心血管反射与慢性心力衰竭.ppt

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,Sympathetic Nerve Activity in Normal and Heart Failure Patients,Correlation between Muscle Sympathetic Nerve Activity and NE in CHF Patients,Cohn,J.N.et al:N.Engl.J.Med.311:819,1984,Survival and Plasma Norepinephrine in Heart Failure Patients,压力感受性反射,化学感受性反射,心交感传入反射,Sympatho-inhibitory reflex,Sympatho-excitatory reflex,Sympatho-excitatory reflex,CHF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,Baroreceptor reflex,A,sympathoinhibitory,reflex,Receptors:aortic arch and carotid sinus,Depressed in experimental and clinical CHF,Depressed,baroreflex,leads to an increase in sympathetic outflow,Depressed,baroreflex,is the consequence(not cause)of sympathetic excitation,because elevated plasma NE is not influenced by baroreceptor denervation in CHF.,Sympathetic,over-activity,in CHF contributes,at least in part,to the activation of excitatory reflexes,rather than the loss of inhibitory reflexes.,Accumulating evidence has shown that augmented excitatory reflexes in CHF may contribute to activation of sympathetic outflow.,Chemoreflex,Receptors:internal carotid and aortic bodies,brain stem,A sympathetic-excitatory reflex,Powerful influences not only on breathing but also on the regulation of cardiovascular functions.,Chemoreflex,activation results in increased sympathetic activity,heart rate,blood pressure,and ventilation.,However,the cardiovascular effects can be subsequently attenuated by the,chemoreflex,response-induced hyperventilation and increased,baroreceptor,input as a result of increased blood pressure.,Accumulating evidence has shown that an enhanced sensitivity of,chemoreflex,in CHF,especially in the late and severe stages.,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。,Cardiac sympathetic afferent reflex,(CSAR),The CSAR induced by epicardial application of capsaicin in normal rats,CSAR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,CSAR,CSAR,A,sympathoexcitatory,reflex,Activation of CSAR results in an increase in sympathetic activity,arterial pressure,heart rate and myocardial contraction.,Sympathetic nerve afferent activity is markedly increased in myocardial ischemia.,Positive-feedback characteristics,Increased oxygen consumption in CHF contributes to myocardial ischemia,which,in turn,stimulates cardiac sympathetic afferents to increase sympathetic outflow.,CSAR is augmented in rats and dogs with CHF.,CSAR与CHF,CSAR,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,Effect of intravenous injection of nitroglycerin(60,g/kg)on(expressed as a%of max)in sham and heart failure rats.,RSNA(%of Max),RSNA was enhanced in rats with CHF,BK 0.4,g,BK 0.4,g,Sham,CHF,10 s,Int RSNA Raw RSNA MAP AP,Enhanced CSAR to epicardial application of bradykinin in CHF rats,Enhanced CSAR evoked by epicardial application of BK or capsaicin in CHF,Dogs,Rats,Dogs Rats,Enhanced CSAR to Cardiac Sympathetic Afferent Stimulation in CHF,Summary 1,CHF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 CHF,Intracerebroventricular administration of losartan normalized the enhanced CSAR in CHF rats,Enhance CSAR induced by chronic Intracerebroventricular infusion of Ang II in dogs,Summary 2,中枢Ang II和AT,1,受体在CHF的CSAR增强机制中起重要作用,Ang II 和AT,1,受体系统调控CSAR的中枢位点？