心血管反射与慢性心力衰竭

心血管反射与慢性心力衰竭南京医科大学生理学系朱国庆SympatheticNerveActivityinNormalandHeartFailurePatientsCorrelationbetweenMuscleSympatheticNerveActivityandNEinCHFPatientsCohn,J.N.etal:N.Engl.J.Med.311:819,1984SurvivalandPlasmaNorepinephrineinHeartFailurePatientsCHF的重要特征之一是交感神经活动增强交感神经系统激活的程度与病人预后密切相关交感活动越强，血浆儿茶酚胺水平越高，存活期越短三个主要心血管反射压力感受性反射化学感受性反射心交感传入反射负反馈正反馈相互作用Lovetriangle：complexinteractionsamongcardiacsympatheticafferent,chemo-,andbaroreflexesJ.Appl.Physiol.2007;102(1):9-10压力感受性反射化学感受性反射心交感传入反射Sympatho-inhibitoryreflexSympatho-excitatoryreflexSympatho-excitatoryreflexCHF状态下心血管反射的异常变化压力感受性反射↓化学感受性反射↑心交感传入反射↑BaroreceptorreflexAsympathoinhibitoryreflexReceptors:aorticarchandcarotidsinusDepressedinexperimentalandclinicalCHFDepressedbaroreflexleadstoanincreaseinsympatheticoutflowDepressedbaroreflexistheconsequence(notcause)ofsympatheticexcitation,becauseelevatedplasmaNEisnotinfluencedbybaroreceptordenervationinCHF.Sympatheticover-activityinCHFcontributes,atleastinpart,totheactivationofexcitatoryreflexes,ratherthanthelossofinhibitoryreflexes.AccumulatingevidencehasshownthataugmentedexcitatoryreflexesinCHFmaycontributetoactivationofsympatheticoutflow.ChemoreflexReceptors:internalcarotidandaorticbodies,brainstemAsympathetic-excitatoryreflexPowerfulinfluencesnotonlyonbreathingbutalsoontheregulationofcardiovascularfunctions.Chemoreflexactivationresultsinincreasedsympatheticactivity,heartrate,bloodpressure,andventilation.However,thecardiovasculareffectscanbesubsequentlyattenuatedbythechemoreflexresponse-inducedhyperventilationandincreasedbaroreceptorinputasaresultofincreasedbloodpressure.AccumulatingevidencehasshownthatanenhancedsensitivityofchemoreflexinCHF,especiallyinthelateandseverestages.心交感传入反射位于心室表面的交感神经末梢受到化学刺激或机械刺激时，兴奋通过心交感传入神经到达中枢，经中枢整合后反射性地引起交感传出活动增强和动脉血压升高。Cardiacsympatheticafferentreflex(CSAR)TheCSARinducedbyepicardialapplicationofcapsaicininnormalratsCSAR的适宜刺激和传入神经CSAR感受器：心室壁的交感传入神经末梢，尤其是左心室浅表部位机械感受器：感受心室扩张引起的机械刺激如CHF时的心室扩张化学感受器：感受多种内源性和外源性化学物质的刺激(缓激肽、腺苷、过氧化氢、腺苷和辣椒素等)传入神经：心交感神经传入神经直接电刺激心交感传入神经亦可引起CSARCSARAsympathoexcitatoryreflexActivationofCSARresultsinanincreaseinsympatheticactivity,arterialpressure,heartrateandmyocardialcontraction.Sympatheticnerveafferentactivityismarkedlyincreasedinmyocardialischemia.Positive-feedbackcharacteristicsIncreasedoxygenconsumptioninCHFcontributestomyocardialischemia,which,inturn,stimulatescardiacsympatheticafferentstoincreasesympatheticoutflow.CSARisaugmentedinratsanddogswithCHF.CSAR与CHFCSAR病理性增强是导致交感活动亢进的重要机制之一增强的CSAR在CHF发病机制中起重要作用Effectofintravenousinjectionofnitroglycerin(60μg/kg)on(expressedasa%ofmax)inshamandheartfailurerats.RSNA(%ofMax)RSNAwasenhancedinratswithCHF↑

