心血管反射與慢性心力衰竭南京醫科大學生理學系朱國慶SympatheticNerveActivityinNormalandHeartFailurePatientsCorrelationbetweenMuscleSympatheticNerveActivityandNEinCHFPatientsCohn,J.N.etal:N.Engl.J.Med.311:819,1984SurvivalandPlasmaNorepinephrineinHeartFailurePatientsCHF的重要特征之一是交感神經活動增強交感神經系統激活的程度與病人預后密切相關交感活動越強，血漿兒茶酚胺水平越高，存活期越短三個主要心血管反射壓力感受性反射化學感受性反射心交感傳入反射負反饋正反饋相互作用Lovetriangle：complexinteractionsamongcardiacsympatheticafferent,chemo-,andbaroreflexesJ.Appl.Physiol.2007;102(1):9-10壓力感受性反射化學感受性反射心交感傳入反射Sympatho-inhibitoryreflexSympatho-excitatoryreflexSympatho-excitatoryreflexCHF狀態下心血管反射的異常變化壓力感受性反射↓化學感受性反射↑心交感傳入反射↑BaroreceptorreflexAsympathoinhibitoryreflexReceptors:aorticarchandcarotidsinusDepressedinexperimentalandclinicalCHFDepressedbaroreflexleadstoanincreaseinsympatheticoutflowDepressedbaroreflexistheconsequence(notcause)ofsympatheticexcitation,becauseelevatedplasmaNEisnotinfluencedbybaroreceptordenervationinCHF.Sympatheticover-activityinCHFcontributes,atleastinpart,totheactivationofexcitatoryreflexes,ratherthanthelossofinhibitoryreflexes.AccumulatingevidencehasshownthataugmentedexcitatoryreflexesinCHFmaycontributetoactivationofsympatheticoutflow.ChemoreflexReceptors:internalcarotidandaorticbodies,brainstemAsympathetic-excitatoryreflexPowerfulinfluencesnotonlyonbreathingbutalsoontheregulationofcardiovascularfunctions.Chemoreflexactivationresultsinincreasedsympatheticactivity,heartrate,bloodpressure,andventilation.However,thecardiovasculareffectscanbesubsequentlyattenuatedbythechemoreflexresponse-inducedhyperventilationandincreasedbaroreceptorinputasaresultofincreasedbloodpressure.AccumulatingevidencehasshownthatanenhancedsensitivityofchemoreflexinCHF,especiallyinthelateandseverestages.心交感傳入反射位于心室表面的交感神經末梢受到化學刺激或機械刺激時，興奮通過心交感傳入神經到達中樞，經中樞整合后反射性地引起交感傳出活動增強和動脈血壓升高。Cardiacsympatheticafferentreflex(CSAR)TheCSARinducedbyepicardialapplicationofcapsaicininnormalratsCSAR的適宜刺激和傳入神經CSAR感受器：心室壁的交感傳入神經末梢，尤其是左心室淺表部位機械感受器：感受心室擴張引起的機械刺激如CHF時的心室擴張化學感受器：感受多種內源性和外源性化學物質的刺激(緩激肽、腺苷、過氧化氫、腺苷和辣椒素等)傳入神經：心交感神經傳入神經直接電刺激心交感傳入神經亦可引起CSARCSARAsympathoexcitatoryreflexActivationofCSARresultsinanincreaseinsympatheticactivity,arterialpressure,heartrateandmyocardialcontraction.Sympatheticnerveafferentactivityismarkedlyincreasedinmyocardialischemia.Positive-feedbackcharacteristicsIncreasedoxygenconsumptioninCHFcontributestomyocardialischemia,which,inturn,stimulatescardiacsympatheticafferentstoincreasesympatheticoutflow.CSARisaugmentedinratsanddogswithCHF.CSAR與CHFCSAR病理性增強是導致交感活動亢進的重要機制之一增強的CSAR在CHF發病機制中起重要作用Effectofintravenousinjectionofnitroglycerin(60μg/kg)on(expressedasa%ofmax)inshamandheartfailurerats.RSNA(%ofMax)RSNAwasenhancedinratswithCHF↑

