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|影响因子|SCI影响因子|SCI检索|SCI收录|被引频次|SCI期刊J_Pharmacol_Exp_Ther-2004-Cahill-59-65[1]12
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J_Pharmacol_Exp_Ther-2004-Cahill-59-65[1]12
/$；THEJOURNALOFPHARMACOLOGY；Vol.308,No.1Copyright?20；PrintedinU.S.A.；PropafenoneandItsMetabol；KrinSeanA.CahillandGilJ.；DepartmentofPediatricsan；ReceivedAugust
/$20.00THEJOURNALOFPHARMACOLOGYANDEXPERIMENTALTHERAPEUTICSVol.308,No.1Copyright?2004byTheAmericanSocietyforPharmacologyandExperimentalTherapeutics5JPET308:59C65,2004PrintedinU.S.A.PropafenoneandItsMetabolitesPreferentiallyInhibitIRabbitVentricularMyocytesKrinSeanA.CahillandGilJ.GrossDepartmentofPediatricsandChildHealth,UniversityofManitoba,InstituteofCardiovascularSciences,St.BonifaceGeneralHospitalResearchCentre,Winnipeg,Manitoba,CanadaReceivedAugust1,2003;acceptedSeptember18,2003ABSTRACTPropafenoneisanantiarrhythmicagentwithrecognizedcar-rentamplitudefollowingrepolarizationfrom?50mVto?30diacmyocyterepolarizingK?currentinhibitoryeffects.IthasmV.Itwoknownelectropharmacologicallyactivemetabolites,5-hy-Krinhibitionwasconcentration-andweaklyvoltage-de-pendent,withatimecoursefromchannelactivationthatwasdroxy-andN-depropylpropafenone,whoseK?currentinhibi-welldescribedbyasingleexponentialmodelandconsistenttoryeffectsarelessthoroughlyelucidatedthanthoseofthewithopenchannelblock.Propafenoneandits5-hydroxyandparentcompound.Thisstudycharacterizesanddirectlycom-N-depropylmetabolitesalsoblockedIparesthepharmacologicinteractionofallthreecompoundstowithIC50valuesof7.27?0.53,40.29?7.55,and44.26?5.73?M,respectively,withtwokeyrepolarizingK?currents,therapidlyactivatingat?50mV.NosignificantdrugeffectswereobservedwithdelayedrectifierIKrandthetransientoutwardcurrentIrespecttoIthewhole-cellpatch-clamptechniqueinisolatedrabbitto,usingventric-tovoltagedependenceofsteady-stateinactivationortimecourseofrecoveryfrominactivation.Thepreferentialularmyocytes.AllthreeagentspotentlyinhibitedIinteractionofpropafenoneanditsmetaboliteswithIvaluesof0.80?0.14,1.88?0.21,and5.78?1.24KrwithIC?Mfor50toIinventricularmyocytesshedsnewlightontheKrrelativepropafenone,5-hydroxypropafenone,andN-depropyl-toanti-andproarrhythmicactivityofpropafenoneinvivo.propafenone,respectively,basedonreductionofpeaktailcur-TheVaughanWilliamsclass1cantiarrhythmicagentpharmacologicallyactivemetabolites,5-hydroxypropafenonepropafenoneinhibitscardiacmyocyterepolarizingcurrentsandN-depropylpropafenone(Hegeetal.,1984;Latinietal.,inanumberofexperimentalpreparations.Propafenone1987;Malfattoetal.,1988).Availablestudieswith5-hy-blocksthetransientoutward(Ito)andultrarapidlyactivatingdroxypropafenoneindicatepotentIdelayedrectifier(ItoinhibitioninculturedKur)currentsinhuman(GrossandCastle,1998;Sekietal.,1999)andrabbit(Duanetal.,1993)atrialneonatalratventricularmyocytes(Cahilletal.,2001)andmyocytesaswellasinadult(SlawskyandCastle,1994)andelectropharmacologiceffectsinintactorganismsandinvitroneonatal(Cahilletal.,2001)ratventricularmyocytes.Inpreparationsconsistentwithinhibitionofanumberofcar-guineapigventricularmyocytes,propafenonepotentlyanddiacmyocyteioniccurrents(vonPhilipsbornetal.,1984;preferentiallyinhibitstherapidlyactivatingcomponentofDelgadoetal.,1987;Valenzuelaetal.,;Malfattodelayedrectifiercurrent,Ietal.,1988;Rouetetal.,1989;Caseetal.,1991;Haefelietal.,Kr(Delpo′netal.,1995).Propafenonealsoblockstheheterologouslyexpressedhuman1991;Boucheretal.,1996;Franquezaetal.,1998).ThecardiacK?channelHERG,whichmediatesIcardiaccellularelectropharmacologyofN-depropyl-Krinlivingcardiacmyocytes(Mergenthaleretal.,2001;Pauletal.,propafenonehasnotbeenpreviouslystudied,althoughlim-2002).iteddatasuggestingioniccurrentblockadeareavailableClinicaluseofpropafenoneisassociatedwithextensivefromintactanimalsandtissuepreparations(Malfattoetal.,hepatictransformationoftheparentagenttotwoelectro-1988;Rouetetal.,1989).Weusedthewhole-cellpatch-clamptechniquetodirectlyThisworkwassupportedbyanoperatinggrantfromtheManitobaMedicalcomparetheinhibitoryeffectsofpropafenone,5-hy-ServiceFoundation.Article,publicationdate,andcitationinformationcanbefoundatdroxypropafenone,andN-depropylpropafenoneontherepo-http://jpet.aspetjournals.org.larizingcurrentsItoandIKrinisolatedrabbitventricularDOI:10.1124/jpet.103.057844.myocytes.ABBREVIATIONS:HERG,humanether-a`-go-IKr,rapidlyactivatingdelayedrectiIKs,slowlyactivatingdelayedrectiIto,transientoutIKur,ultrarapidlyactivatingdelayedrectiHBS,HEPES-bufferedsaline.59Downloaded from jpet.aspetjournals.orgby guest on March 2, 201260CahillandGrossMaterialsandMethodsThisinvestigationconformedwiththeGuidetotheCareandUseofExperimentalAnimalspublishedbytheCanadianCouncilonAnimalCare(2ndedition,1993)andwasapprovedbytheUniversityofManitobaProtocolManagementandReviewCommittee.RabbitVentricularMyocyteIsolation.HealthymaleNewZealandWhiterabbits(2.5C3.5kg)wereanesthetizedwithinhaledisofluranefollowedbyintravenousheparinization(500IU).Afterrapidcardiectomy,theaortawascannulated(?2min)andperfusedretrogradelyat27ml/minwithnominallyCa2?-freeHEPES-buff-eredsaline(HBS)solutionuntilthereturnwasclear(?10min).Theatria,excessconnectivetissue,andpericardiumweretrimmedoff.FreshCa2?-freeHBScontaining1mg/mlcollagenase(class2;WorthingtonBiochemicals,Freehold,NJ)and0.14mg/mlprotease(typeXIV;Sigma-Aldrich,St.Louis,MO)wasthensubstitutedandrecirculateduntiltheventriclessoftened(15C20min),followedbya4-minwashoutwithenzyme-andCa2?-freeHBS.Allperfusatesweregassedwith100%O2andmaintainedat37?1°C.Theventri-clesweregentlyteasedapartwithforceps,dispersingthemyocytes.Theresultingsuspensionwasfiltered,thenmyocyteswereresus-pendedinsequentiallyhigherCa2?concentrations(0.05,0.1,0.2,1.0,and1.8mMinHBS)andstoredatroomtemperatureforstudywithin10hofisolation.ElectrophysiologicRecording.Conventionalwhole-cellpatchclampwasperformedaspreviouslydescribed(Hamilletal.,1981;Grossetal.,1995).Myocyteswereallowedtosettletothebottomofamodified35-mmculturedishmountedonthestageofaninvertedmicroscope(NikonDiaphot300).Thecellsweresuperfusedcontin-uouslyat1to2ml/min.Onlyquiescentrod-shapedcellswithclearstriationswereselectedforstudy.Thin-walledborosilicatemicropi-petteswerepulledandpolishedtoaresistanceof1.5to3.0M?whenfilledwithintracellularsolution.Voltage-clampprotocolswerecon-trolledwithaPentium133MHzpersonalcomputerrunningpClamp6.0.4softwareinterfacedtoanAxopatch200BamplifierviaaDigi-data1200A/Dboard(AxonInstrumentsInc.,UnionCity,CA).Allexperimentswerecarriedoutatroomtemperature(20C22°C).Hold-ingpotentialwas?80mVexceptasotherwiseindicated,andNa?currentwasinactivatedwitha100-msconditioningstepto?50mVpriortoeachtestpulse.L-typeCa2?currentwasblockedwith2mMCoCl2intheextracellularsolution.SolutionsandReagents.HBSusedinventricularmyocyteiso-lationcontained132mMNaCl,4mMKCl,1.2mMMgCl2,10mMHEPES,10mMD-glucose,and0.5%bovineserumalbumin,pH7.4withNaOH.Theextracellularsolutionusedforwhole-cellpatch-clamprecordingincluded135mMNaCl,5.4mMKCl,2.0mMCoCl2,1.0mMCaCl2,1.0mMMgCl2,10mMHEPES,and10mMD-glucose,pH7.4withNaOH.Pipettesolutionconsistedof145mMKCl,5mMNaCl,5mMK2EGTA,10mMHEPES,and4mMMgATP,pH7.2withKOH.Propafenone,5-hydroxypropafenone,andN-depropyl-propafenone(KnollPharma,Markham,ON,Canada)werekeptas10-mMstocksolutionsindimethylsulfoxideandseriallydilutedincontrolextracellularsolutionasrequired.E-4031(WakoPureChem-icals,Osaka,Japan)wasstoredas5mMstocksolutiondissolvedinwaterthendilutedto5?Minextracellularsolution.Allstockdrugsolutionswerestoredat?20°Cuntildilutiontoappropriateconcen-trationsonthedayofuse.Withanychangeinextracellularsolution,atleast5mlofthenewsolutionwereperfusedthroughthebathtoallowforequilibrationpriortoelectrophysiologicrecording.DataAnalysis.IKrwasmeasuredaspeaktailcurrentdensityat?30mVfollowing3-sdepolarizingvoltagestepsfromaholdingpotentialof?80mV(Salataetal.,1996).Toensurethatourmea-surementsofIKrinhibitionbypropafenoneanditsmetaboliteswerenotconfoundedbyIKs,weexcludeddataobtainedfromcellsinwhichanyofthefollowingwereobserved:1)evidenceofmultiplecurrentsina2)thepresenceofaseconddeactivatingtailcurrentat0mVsuggestiveofIKsaccordingtoaprotocolde-scribedbyCarmeliet(1998);and/or3)failuretoobservecompletetail-currentinhibitionwithapplicationofthedofetilideanalogE-4031at5?M(FollmerandColatsky,1990).Transientoutwardcurrent(Ito)anditsinhibitionwereanalyzedaspreviouslydescribed(GrossandCastle,1998;Cahilletal.,2001).Briefly,Itowasmeasuredasthetimeintegralofspontaneouslydecayingoutwardcurrentobservedinresponsetodepolarizing800-msvoltagestepsfromaholdingpotentialof?80mV,adjustedforthe“steady-state”currentremainingattheendofthestep.Dose-responsecurvesweregeneratedusingtheHillequation.Itoinactivationtimeconstantswereobtainedusingsingleordoubleexponentialdecaymodelsfittedtotherawcurrenttracings.Steady-statevoltagedependenceofItoinactivationdatawerefittedwiththeBoltzmannequation,andthetimecourseofrecoveryfrominactiva-tionwithasingleexponentialequation.Allcurve-fittingprocedureswereperformedusingOrigin6.0(OriginLabCorp.,Northampton,MA),yieldingtimeconstantsandmidpointpotentialsforpooleddatawhereappropriate.Resultsarereportedasmean?S.E.exceptasotherwiseindicated.ResultsIKrInhibitionbyPropafenoneandItsMetabolites.Inresponseto3-sdepolarizingvoltagestepsfromaholdingpotentialof?80mVfollowedbyrepolarizationto?30mV,weobservedatime-dependentoutwardcurrentfollowedbyadeactivatingtailcurrent(Fig.1).AlthoughSalataandcol-leagues(1996)haveshownevidenceoftheslowlyactivatingcomponentIKsinthispreparation,thedelayedrectifiercur-rentexpressedinmyocytesstudiedherefeaturedcharacter-isticsconsistentwiththoseofpureIKr.PropafenoneanditsmetabolitespotentlyinhibitedIKrinaconcentration-dependentfashion(Fig.2).Basedonreductionofpeaktailcurrentamplitudefollowingrepolarizationfrom?50mVto?30mV,IC50valuesof0.80?0.14,1.88?0.21,and5.78?1.24?Mwerecalculatedforpropafenone,5-hy-droxypropafenone,andN-depropylpropafenone,respectively(Fig.3A).Figure3BillustratesIKrtailcurrentdensity-volt-agerelationsintheabsenceandpresenceofincreasingcon-centrationsofpropafenone.Voltage-dependentIKrinhibitionisconsistentwithopenchannelblockadeandhaspreviouslybeenreportedwithFig.1.Delayedrectifiercurrent(IRepresentativeillustrationoffamilyKr)inarabbitventricularmyocyte.oftracingselicitedwithaseriesof3-sdepolarizingvoltagestepsfromaholdingpotentialof?80to?40,?ization20,0,to?20,?30?40,mVandtoelicit?60outwardmV(inset),tailfollowedcurrent.ineachcasebyrepolar-Downloaded from jpet.aspetjournals.orgby guest on March 2, 2012VentricularK?CurrentBlockbyPropafenoneandMetabolites61Fig.2.Voltage-gatedactivatingandtailcurrentselicitedintheabsence(left-handpanels)andpresence(right-handpanels)of30?Mpropafenone(A),5-hy-droxypropafenone(5-OHB),andN-depropylpropafenone(N-DPC),usingthesamevoltage-stepprotocolasinFig.1.Currentsthatpersistafterdrugapplicationinthedepolarizationphaseofeachtracingrepresentinwardlyrectify-ingcurrent(IK1)activatedatvoltagesnegativeto0mV,whichwasnotsignifi-cantlyinhibitedbyanyoftheagentstested.dofetilideinrabbitandguineapig(Carmeliet,1992)andwithofItowaselicitedwith800-msdepolarizationsfromaholdingpropafenoneinguineapig(Delpo′netal.,1995)ventricularpotentialof?80mV.Althoughpropafenoneitselfpredictablymyocytes.Inthepresentstudyinvolvingrabbitventricularinhibitedthiscurrentinaconcentration-andtime-depen-myocytes,tailcurrentinhibitionwasmildlyvoltage-depen-dentfashionsimilartothatseeninotherpreparations(Duandentwithallthreeagentstested(Fig.4A).Furtherevidenceetal.,1993;SlawskyandCastle,1994;GrossandCastle,ofopenchannelblockadewasprovidedbyestimationofthe1998)(Fig.5A),boththe5-hydroxyandN-depropylmetabo-timecourseofIKrinhibition,throughcomparisonoftailcur-litesdidsofarlesspotently.TheIC50forpropafenonewasrentamplitudesfollowingdepolarizationsofvaryingdura-7.27?0.53?Mat?50mV,whereas5-hydroxypropafenonetionintheabsenceandpresenceofdrug.AscanbeseeninandN-depropylpropafenoneblockedItowithIC50valuesofFig.4B,thetimecourseofIKrinhibitionwaswelldescribed40.29?7.55and44.26?5.73?M,respectively,at?50mVbyasingleexponentialmodel.Furthermore,tailcurrents(Fig.5B).UnlikepropafenoneinhibitionofIto,whichwasfollowingrelativelyshortdepolarizationsinthepresenceofpromptlyandcompletelyreversibleuponwashout(Fig.6A),drugwereessentiallythesameascontrolcurrents,indicat-blockadebythemetaboliteswasonlypartiallyreversibleinglackoftonicIKrblockadebytheseagents.