BK0.4μg↑

BK0.4μgShamCHF10sIntRSNA

RawRSNAMAPAP

EnhancedCSARtoepicardialapplicationofbradykinininCHFratsEnhancedCSARevokedbyepicardialapplicationofBKorcapsaicininCHFDogsRatsDogs RatsEnhancedCSARtoCardiacSympatheticAfferentStimulationinCHFSummary1CHF大鼠和狗RSNA增强、CSAR增强(中枢敏感性增强)。中枢敏感性增强的机制？Sham CHFIntracerebroventricularadministrationoflosartannormalizedtheenhancedCSARinCHFratsEnhanceCSARinducedbychronicIntracerebroventricularinfusionofAngIIindogsSummary2中枢AngII和AT1受体在CHF的CSAR增强机制中起重要作用AngII和AT1受体系统调控CSAR的中枢位点？IncreasedAngIIBindinginthePVNindogswithCHF(radioautography)ShamCHFAT1receptorinthePVNisupregulatedintheratswithCHFBilateralmicroinjectionofAT1receptorantagonistlosartan(50nmol)intothePVNnormalizedtheenhancedCSARinCHFratBilateralmicroinjectionofangiotensinconvertingenzymeinhibitorcaptopril(10nmol)intothePVNinhibitedtheenhancedCSARinCHFratsAngIIcausedmuchstrongerCSARinCHFratsthaninshamratsPretreatmentwithAT1receptorantagonistlosartanabolishedtheAngII-inducedenhancementoftheCSARSummary3PVN中AngII和AT1受体系统活动增强是导致CHF的CSAR增强的重要机制。抑制PVN中AT1受体生成能否使CHF大鼠增强的CSAR和RSNA恢复正常？IntracerebroventricularadministrationofAT1receptormRNAantisensenormalizedtheenhancedCSARinCHFratsBK0.04μgBK0.4μgBK0.04μgBK0.4μgIntracerebroventricularadministrationofAT1receptormRNAantisensedecreasedRSNA,MAPandHRinCHFratsMicroinjectionofAT1receptormRNAantisenseintothePVNinhibitedtheenhancedCSARinCHFratsBK0.04μgBK0.4μgDecreasedAT1receptormRNAandAT1receptorproteininthePVNafterintracerebroventricularinjectionofAT1receptorAS-ODNAT1receptormRNAAT1receptorproteinSummary4抑制PVN中AT1受体生成使CHF大鼠增强的CSAR和RSNA恢复正常。PVN中ROS是否调控CSAR？Microinjectionofsuperoxideanionscavenger,eithertempol(20nmol)ortiron(10nmol)intothePVNinhibitedtheCSAR,andsuperoxidedismutase(SOD)inhibitordiethyldithio-carbamicacid(DETC,10nmol)enhancedtheCSAR*Superoxideanionscavenger,eithertempolortirondecreasedtheRSNAandMAP,SODinhibitorDETCincreasedtheRSNAandMAPSummary5清除超氧阴离子抑制CSAR，抑制SOD加强CSAR。PVN中ROS是否介导AngII的增强CSAR效应？PretreatmentwithtempolortironinthePVNinhibitedtheaugmentedCSARinducedbyAngIIinthePVN.PretreatmentwithDETChadnosignificanteffectontheaugmentedCSARinducedbyAngIIPretreatmentwithtempolortironinthePVNinhibitedtheincreasedRSNAandMAPcausedbyAngIIinthePVN.PretreatmentwithDETChadnosignificanteffectSummary6

清除超氧阴离子可消除AngII引起的CSAR增强效应，但抑制SOD不能使AngII引起的CSAR增强效应进一步显著加强；心室表面应用BK或PVN注射AngII均引起ROS增多。表明PVN中ROS调控CSAR，并介导AngII引起的CSAR增强效应。PVN中调控CSAR的ROS起源？NAD(P)H氧化酶？黄嘌呤氧化酶？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中调控CSAR的ROS生成主要与NAD(P)H氧化酶有关。PVN中H2O2是否介导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中内源性H2O2介导CSAR和AngII引起的CSAR增强效应。PVN中H2O2参与交感神经活动和动脉血压调控。ROS是否与CHF增强的CSAR有关？Superoxideanionscavenger,eithertempolortironnormalizedtheenhancedCSARinCHFrats,butSODinhibitorDETCenhancedCSARSuperoxideanionscavenger,eithertempolortirondecreasedbutSODinhibitorDETCincreasedtheMAPandRSNAinCHFratsPretreatmentwitheithertempolortironinhibitedbutDETCaugmentedtheenhancedCSARinducedbyAngIIinCHFratsPretreatmentwitheithertempolortironinhibitedbutDETCenhancedtheincreasedRSNAandMAPinducedbyAngIIinCHFratsEffectsofepicardialapplication(Epi)ofsalineandBKaswellasPVNmicroinjectionofsaline,AngII,losartanandtempolonsuperoxideanionandMDAlevelsinthePVN.Summary9CHF大鼠PVN的ROS增多与CSAR病理性增强机制有关持续清除超氧阴离子能否降低CHF大鼠增强的CSAR和交感神经活动？能否改善心功能和降低CHF发病率？冠状动脉结扎诱导CHF大鼠模型。Tempol加入饮用水中，连续6周。第八周末进行进行急性实验。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长期应用Tempol可降低冠状动脉结扎大鼠的CHF发病率，改善心功能，使CSAR、交感神经活动及其中枢控制恢复正常。Summary10PVN的SOD过表达以清除超氧阴离子能否改善CHF？GreenfluorescenceatdifferentlevelsofthePVNtwoweeksafterthePVNmicroinjectionofAd-EGFP