BK0.4μg↑

BK0.4μgShamCHF10sIntRSNA

RawRSNAMAPAP

EnhancedCSARtoepicardialapplicationofbradykinininCHFratsEnhancedCSARevokedbyepicardialapplicationofBKorcapsaicininCHFDogsRatsDogs RatsEnhancedCSARtoCardiacSympatheticAfferentStimulationinCHFSummary1CHF大鼠和狗RSNA增強、CSAR增強(中樞敏感性增強)。中樞敏感性增強的機制？Sham CHFIntracerebroventricularadministrationoflosartannormalizedtheenhancedCSARinCHFratsEnhanceCSARinducedbychronicIntracerebroventricularinfusionofAngIIindogsSummary2中樞AngII和AT1受體在CHF的CSAR增強機制中起重要作用AngII和AT1受體系統調控CSAR的中樞位點？IncreasedAngIIBindinginthePVNindogswithCHF(radioautography)ShamCHFAT1receptorinthePVNisupregulatedintheratswithCHFBilateralmicroinjectionofAT1receptorantagonistlosartan(50nmol)intothePVNnormalizedtheenhancedCSARinCHFratBilateralmicroinjectionofangiotensinconvertingenzymeinhibitorcaptopril(10nmol)intothePVNinhibitedtheenhancedCSARinCHFratsAngIIcausedmuchstrongerCSARinCHFratsthaninshamratsPretreatmentwithAT1receptorantagonistlosartanabolishedtheAngII-inducedenhancementoftheCSARSummary3PVN中AngII和AT1受體系統活動增強是導致CHF的CSAR增強的重要機制。抑制PVN中AT1受體生成能否使CHF大鼠增強的CSAR和RSNA恢復正常？IntracerebroventricularadministrationofAT1receptormRNAantisensenormalizedtheenhancedCSARinCHFratsBK0.04μgBK0.4μgBK0.04μgBK0.4μgIntracerebroventricularadministrationofAT1receptormRNAantisensedecreasedRSNA,MAPandHRinCHFratsMicroinjectionofAT1receptormRNAantisenseintothePVNinhibitedtheenhancedCSARinCHFratsBK0.04μgBK0.4μgDecreasedAT1receptormRNAandAT1receptorproteininthePVNafterintracerebroventricularinjectionofAT1receptorAS-ODNAT1receptormRNAAT1receptorproteinSummary4抑制PVN中AT1受體生成使CHF大鼠增強的CSAR和RSNA恢復正常。PVN中ROS是否調控CSAR？Microinjectionofsuperoxideanionscavenger,eithertempol(20nmol)ortiron(10nmol)intothePVNinhibitedtheCSAR,andsuperoxidedismutase(SOD)inhibitordiethyldithio-carbamicacid(DETC,10nmol)enhancedtheCSAR*Superoxideanionscavenger,eithertempolortirondecreasedtheRSNAandMAP,SODinhibitorDETCincreasedtheRSNAandMAPSummary5清除超氧陰離子抑制CSAR，抑制SOD加強CSAR。PVN中ROS是否介導AngII的增強CSAR效應？PretreatmentwithtempolortironinthePVNinhibitedtheaugmentedCSARinducedbyAngIIinthePVN.PretreatmentwithDETChadnosignificanteffectontheaugmentedCSARinducedbyAngIIPretreatmentwithtempolortironinthePVNinhibitedtheincreasedRSNAandMAPcausedbyAngIIinthePVN.PretreatmentwithDETChadnosignificanteffectSummary6

清除超氧陰離子可消除AngII引起的CSAR增強效應，但抑制SOD不能使AngII引起的CSAR增強效應進一步顯著加強；心室表面應用BK或PVN注射AngII均引起ROS增多。表明PVN中ROS調控CSAR，并介導AngII引起的CSAR增強效應。PVN中調控CSAR的ROS起源？NAD(P)H氧化酶？黃嘌呤氧化酶？MicroinjectionofNAD(P)Hoxidaseinhibitor,apocynin(0.1,1.0nmol)orphenylarsineoxide(PAO,1.0nmol),intothePVNinhibitedtheCSAR.Xanthineoxidaseinhibitorallopurinol(10.0nmol)hadnosignificanteffectonCSARPretreatmentwithmicroinjectionofNAD(P)Hoxidaseinhibitor,apocyninorPAOintothePVNinhibitedtheenhancedCSARinducedbyAngII.PretreatmentwithallopurinolalsoshowedaweakinhibitoryeffectonenhancedCSARPretreatmentwithapocyninorPAOdecreasedtheenhancedRSNAandincreasedMAPinducedbyAngII.PretreatmentwithallopurinolhadnosignificanteffectontheenhancedRSNAandincreasedMAPEitherepicardialapplicationofBKormicroinjectionofAngIIintothePVNincreasedtheNAD(P)Hoxidase

inthePVN.TheeffectofAngIIwasabolishedbypretreatmentwithlosartan.

