阻断肿瘤坏死因子-α的作用对慢性充血性心力衰竭时神经递质失衡的影响

目的 通过中枢阻断肿瘤坏死因子-α（TNF-α）的作用,观察对慢性充血性心力衰竭（心衰）时神经递质失衡的影响,探讨中枢炎性因子对心衰时交感兴奋的作用.方法 采用结扎冠状动脉左前降支致心肌梗死的方法制备心衰大鼠模型,假手术对照只穿线不结扎.对心衰大鼠和假手术大鼠持续4周经侧脑室灌流TNF-α阻断剂依那西普（etanercept,ETN） 10μg/h或人工脑脊液（aCSF）;另一种处理则是以腹腔注射方式给予相似剂量的ETN.4周后测定心脏功能学指标和形态学指标（LVEDP、±dp/dt max、RV/BW、Lung/BW）和肾交感神经放电（RSNA）; ELISA技术测定促炎因子（PIC）在血浆和下丘脑室旁核（PVN）中的含量以及血中血管紧张素Ⅱ（ANGⅡ）水平;PVN中谷氨酸（Glu）、去甲肾上腺素（NE）及血中儿茶酚胺的含量利用高效液相色谱法获得;免疫组织化学染色确定PVN内酪氨酸羟化酶（TH）和谷氨酸脱羧酶（GAD67）,后二者分别为NE和γ-氨基丁酸（GABA）的限速酶,以及神经元型一氧化氮合酶（nNOS）的表达.结果 与假手术组相比,心衰大鼠PVN区NE和TH表达增强,GAD67和nNOS表达减弱;血浆炎性因子、儿茶酚胺、血管紧张素Ⅱ增多;肾交感神经活动增强.对心衰大鼠经侧脑室持续灌流ETN可减轻上述神经递质失衡现象和心衰时肾交感神经的过度兴奋表现;而经腹腔灌注相似剂量的ETN对心衰大鼠PVN处的NE、TH、GAD67和nNOS的含量没有影响,对肾交感神经兴奋也无作用,说明上述影响是通过位于中枢的PIC起作用.结论 心衰时PVN区炎性因子增高,引起中枢兴奋性神经递质增多,抑制性神经递质减少,神经递质平衡失调,从而增强交感兴奋促进心衰发展.     

醛固酮合成酶和盐皮质激素受体基因在充血性心力衰竭心肌的表达

目的　研究醛固酮合成酶 (Aldosterone synthase,CYP11B2 )及盐皮质激素受体 (Mineralocorticoid receptor,MR)基因在心功能不全心肌中的表达。方法　选取 2 5例行瓣膜置换术的慢性心力衰竭 (CHF)患者左心室乳头肌组织 10 0 mg,同时取 6例健康心肌组织作为对照 ,提取组织总 RNA,并逆转录为 c DNA,以特定的寡核苷酸为引物进行聚合酶链反应 ,β- actin作为内参照 ,分别观察 CYP11B2及 MR在不同心功能状态心肌中的表达。结果　在 6例正常心肌组织中 CYP11B2基因的表达为阴性 ,2 5例 CHF患者中有 10例表达阳性 ,分别为心功能 级～ 级 2例 , 级～ 级 8例 ;轻度心力衰竭患者 (心功能 ～ 级 )与重度心力衰竭患者 (心功能 ～ 级 )表达阳性率分别为 15 .4 %和 6 6 .7% ,差异有显著性 (P=0 .0 15 )。正常心肌、心功能 ～ 级和心功能 ～ 级心肌 MR/ β- actin分别为 1.2 8± 0 .13,0 .92± 0 .12 ,0 .80± 0 .2 1,与正常对照组相比 ,CHF时 MR基因表达明显下降 (P<0 .0 0 1) ,而心功能 ～ 级与心功能 ～ 级之间 ,无显著性差异 (P=0 .0 83)。慢性心力衰竭患者中 ,CYP11B2基因表达阳性与阴性组之间 MR/ β- actin表达分别为 0 .78± 0 .2 0和 0 .94± 0 .13,二者间具有显著性差异 (P=0 .0 18)。CYP11B2     

中枢神经系统对心力衰竭的作用

心力衰竭为多数心血管疾病的最终归宿,其发病率呈上升趋势。中枢和外周交感神经系统的过度激活、活性氧、炎性因子的蓄积以及酶和离子通道的病理改变与心力衰竭发生发展密切相关。该文着重论述以室旁核为代表的中枢神经系统在慢性心力衰竭发生发展中作用。     