(Fig.6B).ItoInhibitionbyPropafenoneandItsMetabolites.APreviousstudieshaveshownnosignificanteffectofrapidlyactivating,slowlyinactivatingcurrentcharacteristicpropafenoneonItovoltagedependenceofsteady-stateinac-Downloaded from jpet.aspetjournals.orgby guest on March 2, 201262CahillandGrossFig.3.Concentration-dependentIA,dose-responseKrinhibitionbypropafenoneanditsmetabolites.curvesforpropafenone,5-hy-droxypropafenone,andN-depropylpropafenonegeneratedfrompooledpeaktailcurrentdataelicitedduringrepolarizationto?30mVfrom3-sstepsto?50mV(n?3C9foreachdatapoint)fittedwiththeHillequation.Eachrawdatapointwasgeneratedbynormalizingtheob-servedpeaktailcurrentfollowingdepolarizationto?50mVinthepresenceofthedrug,attheconcentrationindicated,tothecurrentelicitedinthesamecellpriortodrugapplication.B,currentdensity-voltagerelationsforIof0.1(nKrpeaktailcurrentsintheabsence(control,n?14)andpresence?5),1.0(n?9),and10(n?4)?Mpropafenone.tivationortimecourseofrecoveryfrominactivation.Inthepresentstudy,neitherpropafenonenoreitherofthemetab-olitesstudiedhadanyapparenteffectonthesephenomena.NoneofthecompoundsstudiedshowedusedependentItoblock.DiscussionClinicalSignificanceofRepolarizingCurrentBlock-adebyPropafenoneandItsMetabolites.Propafenoneiseffectiveinthemedicaltherapyofavarietyofsupraventric-ularaswellasventriculartachyarrhythmiasinchildren(PaulandJanousek,1994)andadults(Grant,1996).Al-thoughcategorizedasasodiumchannel-blockingagentintheVaughanWilliamsantiarrhythmicdrugclassificationscheme,propafenonepotentlyinhibitsanumberofrepolar-Fig.4.VoltageandtimedependenceofI(Propaf,Krblock.A,voltagedependenceofIKrblockby1?Mn?5),3?M5-hy-droxypropafenone(5-OHpropaf,n?5),and10?MN-depropyl-propafenone(N-DPpropaf,n?3).TheIKrpeaktailcurrentamplitudeinthepresenceofdrugwasdividedbythatrecordedintheabsenceofdrugtoyieldanestimateofresidualcurrentfollowing3-sstepstothevoltagesindicated.IKrblockbyallthreedrugswasvoltage-depen-denttoasimilarextent.B,timedependenceofI5-hydroxypropafenone.Depolarizingstepsto?50mVKrblockby1?Mofvaryingdurationwereappliedinthepresenceofthedrug,followedbyrepolarizationto?density30mVwastodividedelicittailbycurrent.thevalueForobtainedeachcellwith(nafull?3),3-speakdepolarizingtail-currentsteppriortodrugapplicationandthenplottedagainstdepolarizingstepdurationinpresenceofthedrug.Theresultingcurveiswellfittedbyasingleexponentialdecaymodelwithtimeconstant(?)asshownandisconsistentwitharequirementforthechanneltoopeninorderfordruginteractiontotakeplace.izingpotassiumcurrentsincardiacmyocytesisolatedfromhumans(GrossandCastle,1998;Sekietal.,1999)aswellasfromanimals(Duanetal.,1993;SlawskyandCastle,1994;Delpo′netal.,1995;Christe′etal.,1999;Cahilletal.,2001).MostrepolarizingcurrentinvestigationshavefocusedonItoinhibition(Duanetal.,1993;SlawskyandCastle,1994;GrossandCastle,1998;Sekietal.,1999;Cahilletal.,2001).However,morerecentstudiesinvolvingheterologouslyex-pressedHERGchannels,whichmediateIKr,suggestthatHERGisanimportantmoleculartargetforpropafenone(Mergenthaleretal.,2001;Pauletal.,2002).ThissupportstheearlierdemonstrationofguineapigventricularmyocyteIKrinhibitionbyDelpo′netal.