下丘脑室旁核盐皮质激素受体在慢性充血性心力衰竭中的交感兴奋作用及其机制研究
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摘要
尽管近年来的医疗水平已有了很大的提高,但慢性充血性心力衰竭(简称慢性心衰)病人的预后仍不容乐观。很多心血管疾病发展到后期往往会表现有慢性心衰。在对慢性心衰发生机制的研究中,人们已普遍接受神经体液过度兴奋的理论,即交感神经系统的激活在慢性心衰时最先发生,随之带动了一系列体液因素系统如肾素-血管紧张素-醛固酮系统(RAAS)、下丘脑-垂体系统和细胞因子的激活,在这些神经体液因素的共同作用下,心衰的病理进程不断被推进。于是交感神经活动增强的机制一直成为慢性心衰研究的焦点之一。下丘脑室旁核(PVN)作为神经内分泌活动的关键脑区,除了在调节细胞外液容量和交感神经驱动方面具有重要作用外,本课题组前期的研究还发现该脑区肾素-血管紧张素系统(RAS)、氧化应激反应及促炎因子(PIC)在慢性心衰时均有增强表现,并明显影响交感神经放电,同时伴随心功能的恶化,但引起中枢内这些体液因素变化的机制尚需进一步确定。
人们对醛固酮／盐皮质激素功能的传统认识是它主要作用于肾脏和结肠上的受体发挥保盐作用,这种认识在过去的二十年里已有了很大的改变。研究显示,醛固酮在心血管纤维化、调节盐欲的中枢机制、调节交感神经活动以及在高血压和心衰的实验模型中都有作用。Random Aldactone Evaluation Study (RALES),是一大型医学临床研究机构,已证实给心衰病人额外小剂量口服盐皮质激素受体(MR)拮抗剂soironolactone(SL,安体舒通)(同时给予对照组安慰剂)可显著降低其发病率和死亡率,这一发现引发人们对醛固酮在心血管病中的作用给予很大关注。但产生这种有益效果的原因尚不确定。
一直以来人们将中枢MR的激活与提高盐欲和交感神经对高血压的调节联系起来,因此使用MR阻滞剂阻断其激活可能会对心衰产生(至少是部分)有益的影响是说得通的。肿瘤坏死因子-α(TNF-α)是一种促炎因子,也是操纵中枢MR的兴奋性介质。患有严重心衰的病人血浆TNF-α水平升高且与预后相关。缺血所致心衰大鼠血浆TNF-α水平也有升高,而行冠脉结扎术24小时后开始持续经侧脑室灌注SL,可阻止血浆TNF-α水平的升高。相反,对正常大鼠以足以诱导盐欲的剂量使用MR激动剂,可增高血浆TNF-α水平；而这一现象可被侧脑室使用SL所阻断。这两项研究显示：血源性促炎因子受到、至少是部分受到中枢MR的调节。
心衰除了外周炎症性反应,下丘脑PVN处的促炎因子也表现为上调并参与了交感兴奋作用。TNF-α、IL-1β和IL-6都具有激活下丘脑-垂体-肾上腺皮质(HPA)轴和增强交感神经兴奋性的作用,但PIC调节交感活动的机制尚不清楚。在PVN区,一些兴奋性和抑制性神经递质汇聚于此并影响其神经活动,包括谷氨酸、去甲肾上腺素(NE)和γ-氨基丁酸(GABA)。谷氨酸作为中枢神经系统中一种重要的兴奋性神经递质已被人们广泛认识,研究发现PVN处分布有功能性谷氨酸受体,在心血管反射中参与控制；研究还显示心衰大鼠交感神经的高度兴奋与PVN处细胞外升高的NE也有关；作为中枢神经系统中重要的抑制性神经递质,GABA在PVN区也发挥了重要的调节作用。因此我们进一步假设心衰时中枢增多的PIC引起了兴奋性和抑制性神经递质失衡从而导致交感兴奋性增强。
第一部分慢性充血性心力衰竭时中枢盐皮质激素受体的激活对交感神经活动的影响
目的：验证慢性充血性心衰时阻断中枢盐皮质激素受体(MR)能否降低交感神经兴奋性；同时观察对外周和中枢一些活性物质的影响。方法：心衰模型的制备采用结扎SD大鼠冠状动脉左前降支致心肌梗死的方法进行；假手术对照组则在手术中采取只穿线不结扎的方法进行。给药组大鼠六周内每天口服MR选择性阻滞剂RU28318(每天按30mg/kg,溶于饮用水中),对照组给普通饮用水。确保实验结束时各组至少有12只动物存活。6周后,通过对各组大鼠测定血流动力学指标评价心功能,包括左室内压最大上升和下降速率(±dp/dtmax)和左室舒张末压(LVEDP);通过测定右心室／体重比(RV/BW)口肺／体重比(Lung/BW)反映左心室前负荷变化；电生理记录肾交感神经放电活动(RSNA)、ELISA测定血浆去甲肾上腺素(NE)作为交感神经兴奋性指标,以及PIC在血浆和下丘脑的含量,ALDO在血浆中的含量及PGE2在脑脊液中的水平；免疫组织化学染色和Western blot评价PVN内COX-2和CRH的表达。结果：经RU28318处理的心衰大鼠血浆TNF-α水平降低；和心衰对照组大鼠相比PVN区COX-2染色减少,脑脊液中PGE2含量相应减低；表达TNF-α和CRH的神经元数量下降。同时,RU28318处理的心衰大鼠RSNA减弱,伴随血浆去甲肾上腺素水平降低；RV/BW和Lung/BW均降低,但左室功能没有改善。另外,RU28318对心衰大鼠血浆增高的ALDO没有明显作用。结论：慢性心衰时,阻断中枢MR可降低交感神经活动,减轻外周炎症反应及PVN区TNF-a和CRH表达。
第二部分慢性充血性心力衰竭时中枢盐皮质激素受体通过炎性因子发挥其交感兴奋作用