盐皮质激素及其受体在血压调节中的作用

盐皮质激素是由肾上腺皮质球状带分泌的类固醇激素,其中醛固酮作用最强。醛固酮不仅参与肾脏水盐代谢调节,还通过多种途径对靶器官产生一系列负性作用。盐皮质激素受体不仅存在于肾脏上皮细胞中,还在心脏、血管、海马和皮肤等多种肾外组织、器官中表达,介导一系列生理病理过程,参与血压的调控和靶器官的重构。该文主要介绍盐皮质激素及其受体参与血压调节的机制。     

下丘脑室旁核氧化应激反应对心力衰竭时肾交感神经活动的影响

目的 探索心力衰竭(HF)时下丘脑室旁核(PVN)氧化应激反应是否能够增强肾交感神经(RSNA)活动,进而促进HF的发生发展.方法 取SD大鼠行冠脉结扎术制作心衰模型,对照组(SHAM)大鼠不结扎冠脉,两天后通过侧脑室插管给予tempol(氧自由基清除剂)或人工脑脊液(VEH).正常饲养4周后,测量各组大鼠血流动力学、RSNA、PVN区域NADPH亚基gp91 phox的表达.结果 HF组大鼠心功能明显低于SHAM组大鼠,RSNA增强、PVN区域NADPH亚基gp91 phox的表达增加.HF大鼠给予tempol治疗后心功能各项指标有所改善,RSNA减弱,PVN区域gp91 phox的表达降低,但达不到SHAM组水平.结论 心衰时PVN区域氧化应激反应增强与RSNA增加有关,降低该区域氧自由基水平可能延缓HF的发生发展过程.     

老年心力衰竭患者促炎因子与抗炎因子的动态变化与相关性

目的 探讨老年心力衰竭患者血清促炎因子与抗炎因子的动态变化与相关性.方法 选择74例老年心力衰竭患者作为病例组并进行心功能分级,选择同期老年健康体检者68例作为对照组,ELISA法检测血清肿瘤坏死因子-α(TNF-α)、白介素-6(1L-6)、白介素-4(IL-4)和白介素-10(IL-10)的表达.结果 病例组与对照组比较,促炎因子(TNF-α、IL-6)和抗炎因子(IL-4、IL-10)的表达以及促炎因子/抗炎因子的比值(TNF-α/IL-4、TNF-α/IL-10、IL-6/IL-4和IL-6/IL-10)都明显增高(P＜0.05),且随着心功能恶化,以上指标也都明显升高(P＜0.05);TNF-α和IL-4、IL-10以及IL-6和IL-4、IL-10都呈明显的正相关(P＜0.05).结论 老年心力衰竭患者促炎因子与抗炎因子的比例发生变化,促炎因子过度激活,二者关系密切,形成网络,共同促进老年心力衰竭的发生发展.     

雷米普利对慢性心力衰竭大鼠心肌组织中盐皮质激素受体的影响

目的探讨雷米普利对慢性心力衰竭大鼠心肌组织中盐皮质激素受体(MR)表达及心肌纤维化的影响。方法选择SD大鼠39只,选用慢性心力衰竭造模成功SD大鼠26只,随机分为慢性心力衰竭组(心衰组,13只)、雷米普利治疗组(治疗组,13只),另设假手术大鼠为对照组(13只)。雷米普利治疗4周时,用心肌Masson染色法测定大鼠心肌胶原密度,放射性免疫法测定大鼠心肌组织中血管紧张素Ⅱ(AngⅡ)、醛固酮(ALD)含量,实时荧光定量PCR、免疫印迹检测心肌MR表达。结果与对照组比较,心衰组大鼠心肌组织中AngⅡ、ALD显著升高,MR mRNA和蛋白表达显著上调,心肌胶原密度显著增加(P<0.01);与心衰组比较,治疗组大鼠心肌组织中AngⅡ、ALD显著降低.MR mRNA和蛋白表达显著下调,心肌胶原密度显著降低(P<0.01)。结论雷米普利不仅降低慢性心力衰竭大鼠心肌组织中AngⅡ、ALD含量,还可能通过下调心肌MR的表达来抑制心肌纤维化。     