(1995)andisofgreatinterestbecauseIKrinhibitionlikelyplaysakeyroleinsometimesDownloaded from jpet.aspetjournals.orgby guest on March 2, 2012VentricularK?CurrentBlockbyPropafenoneandMetabolites63Fig.5.Itoinhibitionbypropafenoneanditsmetabolites.A,followingaNa?current-inactivating100-msstepto?35mVfromholdingpotential?80mV,an800-msstepto?50mVelicitedItoundercontrolconditions(voltageprotocol,inset).Themyocytewasthensequentiallysuperfusedtopresumedsteadystate(minimum5ml)withextracellularsolutioncon-taining1,10,and100?Mpropafenoneasshown,resultinginmarkedconcentration-andtime-dependentItoblockuponrepetitionofthevoltageprotocol.B,dose-responsecurvesforpropafenone,5-hydroxypropafenone,andN-depropylpropafenonegeneratedfrompooleddataat?50mV(n?3C8foreachdatapoint)fittedwiththeHillequation.lethalproarrhythmiceffectsofantiarrhythmicdrugs,includ-ingpropafenone(Sanguinettietal.,1995).Thus,aprimaryaimofthepresentstudywastodirectlycomparetheIto-andIKr-blockingeffectsofpropafenoneinanisolatedventricularmyocytemodelreliablyexpressingbothcurrents.RoleoftheMetabolites5-Hydroxy-andN-Depropyl-propafenone.Clinicaluseofpropafenoneisassociatedwithextensivehepaticmetabolism(Hegeetal.,1984)toproductsthatincludetwosubstanceswithrecognizedelectropharma-cologicactivityincardiacmusclepreparations,namely5-hy-droxy-andN-depropylpropafenone(Malfattoetal.,1988;Thompsonetal.,1988;Rouetetal.,1989).Theextentofpropafenonemetabolismisphenotype-dependent(Siddowayetal.,1987)butcanresultinsteady-stateplasmaconcentra-tionsof5-hydroxy-andN-depropylpropafenonethatare18and23%,respectively,ofthatoftheparentcompound,withFig.6.ReversibilityofItoblockadebypropafenone(A)and5-hy-droxypropafenone(5-OHP;B).Controlcurrentwaselicitedwitha?extracellular50-mVdepolarizingdrugapplicationstepintheandabsenceequilibrationofdrugatthentherepeatedconcentrationafterindicated.Drug-freeextracellularsolution(minimum5ml)wasthenappliedtoeffectdrugwashout,resultinginnearlycompleterestorationofItoafterpropafenoneexposurebutonlypartialrecoveryafterperfusionwitheithermetabolite(N-depropylpropafenonenotshown).delayedmetaboliteclearanceafterdiscontinuationofpropafenoneadministration(Katesetal.,1985).Moreover,Latiniandcolleagues(1989)demonstratedthat5-hy-droxypropafenoneaccumulatesinhumanatrialmusclewithevengreateraffinitythandoespropafenone,resultingincardiactissuemetaboliteconcentrationsthatcanmatchorexceedthoseoftheparentdrug.Almostnoinformationonthecardiacmyocyterepolarizingcurrentinhibitoryeffectsof5-hydroxy-andN-depropylpropafenonehasthusfarbeenavailable.Characterizationofpropafenonemetaboliteinter-actionwithItoandIKrwasthereforethesecondmajoraimofthiswork.PropafenoneandItsMetabolitesPreferentiallyIn-hibitIKrRelativetoIto.AkeyfindingofthepresentstudyisthatallthreesubstancesassessedpreferentiallyinhibitIKrrelativetoIto,aphenomenonthatisevenmorepronouncedinthemetabolitesthanintheparentcompound.TheIC50valueof0.80?0.14?MobtainedforIKrtail-currentblockadebyDownloaded 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