目的：验证慢性心衰时,中枢内MR的交感兴奋作用是通过提高外周血PIC实现的。方法：心衰模型和假手术对照组制备方法同第一部分。作为对照,部分大鼠仍按第一部分实验方案进行,即给药组大鼠六周内每天口服MR阻滞剂RU28318,每天按30mg/kg,溶于饮用水中,对照组给普通饮用水；另一部分使用抗肿瘤坏死因子-α抑制剂英夫利西(infliximab, INF)每天30mg/kg,溶入饮用水中,以确定单纯由于外周细胞因子的减少是否也能引起RU28318所致的结果；同时还设立了联合用药组(RU28318+INF),以确定能否产生其他额外的效应。保证各组实验结束时至少有12只动物存活。后期处理基本同前部分实验。即6周后,各组大鼠测定血流动力学指标评价心功能；电生理记录RSNA; ELISA技术测定血浆NE、PIC、ALDO含量,及脑组织PIC及脑脊液中PGE2的水平；本部分实验除了继续检测外周和中枢TNF-α含量,还补充了对IL-1β的检测,以进一步探讨RU28318和INF对PICs的确切作用；通过免疫组织化学染色和Western blot评价COX-2和CRH的表达。结果：对心衰大鼠使用TNF-α抑制剂INF以及联合用药(RU28318+INF)产生的各项结果和单独用RU28318处理的心衰大鼠很相似：血浆PIC中TNF-α、IL-1β水平均降低(但血中ALDO水平没有明显改变)；PVN区COX-2染色减弱,表达TNF-α,IL-1β和CRH的神经元数量下降。结论：慢性心衰时,阻断MR产生的交感活动抑制是通过降低血中促炎因子起作用的。
第三部分阻断肿瘤坏死因子-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：心衰模型和假手术对照组制备方法同第一部分。对心衰大鼠和假手术大鼠持续四周经侧脑室灌流TNF-α抑制剂英夫利西(infliximab, INF,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INF。4周后测定心脏功能学指标和形态学指标(LVEDP、±dp/dt max、RV/BW和Lung/BW)和肾交感神经放电(RSNA); ELISA技术测定促炎因子(PIC)在血浆和组织中含量以及血中血管紧张素Ⅱ(ANGⅡ)的含量；神经递质去甲肾上腺素(NE)及血中儿茶酚胺的水平利用高效液相色谱获得；免疫组织化学染色确定PVN内谷氨酸(Glu)和γ-氨基丁酸(GABA)的限速酶酪氨酸羟化酶(TH)和谷氨酸脱羧酶(GAD67)以及神经元型一氧化氮合酶(nNOS)的表达；结果：和假手术组相比,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INF可减轻上述神经递质失衡现象,以及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INF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起作用的。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。
Despite recent therapeutic advanced, the prognosis for patients with congestiveheart failure (CHF) remains dismal. CHF is the common outcome of a variety ofcardiovascular diseases. Neurohumoral excitation (NHE) is a cardinal manifestationof the CHF syndrome,closely correlated with disease severity and adverse prognosis.Sympathoexcitation is considered a trigger point that promotes the excessive releaseof neurohormones in CHF, where plasma norepinephrine (NE), angiotensin (ANGⅡ),aldosterone, cytokines,etc. were found to be correlated with severity of CHF.However, the mechanisms of sympathoexcitation are still not fully understood. Thehypothalamic paraventricular nucleus (PVN) is a principal central site mediatingneurohumoral responses. PVN is also a critical brain site to regulate extracellularfluid volume and sympathetic drive.
