwas2/3thelengthofthe upperarm,avoidingtwistsorfolds.Thelowerborderline ofthecafjfwas2.5cm3cmabovethecrossstriationof

    theelbow.Thebelltypechestpieceofthestethoscope wasplacedunderthecuffborderlineonthebrachial arteryatthemedialsideofthecubitalfossa,avoiding frictionagainstthecuff.

    Beforethetest,theradialarterypulsewaspalpated. Duringthetest,airwaspumpedrapidly,andthereading ofthemercurycolumnwasinstantlyrecordedwhenthe pulsecouldnolongerbepalpated.Theairwasreleased. Wewaitedfor1minuteandthenraisedtheupperarmfor 56seconds.TIleairwaspumpedagainuntilthe mercurylevelreached30mmHgabovethereadingwhere thepulsecouldnolongerbepalpated.Airwasreleasedat aspeedof2mmHgpersecond,andthebloodpressure wastakendown.TheKorotkofjf1st,4th,and5thsound (mufflingsound)wasrecorded.Threesetsofconsecutive testingwerecardedout.1eavingatimeintervalof1 minuteaftereachtrialandraisingtheupperarlnfor56

    seconds.Thebloodpressurerecordsofthesecondand thirdtrialsweretakenandtheirmeanvaluewasdeducted. The1stKorotkoffsoundwastakenasthesystolic pressurewhilethe4thsoundwasthediastolicpressure. DetectioilofplasmaHcy

    TheserumHcydetectionkit(Abbott,USA)wasused alongwiththeAbbottIrnxAutomaticIrnmunoanalyzer,

    producedbytheAmericanAbbottCompany.The fluorescencepolarizationimmunoassay(FPIA)was adoptedfordetection.TheHcvsynthesizedinnormal humanplasmaexistsintheformofreductive, proteinconjugatedfPSSHey)mixeddisulfide

    compound(CySSHey)aswellasthehomocystineform (HeySSHey).Therefore.thedetectionmethodineluded: (1)theplasmasamplebeingpretreatedwith

    dithiothreitol(DDT).Hcv,themixeddisulfideformas

wellastheproteinconjugatedformwereallreducedto

    freeHcy(tHcv);(2)withtheexistenceof

    Sadenosylhomocysteinehydrase(SAH)andexcessive adenosine,Heyintheserumwouldbetrailsformedinto SAH;(3)thepredilutedSAHmixture,antiSAH

    monoclonalantibodyandthemarkedfluorescent S.-adenosine.-L..cysteinetracerwereincubated simultaneously.wethenemployedtheAbbottImx AutomaticImmunoanalyzertoautomaticallydetectany changesinthepolarizationspectrum.Finally,according tothestandardcurve,thequantityofHcvinthesample couldbedetected.12一一一

    DetectioilofplasmaHzS

    ThePXS270modelionicmeter(ShanghaiLeici.China) wasemployedfordetectionthroughthesensitivesulfur electrodemethod.H2Sintheplasmausuallyexistsinthe formofgas(1/3)andNaHS(2/3)enanantioxidantis addedtoit,H2SandNaHSreactwithNaOHtogiveS. P1asmaS''wasdetectedthroughthesensitivesulfur electrodeinordertoindirectlyreflecttheH2S concentration.Hencethedetectionprocedurewasas follows:(1)preparethestandardsulfurionsolutionand theantioxidantsolution;(2)beforeusingtheelectrode,be sureitwasactivatedforover2hoursindeiouizedwater.

    Switchontheionicmeter,thedetectionitemwas adjustedto''my"statusandtheslantingratewasadjusted to100%:(3)boththesensitivesulfurelectrodeandthe controlelectrodewereimmersedintothespecimen,and werecordedthereadingwhenitreachedstability.The

electrodeshouldbewashedwithdeionizedwater.After

    eachtesting,electrodesweI.eimmersedindeionjzed

    watertomaintainactivateI1statIls.Bef_oreeachtesting, astaIldardSsolutionwasusedtogeneratetl1estaIldard CUr,,e

    ticalanalysis

    111eSPSSl0.0soarewasusedfortaaJ1sis.Data

    ChineseMedicalJournal2007;120(5):389.393 'Significantdifferenceinsystolicpressureanddiastolicpressurebetweenhypertensivegrou

    pandcontrolgroupfP<0.05)

    Table2.Comoarisonofolasma1eve1ofHcv,H2SandH2S/I-Icybetweenthetwogroups(mea

    n+SD

    SignificantdifferenceinHcy,H2SandH2S/I-Icybetweenhypertensivegroupandcontrolgr

    oup(P<0.01).

    wererepresentedbymean?standarddeviation(mean?