,Increased Ang II Binding in the PVN in dogs with CHF(radioautography),Sham,CHF,AT1 receptor in the PVN is upregulated in the rats with CHF,Bilateral microinjection of AT1 receptor antagonist losartan(50 nmol)into the PVN normalized the enhanced CSAR in CHF rat,Bilateral microinjection of angiotensin converting enzyme inhibitor captopril(10 nmol)into the PVN inhibited the enhanced CSAR in CHF rats,Ang II caused much stronger CSAR in CHF rats than in sham rats,Pretreatment with AT1 receptor antagonist losartan abolished the Ang II-induced enhancement of the CSAR,Summary 3,PVN中Ang II和AT,1,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？,Intracerebroventricular administration of AT1 receptor mRNA antisense normalized the enhanced CSAR in CHF rats,BK 0.04,g,BK 0.4,g,BK 0.04,g,BK 0.4,g,Intracerebroventricular administration of AT1 receptor mRNA antisense decreased RSNA,MAP and HR in CHF rats,Microinjection of AT1 receptor mRNA antisense into the PVN inhibited the enhanced CSAR in CHF rats,BK 0.04,g,BK 0.4,g,Decreased AT1 receptor mRNA and AT1 receptor protein in the PVN after intracerebroventricular injection of AT1 receptor AS-ODN,AT1 receptor mRNA,AT1 receptor protein,Summary 4,抑制PVN中AT,1,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？,Microinjection of superoxide anion scavenger,either tempol(20 nmol)or tiron (10 nmol)into the PVN inhibited the CSAR,and superoxide dismutase(SOD)inhibitor diethyldithio-carbamic acid(DETC,10 nmol)enhanced the CSAR,*,Superoxide anion scavenger,either tempol or tiron decreased the RSNA and MAP,SOD inhibitor DETC increased the RSNA and MAP,Summary 5,清除超氧阴离子抑制CSAR，抑制SOD加强CSAR。,PVN中ROS是否介导Ang II的增强CSAR效应？,Pretreatment with tempol or tiron in the PVN inhibited the augmented CSAR induced by Ang II in the PVN.Pretreatment with DETC had no significant effect on the augmented CSAR induced by Ang II,Pretreatment with tempol or tiron in the PVN inhibited the increased RSNA and MAP caused by Ang II in the PVN.Pretreatment with DETC had no significant effect,Summary 6,清除超氧阴离子可消除Ang II引起的CSAR增强效应，但抑制SOD不能使Ang II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Ang II均引起ROS增多。,表明PVN中ROS调控CSAR，并介导Ang II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？,Microinjection of NAD(P)H oxidase inhibitor,apocynin(0.1,1.0 nmol)or phenylarsine oxide(PAO,1.0 nmol),into the PVN inhibited the CSAR.Xanthine oxidase inhibitor allopurinol(10.0 nmol)had no significant effect on CSAR,Pretreatment with microinjection of NAD(P)H oxidase inhibitor,apocynin or PAO into the PVN inhibited the enhanced CSAR induced by Ang II.Pretreatment with allopurinol also showed a weak inhibitory effect on enhanced CSAR,Pretreatment with apocynin or PAO decreased the enhanced RSNA and increased MAP induced by Ang II.Pretreatment with allopurinol had no significant effect on the enhanced RSNA and increased MAP,Either epicardial application of BK or microinjection of Ang II into the PVN increased the,NAD(P)H oxidase in the PVN.The effect of Ang II was abolished by pretreatment with losartan.,Summary 7,PVN中调控CSAR的ROS生成主要与NAD(P)H氧化酶有关。,PVN中H,2,O,2,是否介导CSAR？,PEG-CAT inhibited the CSAR,and decreased the RSNA and MAP in a dose-dependent manner.Pretreatment with PEG-CAT inhibited the effects of microinjection of Ang II into the PVN on the CSAR,RSNA and MAP in a dose-dependent manner.,PEG-CAT,PEG-SOD,PEG-SOD+PEG-CAT or PEG-SOD+ATZ almost completely abolished the CSAR.ATZ alone enhanced the CSAR.The effect of ATZ was reversed by pretreatment with PEG-SOD.,EG-CAT,PEG-SOD,and PEG-SOD+PEG-CAT significantly inhibited the RSNA and decreased MAP,but ATZ significantly increased the RSNA and MAP.Pretreatment with PEG-SOD failed to abolish the effects of aminotriazole on the RSNA and MAP,Microinjection of Ang II into the PVN enhanced the CSAR.PEG-CAT,PEG-SOD,PEG-SOD+PEG-CAT or PEG-SOD+ATZ almost completely abolished effect of Ang II on the CSAR,but ATZ did not further augment the Ang II-induced CSAR enhancement.,PEG-CAT,PEG-SOD,PEG-SOD+PEG-CAT,or PEG-SOD+ATZ completely abolished the effect of Ang II on the RSNA and MAP.ATZ alone did not further enhance the effects of Ang II on the RSNA and MAP.,Summary 8,PVN中内源性H,2,O,2,介导CSAR和Ang II引起的CSAR增强效应。