The traditional view of aldosterone/mineralocorticoid as a hormone actingprimarily upon receptors in the kidneys and the colon to conserve sodium hasundergone substantial modification in the past two decades, as evidence has emergedfor its involvement in cardiac and vascular fibrosis, central nervous systemmechanisms regulating sodium appetite and sympathetic nerve activity, andexperimental models of hypertension and heart failure. Interest in the role ofaldosterone in cardiovascular diseases was heightened by the Random AldactoneEvaluation Study (RALES), a large clinical trial demonstrating that the addition of asmall oral dose of the mineralocorticoid receptor (MR) antagonist spironolactone (SL)to the regimen of otherwise optimally managed patients with established heart failuredramatically reduced morbidity and mortality. The mechanism(s) accounting for thesebeneficial effects were unknown.
Activation of MR in the brain has long been associated with increased saltappetite and sympathetically mediated hypertension. It is therefore reasonable to hypothesize that blocking the activation of brain MR might account, at least inpart, for the salutary influences of MR antagonist in HF.
One excitatory mediator that responds to manipulations of brain MR is tumornecrosis factor alpha (TNF--inflammatory cytokine. Plasma levels ofTNF-with ischemia-induced HF also have high circulating levels of TNF-continuous ICV infusion of SL, initiated within24hours of coronary artery ligation,prevents the expected rise in plasma TNF-treatment with the MR agonist in a dose sufficient to induce sodium appetiteincreases plasma TNF-SL. These two studies demonstrated the surprising finding that plasma levels ofpro-inflammatory cytokines are regulated, at least in part, by brain MR.
Our recent studies suggest that, in addition to the neurohormones,proinflammatory cytokines (PICs) are upregulated in the PVN and contribute tosympathoexcitation in HF. TNF---6share a common property ofactivating the hypothalamic-pituitary-adrenal axis (HPA) and increasing sympatheticnerve activity. However, the mechanisms by which PICs modulate sympatheticactivity in HF are not clear. A number of excitatory and inhibitory neurotransmittersconverge in the PVN to influence its neuronal activity, including glutamate(Glu),norepinephrine (NE), and gamma-aminobutyric acid (GABA). Glutamate is awell-known excitatory neurotransmitter in the central nervous system and it has beenreported that functional glutamate receptors expressed in the PVN are involved in thecontrol of cardiovascular reflexes. It has also been shown that sympathetichyperactivity in rats with HF is associated with increased extracellular norepinephrine(NE) in the PVN. GABA is a well-known inhibitory neurotransmitter in the centralnervous system and is a dominant inhibitory neurotransmitter within the PVN.Previous work demonstrated a GABA-mediated inhibitory mechanism within thePVN contributing to sympathoexcitation in HF rats. Therefore, we hypothesized thatincreased PICs in the brains of HF rats caused an imbalance in the excitatoryand inhibitory neurotransmitters in the PVN, contributing to increased sympathoexcitation in HF.
Part One: Activation of Mineralocorticoid Receptorin Hypothalamic Paraventricular Nucleus Contributes toSympathoexcitation in Congestive Heart Failure
Aims: To observe the primary hypothesis that mineralocorticoid receptorantagonism would reduce sympathetic activity in rats with HF. Methods:Sprague-Dawly (SD) rats were subjected to coronary artery ligation to induce heartfailure (HF), or sham surgery without ligating the vessel (SHAM). Followed by6weeks treatment with RU28318,30mg/kg per day, orally) or vehicle (drinking water).At the end of the experiment, ensure that in each group there are at least12animalssurvived. After6weeks, left ventricular function parameters, such as left ventricularend-diastolic pressure (LVEDP) and maximum change in pressure over time (±dp/dtmax) were determined by hemodynamic measurements. The right ventricular-to-bodyweight (RV/BW) and lung-to-body weight (lung/BW) ratios were calculated asindices of pulmonary congestion and right ventricular remodeling, two indices of theseverity of HF. The renal sympathetic nerve activity (RSNA) was recorded and theplasma NE level was measured using an ELISA kit, two indices of the severity ofsympathetic nervous excitation. ELISA techniques was also used to measure TNF-ALDO levels in plasma and PGE2level in CSF. Immunohistochemical studies wereperformed to assess the expression of TNF--2, and CRH in PVN. Results:RU28318treated HF rats had lower plasma TNF--2staining of PVNneurons, and fewer PVN neurons staining for TNF--treatedHF rats. RU28318.