下丘脑室旁核miR-132对心力衰竭大鼠外周交感神经兴奋性的影响

目的 观察下丘脑室旁核(PVN)灌注miR-132特异抑制剂对心力衰竭(HF)大鼠外周交感神经兴奋性、下丘脑谷氨酸(Glu)含量及心脏功能的影响。方法 雄性SD大鼠随机分为正常对照(Ctrl)+人工脑脊液(ACSF)组、HF+ACSF组、HF+miR-132抑制剂组。结扎心脏左冠状动脉前降支制造HF动物模型,HF+miR-132抑制剂组侧脑室插管向PVN内灌注miR-132特异抑制剂,Ctrl+ACSF组和HF+ACSF组灌注等量ACSF,灌注后4 w进行心脏功能指标检测;镜下观察心肌结构变化;检测肾脏交感神经放电(RSNA)、HF标志物脑钠肽(BNP)和外周交感神经兴奋标志物去甲肾上腺素(NE)在血浆中的含量;检测Glu在下丘脑PVN的含量。结果 与Ctrl+ACSF组相比,HF+ACSF组心功能指标恶化、外周交感神经兴奋性增强、下丘脑PVN Glu含量升高、心肌组织病理改变明显(P<0.05);HF+miR-132抑制剂组与HF+ACSF组比较,HF大鼠上述检测指标均显著改善(P<0.05)。结论 下丘脑PVN miR-132可影响HF大鼠的外周交感神经兴奋性和心脏功能...     

依普利酮对心力衰竭大鼠下丘脑室旁核内炎性因子的抑制作用

目的探讨依普利酮对心力衰竭大鼠下丘脑室旁核(PVN)内炎性因子的抑制作用。方法 SD大鼠结扎冠状动脉前降支造成急性心肌梗死后心力衰竭模型。其中一组给予核因子(NF)-κB拮抗剂PDTC灌胃(0.2 g/kg);另一组给予依普利酮(30 mg/kg);第3组以相同体积的蒸馏水灌胃作为对照。6 w后测量心脏功能,采集PVN和外周血标本,检测炎性细胞因子等指标。结果依普利酮与PDTC干预的大鼠心功能较心力衰竭组明显改善。心力衰竭组神经元活性增强,PDTC和依普利酮可显著降低PVN内神经元活性。对照组PVN内肿瘤坏死因子(TNF)-α、促肾上腺皮质激素释放激素(CRH)、NF-κB表达明显升高(P0.05)。依普利酮与PDTC干预的大鼠与心力衰竭组大鼠相比这些指标表达减少(P0.05)。心力衰竭组外周血醛固酮(ALD)、去甲肾上腺素(NE)、TNF-α水平升高。依普利酮、PDTC治疗组ALD、NE、TNF-α水平较对照组明显降低。结论依普利酮可以改善大鼠心功能,可能与其抑制PVN内NF-κB表达,进而抑制PVN内炎性反应有关。     

阻断中枢肿瘤坏死因子α合成对缺血诱发心力衰竭大鼠交感神经活动的影响

目的观察缺血诱发心力衰竭大鼠心血管中枢肿瘤坏死因子(TNF)α水平的变化,以及采用己酮可可碱(PTX)阻断中枢TNF-α合成对心力衰竭大鼠交感神经活动的影响。方法 48只雄性SD大鼠分为心力衰竭干预组(HF+PTX)、心力衰竭对照组(HF+VEH)、假手术干预组(SHAM+PTX)和假手术对照组(SHAM+VEH),每组12只。心力衰竭组采用冠状动脉结扎诱导心力衰竭,假手术组仅进行手术而不造成缺血状态。干预组通过侧脑室插管给予PTX,对照组给予人工脑脊液。4周后各组大鼠分别进行肾交感神经活动记录及血流动力学、右心室/体质量比值、肺/体质量比值的测量。免疫印迹法检测下丘脑室旁核TNF-α表达,酶联免疫吸附试验(ELISA)检测血浆去甲肾上腺素及细胞因子水平变化。结果 HF+VEH组与SHAM+VEH组相比,下丘脑室旁核中TNF-α水平升高,交感神经活动增强,左室舒张末压(LVEDP)及右心室/体质量比值、肺/体质量比值均明显升高,血浆去甲肾上腺素水平升高(均P<0.05)。左室最大上升速率和最大下降速率(LV±dp/dt_(max))明显降低(P<0.05)、HF+PTX组与HF+VEH组相比,中枢TNF-α水平下降,交感神经活动减弱,心功能改善(均P<0.05),右心室/体质量比值、肺/体质量比值均减小(P<0.05)。结论心力衰竭大鼠中枢TNF-α水平升高,交感神经活动增强,阻断中枢TNF-α合成可在一定程度上降低交感神经兴奋性,改善心力衰竭大鼠心功能。     