PVN中H,2,O,2,参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？,Superoxide anion scavenger,either tempol or tiron normalized the enhanced CSAR in CHF rats,but SOD inhibitor DETC enhanced CSAR,Superoxide anion scavenger,either tempol or tiron decreased but SOD inhibitor DETC increased the MAP and RSNA in CHF rats,Pretreatment with either tempol or tiron inhibited but DETC augmented the enhanced CSAR induced by Ang II in CHF rats,Pretreatment with either tempol or tiron inhibited but DETC enhanced the increased RSNA and MAP induced by Ang II in CHF rats,Effects of epicardial application(Epi)of saline and BK as well as PVN microinjection of saline,Ang II,losartan and tempol on superoxide anion and MDA levels in the PVN.,Summary 9,CHF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。,Tempol improves cardiac contractile function and normalizes sympathetic activity in CHF,Echocardiographic data showing that tempol improves cardiac contractile functionin CHF,LVEDD=left ventricular end-diastolic diameter;LVESD=left ventricular end-systolic diameter;LVEDV=left ventricular end-diastolic volume;LVESV=left ventricular end-systolic volume;IVSd=interventricular septal thickness in diastole;IVSs=interventricular septal thickness in systole;LVPWd=left ventricular posterior wall thickness in diastole;LVPWs=left ventricular posterior wall thickness in systole;SI=sphericity index;FS=fractional shortening;EF=Ejection fraction.,Tempol prevents the enhancement of the CSAR in CHF,Tempol normalizes the plasma level in CHF,The enhanced CSAR response of Ang II in CHF rats was normalized by tempol,Tempol decreases the AT1 receptor expression in the PVN and RVLM in CHF rats,Tempol normalizes the superoxide anion level in the PVN and RVLM in CHF rats,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。,Summary 10,PVN的SOD过表达以清除超氧阴离子能否改善CHF？,Green fluorescence at different levels of the PVN two weeks after the PVN microinjection of Ad-EGFP,SOD1 expression(a and b),SOD1 activity(c)and superoxide anion level(d)in PVN at the 2nd and 8th week,Sympathetic activity,plasma norepinephrine level and the CSAR at the 8th week,Histological changes of myocardium at the 8th week.a.Sections in mid-region of the ventricle;b.Visualization of cardiomyocytes stained with hematoxylin-eosin in the border and remote zones of the infarction;c.Average of cardiomyocyte size,Collagen deposition and cardiomyocyte apoptosis at the 8th week,a.Collagen deposition detected by Massons trichrome staining in the border zones of the infarction;b.Quantification of collagen deposition expressed as collagen volume fraction in the border and remote zones of the infarction;c.Triple-staining with TUNEL(green),anti-sarcomeric actin antibody(red)and DAPI(blue)in the border zone of the myocardial infarction;d.Quantification of TUNEL-positive cardiomyocytes in the border and remote zones of the infarction.,Echocardiographic data at the 8th week,Table showing echocardiographic data at the 8th week,Summary 11,PVN CuZnSOD过表达：,改善心功能,降低交感神经活动和血浆去甲肾上腺素水平,减弱CSAR,改善心肌重构,减少心肌细胞凋亡,Thank You,