-treated HF rats had less prostaglandin E2in cerebrospinal fluid,lower RSNA and plasma norepinephrine levels, lower left ventricular end-diastolicpressure,and lower right ventricle/body weight and lung/body weight ratios, but noimprovement in left ventricular function. Conclusion: This study demonstrates thatmineralocorticoid receptor antagonism would reduce sympathetic activity andcytokine stress peripherally and centrally
Part Two: Brain Mineralocorticoid Receptor InducesSympathetic Drive by Increasing Circulating ProinflammatoryCytokines in Congestive Heart Failure
Aims: To examined the potential impact of oral administration of a selective MRantagonist, RU28318, on blood-borne cytokines and on cytokine-driven central neuralmechanisms that may contribute to the progression of heart failure. Methods:Sprague-Dawly (SD) rats were underwent coronary ligation to induce HF, or shamsurgery. Followed by6weeks treatment with RU28318,30mg/kg per day, orally orvehicle (drinking water), as in Part One. Another set of rats were treated withanticytokine agents infliximab (INF,30mg/kg daily, in drinking water) to determinewhether the cytokine lowering effect of MR antagonism is sufficient to account forthe observed responses to RU28318. Combined MR antagonism and cytokineinhibition to determine whether it would produce additive or facilitative responses. Atthe end of the experiment, ensure that in each group there are at least12animalssurvived. After6weeks, left ventricular function parameters were determined byhemodynamic measurements. RV/BW and lung/BW ratios were calculated, the RSNAwas recorded. The plasma NE, PIC, ALDO level and concentration of PIC in PVNwas measured using ELISA techniques. Immunohistochemical studies wereperformed to assess the expression of TNF---2, and CRH in PVN.Western blot was used to measure COX-2and CRH protein expression. Results:Treatment of HF rats with anticytokine agents, infliximab, or combined MRantagonist and cytokine inhibition produced very similar results. Conclusion: Thisstudy reveals an effect of MR antagonism to minimize cytokine-induced centralneural excitation in rats with HF.
Part Three: Effect of Tumour Necrosis Factor-to Attenuate Neurotransmitters Imbalancedin Congestive Heart Failure
Aims: Blocking brain tumour necrosis factor-(TNF-neurotransmitters imbalanced in congestive heart failure (HF). we explored thepossible roles of brain proinflammatory cytokines (PIC) on modulatingneurotansmitters in the exaggerated sympathetic activity in HF. Methods:Sprague-Dawley rats were underwent coronary ligation to induce HF or SHAMcontrol. And then, they were treated for4-weeks with a continuousintracerebroventricular (ICV) infusion of the TNF-infliximab (INF,10g/h), or vehicle. Another set of HF and SHAM rats were treated withintraperitoneal (ip) infusion of a similar dose of INF. After4weeks, LVEDP and±dp/dtmaxwere measured by hemodynamic measurements. The RV/BW and lung/BWratios were calculated. The RSNA was recorded. Plasma and tissue inflammatorycytokine levels were measured using ELISA techniques. The concentrations of NEand the rate-limiting enzymes of glutamate and GABA, respectively, TH and GAD67,and circulating catecholamine levels were measured using HPLC withelectrochemical detection. Immunohistochemical labelling was performed to identifyTH, GAD67and nNOS in PVN. Results: HF rats had higher levels of glutamate, NE,and TH, and lower levels of GABA, nNOS, and67-kDa isoform of glutamatedecarboxylase (GAD67) in the PVN when compared with SHAM rats. Plasmacytokines, NE, epinephrine, angiotensin and renal sympathetic nerve activity(RSNA) were also increased in HF rats. The same ICV treatments also attenuated theincreased RSNA in HF rats. IP treatment with similar doses of INF did not affectglutamate, NE, TH, GABA, nNOS, and GAD67in the PVN and had no effect onRSNA of HF rats. Conclusion: These findings indicate that brain PICs induceneurotransmitters imbalanced and contribute to the increased sympathetic drive inHF.