Aldosterone, mineralocorticoid receptor, and heart failure

Several large clinical studies have demonstrated the important benefit of mineralocorticoid receptor (MR) antagonists in patients with heart failure, left ventricular dysfunction after myocardial infarction, hypertension or diabetic nephropathy. Aldosterone adjusts the hydro-mineral balance in the body, and thus participates decisively to the control of blood pressure. This traditional view of the action of aldosterone restricted to sodium reabsorption in epithelial tissues must be revisited. Clinical and experimental studies indicated that chronic activation of the MR in target tissues induces structural and functional changes in the heart, kidneys and blood vessels. These deleterious effects include cardiac and renal fibrosis, inflammation and vascular remodeling. It is important to underscore that these effects are due to elevated MR activation that is inadequate for the body salt requirements.Aldosterone is generally considered as the main ligand of MR. However, this is a matter of debate especially in heart. Complexity arises from the glucocorticoids with circulating concentrations much higher than those of aldosterone, and the fact that the MR has a high affinity for 11β-hydroxyglucocorticoids. Nevertheless, the beneficial effects of MR inhibition in patients with heart failure emphasize the importance of this receptor in cardiovascular tissue. Diverse experimental models and strains of transgenic mice have allowed to dissect the effects of aldosterone and the MR in the heart. Taken together experimental and clinical data clearly highlight the deleterious cardiovascular effects of MR stimulation.     

Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure

Heart failure (HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic (adrenergic) nervous system (SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases (GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell (receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically.     

下丘脑室旁核肾素-血管紧张素系统对心衰时炎性细胞因子及交感神经的影响

目的研究心衰时下丘脑室旁核中肾素一血管紧张素系统对炎性细胞因子表达水平的影响,及在外周交感神经过度兴奋和心衰发生发展中发挥的作用。方法雄性sD大鼠28只,体重（250±20）g,结扎冠状动脉左前降支制备心衰模型。给药组通过双侧室旁核给予血管紧张素转化酶抑制剂依那普利（EPI,10μg／rrd）4周,对照组给予人工脑脊液。检测全心体重比、肺体重比、血浆中去甲肾上腺素水平、血浆中自介素-1β含量。结果心衰组大鼠全心体重比为（7．2±0．6）,肺体重比为（11．6±0．9）,较假手术组升高（P〈0．05）,血浆中去甲肾上腺素水平为（251．7±22．4）pg／ml,较假手术组升高（P〈O．05）,血浆中白介素-1β表达水平为（112．3±10．5）pg／ml,较假手术组升高（P〈0．05）。给药组全心体重比为（5．4±0．5）,肺体重比为（7．8±0．8）,较心衰组降低（P〈0．05）,血浆中去甲肾上腺素水平为（209．6±20．5）pg／ml,较心衰组降低（P〈0．05）,血浆中白介素-18含量为（84．7±7．6）pg／ml,较心衰组降低（P〈0．05）。结论心衰时下丘脑室旁核中肾素-血管紧张素系统促进炎性细胞因子表达,激活外周交感神经,促进心衰的发生发展。     

培哚普利、福辛普利对心衰和炎性细胞因子影响的比较

目的:比较培跺普利、福辛普利对心力衰竭患者的生存质量和炎性细胞因子的影响。探讨两药治疗心力衰竭的疗效与安全性。方法:87例心衰患者随机分为培跺普利组、福辛普利组和对照组。治疗前、后测定血清肿瘤坏死因子α(TNFα)、白介素 6(IL-6)、白介素1β(IL-1β)、血肌酐(Cr)、尿素氮(BUN)、血钾(K~+)、每搏量(SV)、心输血量(CO)、左室射血分数(LVEF)。同时进行6分钟步行试验(6MWT)、明尼苏达心衰问卷评分(ML WHF),记录用药过程中的不良反应。结果:治疗4周后,两组患者IL-6水平显著下降(P<0.01),福辛普利组TNFα水平下降(P<0.05)。两组患者SV、CO、LVEF水平均上升(P<0.01);6MWT显著增加(P<0.001);ML WHF明显下降(P<0.001);BUN、SCr、K~+无统计学变化。结论:培哚普利和福辛普利都能有效治疗心衰,减少炎性细胞因子,改善生活质量。福辛普利在降低TNFα上更有优势。     

Long-term outcome in relation to renal sympathetic activity in patients with chronic heart failure.