Summary7PVN中調控CSAR的ROS生成主要與NAD(P)H氧化酶有關。PVN中H2O2是否介導CSAR？PEG-CATinhibitedtheCSAR,anddecreasedtheRSNAandMAPinadose-dependentmanner.PretreatmentwithPEG-CATinhibitedtheeffectsofmicroinjectionofAngIIintothePVNontheCSAR,RSNAandMAPinadose-dependentmanner.

PEG-CAT,PEG-SOD,PEG-SOD+PEG-CATorPEG-SOD+ATZalmostcompletelyabolishedtheCSAR.ATZaloneenhancedtheCSAR.TheeffectofATZwasreversedbypretreatmentwithPEG-SOD.EG-CAT,PEG-SOD,andPEG-SOD+PEG-CATsignificantlyinhibitedtheRSNAanddecreasedMAP,butATZsignificantlyincreasedtheRSNAandMAP.PretreatmentwithPEG-SODfailedtoabolishtheeffectsofaminotriazoleontheRSNAandMAPMicroinjectionofAngIIintothePVNenhancedtheCSAR.PEG-CAT,PEG-SOD,PEG-SOD+PEG-CATorPEG-SOD+ATZalmostcompletelyabolishedeffectofAngIIontheCSAR,butATZdidnotfurtheraugmenttheAngII-inducedCSARenhancement.PEG-CAT,PEG-SOD,PEG-SOD+PEG-CAT,orPEG-SOD+ATZcompletelyabolishedtheeffectofAngIIontheRSNAandMAP.ATZalonedidnotfurtherenhancetheeffectsofAngIIontheRSNAandMAP.Summary8PVN中內源性H2O2介導CSAR和AngII引起的CSAR增強效應。PVN中H2O2參與交感神經活動和動脈血壓調控。ROS是否與CHF增強的CSAR有關？Superoxideanionscavenger,eithertempolortironnormalizedtheenhancedCSARinCHFrats,butSODinhibitorDETCenhancedCSARSuperoxideanionscavenger,eithertempolortirondecreasedbutSODinhibitorDETCincreasedtheMAPandRSNAinCHFratsPretreatmentwitheithertempolortironinhibitedbutDETCaugmentedtheenhancedCSARinducedbyAngIIinCHFratsPretreatmentwitheithertempolortironinhibitedbutDETCenhancedtheincreasedRSNAandMAPinducedbyAngIIinCHFratsEffectsofepicardialapplication(Epi)ofsalineandBKaswellasPVNmicroinjectionofsaline,AngII,losartanandtempolonsuperoxideanionandMDAlevelsinthePVN.Summary9CHF大鼠PVN的ROS增多與CSAR病理性增強機制有關持續清除超氧陰離子能否降低CHF大鼠增強的CSAR和交感神經活動？能否改善心功能和降低CHF發病率？冠狀動脈結扎誘導CHF大鼠模型。Tempol加入飲用水中，連續6周。第八周末進行進行急性實驗。TempolimprovescardiaccontractilefunctionandnormalizessympatheticactivityinCHFEchocardiographicdatashowingthattempolimprovescardiaccontractilefunctioninCHFLVEDD=leftventricularend-diastolicdiameter;LVESD=leftventricularend-systolicdiameter;LVEDV=leftventricularend-diastolicvolume;LVESV=leftventricularend-systolicvolume;IVSd=interventricular

septalthicknessindiastole;IVSs=interventricular

septalthicknessinsystole;LVPWd=leftventricularposteriorwallthicknessindiastole;LVPWs=leftventricularposteriorwallthicknessinsystole;SI=sphericityindex;FS=fractionalshortening;EF=Ejectionfraction.TempolpreventstheenhancementoftheCSARinCHFTempolnormalizestheplasmalevelinCHFTheenhancedCSARresponseofAngIIinCHFratswasnormalizedbytempol

TempoldecreasestheAT1receptorexpressioninthePVNandRVLMinCHFratsTempolnormalizesthesuperoxideanionlevelinthePVNandRVLMinCHFrats長期應用Tempol可降低冠狀動脈結扎大鼠的CHF發病率，改善心功能，使CSAR、交感神經活動及其中樞控制恢復正常。Summary10PVN的SOD過表達以清除超氧陰離子能否改善CHF？GreenfluorescenceatdifferentlevelsofthePVNtwoweeksafterthePVNmicroinjectionofAd-EGFP