人们对醛固酮／盐皮质激素功能的传统认识是它主要作用于肾脏和结肠上的受体发挥保盐作用,这种认识在过去的二十年里已有了很大的改变。研究显示,醛固酮在心血管纤维化、调节盐欲的中枢机制、调节交感神经活动以及在高血压和心衰的实验模型中都有作用。Random Aldactone Evaluation Study (RALES),是一大型医学临床研究机构,已证实给心衰病人额外小剂量口服盐皮质激素受体(MR)拮抗剂soironolactone(SL,安体舒通)(同时给予对照组安慰剂)可显著降低其发病率和死亡率,这一发现引发人们对醛固酮在心血管病中的作用给予很大关注。但产生这种有益效果的原因尚不确定。
一直以来人们将中枢MR的激活与提高盐欲和交感神经对高血压的调节联系起来,因此使用MR阻滞剂阻断其激活可能会对心衰产生(至少是部分)有益的影响是说得通的。肿瘤坏死因子-α(TNF-α)是一种促炎因子,也是操纵中枢MR的兴奋性介质。患有严重心衰的病人血浆TNF-α水平升高且与预后相关。缺血所致心衰大鼠血浆TNF-α水平也有升高,而行冠脉结扎术24小时后开始持续经侧脑室灌注SL,可阻止血浆TNF-α水平的升高。相反,对正常大鼠以足以诱导盐欲的剂量使用MR激动剂,可增高血浆TNF-α水平；而这一现象可被侧脑室使用SL所阻断。这两项研究显示：血源性促炎因子受到、至少是部分受到中枢MR的调节。
心衰除了外周炎症性反应,下丘脑PVN处的促炎因子也表现为上调并参与了交感兴奋作用。TNF-α、IL-1β和IL-6都具有激活下丘脑-垂体-肾上腺皮质(HPA)轴和增强交感神经兴奋性的作用,但PIC调节交感活动的机制尚不清楚。在PVN区,一些兴奋性和抑制性神经递质汇聚于此并影响其神经活动,包括谷氨酸、去甲肾上腺素(NE)和γ-氨基丁酸(GABA)。谷氨酸作为中枢神经系统中一种重要的兴奋性神经递质已被人们广泛认识,研究发现PVN处分布有功能性谷氨酸受体,在心血管反射中参与控制；研究还显示心衰大鼠交感神经的高度兴奋与PVN处细胞外升高的NE也有关；作为中枢神经系统中重要的抑制性神经递质,GABA在PVN区也发挥了重要的调节作用。因此我们进一步假设心衰时中枢增多的PIC引起了兴奋性和抑制性神经递质失衡从而导致交感兴奋性增强。
第一部分慢性充血性心力衰竭时中枢盐皮质激素受体的激活对交感神经活动的影响
目的：验证慢性充血性心衰时阻断中枢盐皮质激素受体(MR)能否降低交感神经兴奋性；同时观察对外周和中枢一些活性物质的影响。方法：心衰模型的制备采用结扎SD大鼠冠状动脉左前降支致心肌梗死的方法进行；假手术对照组则在手术中采取只穿线不结扎的方法进行。给药组大鼠六周内每天口服MR选择性阻滞剂RU28318(每天按30mg/kg,溶于饮用水中),对照组给普通饮用水。确保实验结束时各组至少有12只动物存活。6周后,通过对各组大鼠测定血流动力学指标评价心功能,包括左室内压最大上升和下降速率(±dp/dtmax)和左室舒张末压(LVEDP);通过测定右心室／体重比(RV/BW)口肺／体重比(Lung/BW)反映左心室前负荷变化；电生理记录肾交感神经放电活动(RSNA)、ELISA测定血浆去甲肾上腺素(NE)作为交感神经兴奋性指标,以及PIC在血浆和下丘脑的含量,ALDO在血浆中的含量及PGE2在脑脊液中的水平；免疫组织化学染色和Western blot评价PVN内COX-2和CRH的表达。结果：经RU28318处理的心衰大鼠血浆TNF-α水平降低；和心衰对照组大鼠相比PVN区COX-2染色减少,脑脊液中PGE2含量相应减低；表达TNF-α和CRH的神经元数量下降。同时,RU28318处理的心衰大鼠RSNA减弱,伴随血浆去甲肾上腺素水平降低；RV/BW和Lung/BW均降低,但左室功能没有改善。另外,RU28318对心衰大鼠血浆增高的ALDO没有明显作用。结论：慢性心衰时,阻断中枢MR可降低交感神经活动,减轻外周炎症反应及PVN区TNF-a和CRH表达。
第二部分慢性充血性心力衰竭时中枢盐皮质激素受体通过炎性因子发挥其交感兴奋作用
目的：验证慢性心衰时,中枢内MR的交感兴奋作用是通过提高外周血PIC实现的。方法：心衰模型和假手术对照组制备方法同第一部分。作为对照,部分大鼠仍按第一部分实验方案进行,即给药组大鼠六周内每天口服MR阻滞剂RU28318,每天按30mg/kg,溶于饮用水中,对照组给普通饮用水；另一部分使用抗肿瘤坏死因子-α抑制剂英夫利西(infliximab, INF)每天30mg/kg,溶入饮用水中,以确定单纯由于外周细胞因子的减少是否也能引起RU28318所致的结果；同时还设立了联合用药组(RU28318+INF),以确定能否产生其他额外的效应。保证各组实验结束时至少有12只动物存活。后期处理基本同前部分实验。即6周后,各组大鼠测定血流动力学指标评价心功能；电生理记录RSNA; ELISA技术测定血浆NE、PIC、ALDO含量,及脑组织PIC及脑脊液中PGE2的水平；本部分实验除了继续检测外周和中枢TNF-α含量,还补充了对IL-1β的检测,以进一步探讨RU28318和INF对PICs的确切作用；通过免疫组织化学染色和Western blot评价COX-2和CRH的表达。结果：对心衰大鼠使用TNF-α抑制剂INF以及联合用药(RU28318+INF)产生的各项结果和单独用RU28318处理的心衰大鼠很相似：血浆PIC中TNF-α、IL-1β水平均降低(但血中ALDO水平没有明显改变)；PVN区COX-2染色减弱,表达TNF-α,IL-1β和CRH的神经元数量下降。结论：慢性心衰时,阻断MR产生的交感活动抑制是通过降低血中促炎因子起作用的。
第三部分阻断肿瘤坏死因子-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：心衰模型和假手术对照组制备方法同第一部分。对心衰大鼠和假手术大鼠持续四周经侧脑室灌流TNF-α抑制剂英夫利西(infliximab, INF,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INF。4周后测定心脏功能学指标和形态学指标(LVEDP、±dp/dt max、RV/BW和Lung/BW)和肾交感神经放电(RSNA); ELISA技术测定促炎因子(PIC)在血浆和组织中含量以及血中血管紧张素Ⅱ(ANGⅡ)的含量；神经递质去甲肾上腺素(NE)及血中儿茶酚胺的水平利用高效液相色谱获得；免疫组织化学染色确定PVN内谷氨酸(Glu)和γ-氨基丁酸(GABA)的限速酶酪氨酸羟化酶(TH)和谷氨酸脱羧酶(GAD67)以及神经元型一氧化氮合酶(nNOS)的表达；结果：和假手术组相比,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INF可减轻上述神经递质失衡现象,以及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INF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起作用的。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。
Despite recent therapeutic advanced, the prognosis for patients with congestiveheart failure (CHF) remains dismal. CHF is the common outcome of a variety ofcardiovascular diseases. Neurohumoral excitation (NHE) is a cardinal manifestationof the CHF syndrome,closely correlated with disease severity and adverse prognosis.Sympathoexcitation is considered a trigger point that promotes the excessive releaseof neurohormones in CHF, where plasma norepinephrine (NE), angiotensin (ANGⅡ),aldosterone, cytokines,etc. were found to be correlated with severity of CHF.However, the mechanisms of sympathoexcitation are still not fully understood. Thehypothalamic paraventricular nucleus (PVN) is a principal central site mediatingneurohumoral responses. PVN is also a critical brain site to regulate extracellularfluid volume and sympathetic drive.