    SD1.Thettestwasappliedtothemeanvalueofboth groupsofspecimen.Pearsonlinearcorrelationanalysis wasappliedtotheplasmaHcyandH2Sdataaswellasto theratioofthesystolicbloodpressureagainsttheplasma H'S/Hcyratio.P<O.O5wasconsideredstatistically significant.

    RESUI'S

    Ag9andbloodpressuremeanvaluesofbothgroups Theaverageageofchildreninthehypertensiongroup was(10.48?3.23)yearsold.Theaveragesystolic

    pressureofthegroupwas(129.68?6.55)mmHg.and

    thediastolicpressurewas(76.88?8.89)mmHg.The

    averageageofchildreninthecontrolgroupwas(10.57

    ?0.73)yearsold.Theiraveragesystolicbloodpressure was(95.4O?6.56)mmHgandtheirdiastolicblood

    pressurewas(60.60?4.64)mmHg.Theaverageblood

    pressureofthetwogroupswassignificantlydifferent (P<O.05)(Tablel1.

    DetectionofplasmaHcyinchildren

    TheaverageplasmaHcyinchildrenfromthe

    hypertensiongroupwas(12.68?9.69)pmo1/L.whilethat

    ofthecontrolgroupwasf6.62?4.79)pmol/L.P1asma

    Hcylevelsweremuchhigherinchildrenwitll hypertensionthaninthecontrolgroup;withat=2.996 andP<O.O1demonstratingastatisticalsignificance betweenthetwogroups(Table21.

    DetectionofplasmaH2Sinchildren

    PlasmaH2Sinchildrenwithhypertensionwasfoundto be(51.93?6.01)pmol/L.whilethatofthecontrolgroup was(65.7O?5.50)pmol/L.TheplasmaH2Slevelin

    childrenwithhypertensionwassignificantlylowerthan theH2Slevelinthecontrolgroup.(f=8.670and

    P<0.Ol1.

    RatioofplasmaH~S/l-lcyinbothgroups

    TheratioofplasmaH2S/Hcvinchildrenwith

    hypertensionwasfoundtobe5.83?2.91whilethatof

    thecontrolgroupwasl1.6O?3.3O.Theratioofthe

    plasmaH2S/Hcywaslowerinchildrenwithhypertension thaninthecontrolgroup,(r---6.610andP<O.01).andthe

    differenceisstatisticallysignificant(Table21. CorrelationbetweenplasmaHcyandH2s

    levelsinbothgroups

    Throughapplyingthelinearcorrelationanalysistoboth

Plasmaslevel(~mol/L)

    Fig.1.CorrelationbetweenplasmalevelsofH2SandHcy (0.379,P<0.05).lateralaxisstandsfortheplasma H2SlevelandtheaxisofordinatestandsfortheplasmaHcy leve1.AcorrelationbetweenplasmaHcyandH2Slevelsin childrenwascreated.

    values,theresultsdemonstratedanegativecorrelation (0.379,P<O.05).Thatis,thehighertheplasmaHcy level,thelowertheplasmaH2S(Fig.1).

    Correlationbetweenthesystolicbloodpressureand thevalueoftheplasmaH2S/Hcyinbothgroups

    Alinearcorrelationanalysiswasappliedtocomparethese data.TheresultsdemonstratedanobviOUSnegative correlation,(0.687,P<O.05).means,thehigher

    thesystolicpressure,thelowertheplasmaH2S/Hcyvalue (Fig.21.

    PlasmaH2S/I-Icylevel

    Fig.2.Correlationbetweensystolicpressureandplasma H2S/I-Icyratio(r=-0.687,P<0.05).The1ateralaxisstandsfor theplasmaH2S/Hcylevelandtheaxisofordinatestandsfor thesystoficpressure.Thecorrelationbetweenthesystolic pressureandthevalueoftheplasmaH2S/Hcyinbothgroups ofchildrenwascfeated.一一

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392ChinMedJ2007|.120(5).'389-393

    DISCUSSIoN

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