AIMS: Although cardiac sympathetic activation is associated with adverse outcome in patients with chronic heart failure (CHF), the influence of renal sympathetic activity on outcome is unknown. We assessed the hypothesis that renal noradrenaline (NA) spillover is a predictor of the combined endpoint of all-cause mortality and heart transplantation in CHF. METHODS AND RESULTS: Sixty-one patients with CHF, New York Heart Association (NYHA) I-IV (66% NYHA III-IV), and left ventricular ejection fraction (LVEF) 26+/-9% (mean+/-SD) were studied with cardiac and renal catheterizations at baseline and followed for 5.5+/-3.7 years (median 5.5 years, range 12 days to 11.6 years). Nineteen deaths and 13 cases of heart transplantation were registered. Only renal NA spillover above median, 1.19 (interquartile range 0.77-1.43) nmol/min, was independently associated with an increased relative risk (RR) of the combined endpoint (RR 3.1, 95% CI 1.2-7.6, P=0.01) in a model also including total body NA spillover, LVEF, glomerular filtration rate (GFR), renal blood flow, cardiac index, aetiology, and age. CONCLUSION: Renal noradrenergic activation has a strong negative predictive value on outcome independent of overall sympathetic activity, GFR, and LVEF. These findings suggest that treatment regimens that further reduce renal noradrenergic stimulation could be advantageous by improving survival in patients with CHF.     

Renal denervation and heart failure

Renal denervation has been developed in order to lower systolic blood pressure in resistant hypertension by a reduction in renal afferent and efferent sympathetic nerve activity. In heart failure sympathetic activation, in particular, renal norepinephrine release is closely associated with morbidity and mortality. Initial studies have shown that renal denervation is able to reduce not only blood pressure but also heart rate, and is associated with a reduction in myocardial hypertrophy, improved glucose tolerance, and ameliorated microalbuminuria. Since some experimental and observational data suggest an antiarrhythmic effect, it is possible that renal denervation might also play a therapeutic role in arrhythmias often occurring in chronic heart failure. The first proof‐of‐concept studies are planned to evaluate the clinical effect of this pathophysiologically plausible method, which might be able to change clinical practice.     

Decreased renal sympathetic activity in response to cardiac unloading with nitroglycerin in patients with heart failure

AIMS: To examine changes in renal sympathetic outflow in response to cardiac unloading with nitroglycerin (GTN) in patients with chronic heart failure (CHF) and healthy subjects (HS). METHODS AND RESULTS: Renal (RNAsp) and total body (TBNAsp) noradrenaline (NA) spillover were measured with radiotracer methods in 16 patients with CHF (50+/-3 years, LVEF 20+/-1%) and nine HS (57+/-2 years) during right heart and renal vein catheterisation. Low dose GTN decreased mean pulmonary artery pressure (PAm: CHF -7+/-2 mm Hg, HS -4+/-1 mm Hg, p<0.05 vs. baseline) but not mean arterial pressure (MAP: CHF -2+/-1 mm Hg, HS -2+/-1 mm Hg) and did not affect RNAsp in any of the study groups. High dose GTN lowered MAP (CHF -12+/-1 mm Hg, HS -12+/-2 mm Hg, p<0.05 vs. baseline) and PAm (CHF -13+/-2 mm Hg, HS -5+/-1 mm Hg, p<0.05 vs. baseline) and was accompanied by a significant reduction in RNAsp only in CHF (1.3+/-0.1 nmol/min baseline to 0.9+/-0.2 nmol/min, p<0.05), whereas RNAsp in HS remained unchanged. CONCLUSIONS: In spite of a reduction in both arterial pressure and cardiac filling pressures, renal sympathetic activity decreased in CHF and did not increase in HS. These findings suggest that the altered loading conditions resulting from high-dose GTN infusion have renal sympathoinhibitory effects.