The traditional view of aldosterone/mineralocorticoid as a hormone actingprimarily upon receptors in the kidneys and the colon to conserve sodium hasundergone substantial modification in the past two decades, as evidence has emergedfor its involvement in cardiac and vascular fibrosis, central nervous systemmechanisms regulating sodium appetite and sympathetic nerve activity, andexperimental models of hypertension and heart failure. Interest in the role ofaldosterone in cardiovascular diseases was heightened by the Random AldactoneEvaluation Study (RALES), a large clinical trial demonstrating that the addition of asmall oral dose of the mineralocorticoid receptor (MR) antagonist spironolactone (SL)to the regimen of otherwise optimally managed patients with established heart failuredramatically reduced morbidity and mortality. The mechanism(s) accounting for thesebeneficial effects were unknown.
Activation of MR in the brain has long been associated with increased saltappetite and sympathetically mediated hypertension. It is therefore reasonable to hypothesize that blocking the activation of brain MR might account, at least inpart, for the salutary influences of MR antagonist in HF.
One excitatory mediator that responds to manipulations of brain MR is tumornecrosis factor alpha (TNF--inflammatory cytokine. Plasma levels ofTNF-with ischemia-induced HF also have high circulating levels of TNF-continuous ICV infusion of SL, initiated within24hours of coronary artery ligation,prevents the expected rise in plasma TNF-treatment with the MR agonist in a dose sufficient to induce sodium appetiteincreases plasma TNF-SL. These two studies demonstrated the surprising finding that plasma levels ofpro-inflammatory cytokines are regulated, at least in part, by brain MR.
Our recent studies suggest that, in addition to the neurohormones,proinflammatory cytokines (PICs) are upregulated in the PVN and contribute tosympathoexcitation in HF. TNF---6share a common property ofactivating the hypothalamic-pituitary-adrenal axis (HPA) and increasing sympatheticnerve activity. However, the mechanisms by which PICs modulate sympatheticactivity in HF are not clear. A number of excitatory and inhibitory neurotransmittersconverge in the PVN to influence its neuronal activity, including glutamate(Glu),norepinephrine (NE), and gamma-aminobutyric acid (GABA). Glutamate is awell-known excitatory neurotransmitter in the central nervous system and it has beenreported that functional glutamate receptors expressed in the PVN are involved in thecontrol of cardiovascular reflexes. It has also been shown that sympathetichyperactivity in rats with HF is associated with increased extracellular norepinephrine(NE) in the PVN. GABA is a well-known inhibitory neurotransmitter in the centralnervous system and is a dominant inhibitory neurotransmitter within the PVN.Previous work demonstrated a GABA-mediated inhibitory mechanism within thePVN contributing to sympathoexcitation in HF rats. Therefore, we hypothesized thatincreased PICs in the brains of HF rats caused an imbalance in the excitatoryand inhibitory neurotransmitters in the PVN, contributing to increased sympathoexcitation in HF.
Part One: Activation of Mineralocorticoid Receptorin Hypothalamic Paraventricular Nucleus Contributes toSympathoexcitation in Congestive Heart Failure
Aims: To observe the primary hypothesis that mineralocorticoid receptorantagonism would reduce sympathetic activity in rats with HF. Methods:Sprague-Dawly (SD) rats were subjected to coronary artery ligation to induce heartfailure (HF), or sham surgery without ligating the vessel (SHAM). Followed by6weeks treatment with RU28318,30mg/kg per day, orally) or vehicle (drinking water).At the end of the experiment, ensure that in each group there are at least12animalssurvived. After6weeks, left ventricular function parameters, such as left ventricularend-diastolic pressure (LVEDP) and maximum change in pressure over time (±dp/dtmax) were determined by hemodynamic measurements. The right ventricular-to-bodyweight (RV/BW) and lung-to-body weight (lung/BW) ratios were calculated asindices of pulmonary congestion and right ventricular remodeling, two indices of theseverity of HF. The renal sympathetic nerve activity (RSNA) was recorded and theplasma NE level was measured using an ELISA kit, two indices of the severity ofsympathetic nervous excitation. ELISA techniques was also used to measure TNF-ALDO levels in plasma and PGE2level in CSF. Immunohistochemical studies wereperformed to assess the expression of TNF--2, and CRH in PVN. Results:RU28318treated HF rats had lower plasma TNF--2staining of PVNneurons, and fewer PVN neurons staining for TNF--treatedHF rats. RU28318.-treated HF rats had less prostaglandin E2in cerebrospinal fluid,lower RSNA and plasma norepinephrine levels, lower left ventricular end-diastolicpressure,and lower right ventricle/body weight and lung/body weight ratios, but noimprovement in left ventricular function. Conclusion: This study demonstrates thatmineralocorticoid receptor antagonism would reduce sympathetic activity andcytokine stress peripherally and centrally
Part Two: Brain Mineralocorticoid Receptor InducesSympathetic Drive by Increasing Circulating ProinflammatoryCytokines in Congestive Heart Failure
Aims: To examined the potential impact of oral administration of a selective MRantagonist, RU28318, on blood-borne cytokines and on cytokine-driven central neuralmechanisms that may contribute to the progression of heart failure. Methods:Sprague-Dawly (SD) rats were underwent coronary ligation to induce HF, or shamsurgery. Followed by6weeks treatment with RU28318,30mg/kg per day, orally orvehicle (drinking water), as in Part One. Another set of rats were treated withanticytokine agents infliximab (INF,30mg/kg daily, in drinking water) to determinewhether the cytokine lowering effect of MR antagonism is sufficient to account forthe observed responses to RU28318. Combined MR antagonism and cytokineinhibition to determine whether it would produce additive or facilitative responses. Atthe end of the experiment, ensure that in each group there are at least12animalssurvived. After6weeks, left ventricular function parameters were determined byhemodynamic measurements. RV/BW and lung/BW ratios were calculated, the RSNAwas recorded. The plasma NE, PIC, ALDO level and concentration of PIC in PVNwas measured using ELISA techniques. Immunohistochemical studies wereperformed to assess the expression of TNF---2, and CRH in PVN.Western blot was used to measure COX-2and CRH protein expression. Results:Treatment of HF rats with anticytokine agents, infliximab, or combined MRantagonist and cytokine inhibition produced very similar results. Conclusion: Thisstudy reveals an effect of MR antagonism to minimize cytokine-induced centralneural excitation in rats with HF.
Part Three: Effect of Tumour Necrosis Factor-to Attenuate Neurotransmitters Imbalancedin Congestive Heart Failure
Aims: Blocking brain tumour necrosis factor-(TNF-neurotransmitters imbalanced in congestive heart failure (HF). we explored thepossible roles of brain proinflammatory cytokines (PIC) on modulatingneurotansmitters in the exaggerated sympathetic activity in HF. Methods:Sprague-Dawley rats were underwent coronary ligation to induce HF or SHAMcontrol. And then, they were treated for4-weeks with a continuousintracerebroventricular (ICV) infusion of the TNF-infliximab (INF,10g/h), or vehicle. Another set of HF and SHAM rats were treated withintraperitoneal (ip) infusion of a similar dose of INF. After4weeks, LVEDP and±dp/dtmaxwere measured by hemodynamic measurements. The RV/BW and lung/BWratios were calculated. The RSNA was recorded. Plasma and tissue inflammatorycytokine levels were measured using ELISA techniques. The concentrations of NEand the rate-limiting enzymes of glutamate and GABA, respectively, TH and GAD67,and circulating catecholamine levels were measured using HPLC withelectrochemical detection. Immunohistochemical labelling was performed to identifyTH, GAD67and nNOS in PVN. Results: HF rats had higher levels of glutamate, NE,and TH, and lower levels of GABA, nNOS, and67-kDa isoform of glutamatedecarboxylase (GAD67) in the PVN when compared with SHAM rats. Plasmacytokines, NE, epinephrine, angiotensin and renal sympathetic nerve activity(RSNA) were also increased in HF rats. The same ICV treatments also attenuated theincreased RSNA in HF rats. IP treatment with similar doses of INF did not affectglutamate, NE, TH, GABA, nNOS, and GAD67in the PVN and had no effect onRSNA of HF rats. Conclusion: These findings indicate that brain PICs induceneurotransmitters imbalanced and contribute to the increased sympathetic drive inHF.
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5.Kang YM, Zhang ZH, Xne B, Weiss RM, Felder RB.Novel effect of mineralocorticoid receptor antagonism to reduce proinflammatory cytokines and hypothalamic activation in rats with ischemia-induced heart failure. Circ Res.2006;99:758-766.
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1.Connell JM, Davies E. The new biology of aldosterone. J Endocrinol.2005;186:1-20.
2.Weber KT, Sun Y, Campbell SE, Slight SH, Ganjam VK, Griffing GT, Swinfard RW,Diza-Arias AA. Chronic mineralocorticoid excess and cardiovascular remodeling.Steroids.1995;60:125-132.
3.De Nicola AF, Grillo C, Gonzalez S. Physiological, biochemical and molecularmechanisms of salt appetite control by mineralocorticoid action in brain. BrazilianJournal of Medical&Biological Research.1992;25:1153-1162.
4.Francis J, Weiss RM, Wei S-G,Johnson AK, Beltz TG, Zimmerman K, Felder RB,Central mineralocorticoid receptor blockade improves volume regulation and reducessympathetic drive in heart failure. Am J Physiol Heart Circ Physiol.2001a;281:H2241-2251.
5.Gomez-Aanchez EP, Fort CM, Gomez-Aanchez CE. Intracerebroventricularinfusion of RU28318blocks aldosterone-salt hypertension. Am J Physiol EndocrinolMetab.1990;258:E482-484.
6.Francis J, Wei S-G, Weiss RM. Brain angiotensin-converting enzyme activity andautonomic regulation in heart failure. Am J Physiol Heart Circ Physiol.2004b;287:H2138-2146.
7.Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J,The effect of spironolactone on morbidty and mortality in patients with severe heartfailure. Random Aldactone Evaluation Study Investigators. N Engl J Med.1999;341709-717.
8.Gomez-Aanchez EP. Central hypertensive effects of aldosterone. FrontNeuroendocrinol.1997;18:440-462.
9. Francis J, Weiss RM Wei S-G, Johnson AK Beltz TG, Zimmerman K, Felder RB.Central mineralocorticoid receptor blockade improves volume regulation and reducessympathetic drive in heart failure. Am J Physiol Heart Circ Physiol.2001a;281:H2241-2251.
10.Leenen FH, Skarda V, Yuan B, White R. Changes in cardiac ANGpostmyocardial infarction in rats: effect of nephrectomy and ACE inhibitors. Am JPhysiol Heart Circ Physiol.1999;276:H317-325.
11.Yu Y, Wei S-G, Zhang Z-H, Ginez-Sanchez E, Weiss RM, Felder RB. Doesaldosterone upregulate the brain rennin-angiotensin system in rats with heart failure?Hypertension.2008;51:727-733.
12. Francis J, Chu Y, Johnson AK, Weiss RM, Felder RB. Acute myocardial infarctioninduces hypothalamic cytokine synthesis. Am J Physiol Heart Circ Physiol.2004a;286:H2264-2271.
13.Kang Y-M, Zhang Z-H, Xne B, Weiss RM, Felder RB.Novel effect ofmineralocorticoid receptor antagonism to reduce proinflammatory cytokines andhypothalamic activation in rats with ischemia-induced heart failure. Circ Res.2006;99:758-766.
14.Francis J, Weiss RM Wei S-G, Johnson AK Felder RB. Progression of heartfailure after myocardial infarction in the rat. Am J Physiol Regul Integr CompPhysiol.2001b;281:R1734-1745.
15.Kang Y-M, Zhang Z-H, Xne B, Weiss RM, Felder RB. Inhibition of brainproinflammatory cytokines and hypothalamic activation in rats with ischemia-inducedheart failure. Circ Res.2008;295:H227-236.
16.Rahmouni K, Barthelmebs M, Grima M, Imbs JL, Wybren De J. Brainmineralocoticoid receptor control of blood pressure and kidney function innormotensive rats. Hypertension.1999;331201-1206.
17.Grossmann C, Gekle M. Nongenotropic aldosterone effects and the EGFR:interaction and biological relevance.Steroids.2008;73:973-978.
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