醛固酮拮抗剂治疗心血管疾病的研究进展

醛固酮的经典作用是与肾脏远曲小管和集合管细胞中醛固酮受体结合,引起保钠排钾和水钠潴留.近年研究发现,醛固酮受体广泛分布于心肌细胞、血管平滑肌细胞、成纤维细胞.在心力衰竭、高血压、急性心肌梗死(AMI)等病理条件下,血浆或心血管局部组织中醛固酮水平可明显升高,过多的醛固酮通过其受体可引起心肌纤维化、血管顺应性下降、内皮功能失调、儿茶酚胺释放、心律失常等有害作用.可见醛固酮是导致心血管损害的重要的神经内分泌因素,而醛固酮拮抗剂如:螺内酯、依普利酮(eplerenone)、坎利酮(canrenone)、坎利酸(canrenate)可逆转上述不利作用,在心力衰竭、高血压、AMI患者的治疗中有望发挥重要作用[1].     

肾上腺醛固酮腺瘤术后临床转归的影响因素

肾上腺醛固酮腺瘤是原发性醛固酮增多症的一种常见类型,一般对单侧肾上腺醛固酮腺瘤的治疗方案是进行手术切除.经手术治疗可以降低高血压,影响术后血压恢复的因素有年龄、高血压持续时间、肾功能、基因型和醛固酮受体拮抗剂敏感,但也可以在术后并发高钾血症和慢性肾脏疾病,引起术后发生高钾血症的因素有高血压持续时间和肾小球滤过率,引起术后发生慢性肾脏疾病的因素有术前肾小球滤过率和醛固酮肾素比值.因此,应该对单侧肾上腺醛固酮腺瘤手术治疗的患者进行全方面的评估,以避免术后并发症的发生.     

醛固酮受体拮抗剂在扩张型心肌病中的应用

扩张型心肌病患者神经激素长期过度激活机制对心血管系统产生不良作用,导致预后不佳。患者体内肾素-血管紧张素系统的过度激活导致了醛固酮合成增加,过多产生的醛固酮导致水钠潴留,心肌纤维化。在扩张型心肌病治疗上加用醛固酮受体拮抗剂可改善发病率和死亡率。     

醛固酮对肝星状细胞Ⅰ、Ⅲ型胶原合成及组织金属蛋白酶抑制因子-1 mRNA表达的作用

肾素-血管紧张素-醛固酮系统(RAAS)可能在肝纤维化形成中发挥重要作用，利用醛固酮受体拮抗剂、血管紧张素Ⅱ1型(AT1)受体拮抗剂和血管紧张素转换酶抑制剂(ACEI)等药物阻断RAAS可以显著抑制实验性大鼠肝纤维化的形成。现在体外现察了醛固酮对肝星状细胞株HSC-T6 Ⅰ，Ⅲ型胺原合成和组织基质金属蛋白酶抑制因于-1(TIMP-1)mRNA表达的作用。     

醛固酮受体拮抗剂联合ARB治疗难治性高血压醛固酮逃逸现象(附1例报告)

目的分析顽固性高血压的醛固酮逃逸现象。方法结合具体病例复习相关知识。结果女性患者,头晕20天入院,入院后血压控制不佳,排除继发性高血压后,联合使用血管紧张素受体阻滞剂(ARB)、醛固酮拮抗剂,完全阻断了肾素-血管紧张素-醛固酮系统(RAAS),从而平稳控制血压。结论血管紧张素转换酶抑制剂(AECI)或者ARB联合使用螺内酯可能是治疗难治性高血压的一种有效手段。     

醛固酮拮抗剂依普利酮治疗高血压病研究进展

肾素-血管紧张素-醛固酮系统(RAAS)在高血压病病理生理和临床治疗中的作用已经得到了深入的研究.血管紧张素转换酶抑制剂(ACEI)和血管紧张素受体拮抗剂(ARB)均能有效降低血压,保护肾脏,并能降低心力衰竭患者的发病率和病死率.     

埃普利酮:一种选择性醛固酮受体拮抗剂在治疗心力衰竭中的作用

近年来多项动物和临床研究已证实醛固酮对心血管系统有多种毒性作用 ,在心力衰竭的病理生理过程中起重要作用 ,醛固酮在高盐和高血管紧张素Ⅱ状态下可引起心肌纤维化 ,且这一作用独立于其致高血压作用。醛固酮可诱导多种血管炎症反应 ,可能有致急性心肌梗死作用 ,并可能在急性心肌梗死后的心室重构中起重要作用。已有多项大型临床试验证明醛固酮受体拮抗剂能明显降低心力衰竭病人的死亡率。埃普利酮对醛固酮受体的选择性大大高于安体舒通 ,所以其激素样不良反应发生率明显低于安体舒通 ,而同样能对心力衰竭病人起保护作用。     

盐皮质激素受体相关高血压及其靶器官损害:难治性高血压的临床相关特点

Hirotaka Shibata,Hiroshi Itoh.Am J Hypertens,2012,25(5):514-523.在难治性高血压(定义为降压治疗中同时应用至少3种不同种类的降压药物后血压仍不达标)治疗中加用盐皮质激素受体(mineralocorticoid receptor,MR)拮抗剂治疗通常有效,该型高血压定义为"MR相关性高血压"。MR相关性高血压分为两种亚型,高血浆醛固酮水平和正常血浆醛固酮水平。前者包括原发性醛固酮增多症(primary aldosteronism,PA)     

血管紧张素Ⅱ1型受体拮抗剂与醛固酮受体拮抗剂对逆转高血压大鼠心肌重塑的作用

在受体水平阻断肾素—血管紧张素系统 ,比较血管紧张素Ⅱ 1型受体拮抗剂与醛固酮受体拮抗剂对逆转高血压心肌重塑的作用 ,来探讨高血压性心肌重塑的可能机理。为此 ,制作二肾一夹型高血压大鼠模型形成心肌肥厚及纤维化 ,然后分成高血压对照组、缬沙坦组 [10 μg (kg·d) ]和螺内酯组 [4 0mg (kg·d) ]。分别观察给药前、给药后 4周和 12周血浆及心肌血管紧张素Ⅱ和醛固酮含量、左心室重量指数、心肌胶原含量、心肌胶原容积分数及Ⅰ、Ⅲ型胶原的病理特征。结果发现 ,与高血压对照组比较 ,缬沙坦组左心室重量指数、心肌胶原含量和心肌胶原容积分数显著下降 (P <0 .0 5 ) ,以降低Ⅰ型胶原沉积为主 ;螺内酯组左心室重量指数、心肌胶原含量和心肌胶原容积分数亦有所下降 (P <0 .0 5 ) ,以降低Ⅲ型胶原沉积为主 ,但作用不如缬沙坦。结果提示 ,左心室肥厚发展过程与心肌纤维化存在异时性。血管紧张素Ⅱ和醛固酮在心肌重塑过程中起关键作用 ,血管紧张素Ⅱ 1型受体可能主要介导Ⅰ型胶原的沉积 ,而醛固酮受体可能主要介导Ⅲ型胶原的沉积。     

依普利酮在心血管疾病中应用的新进展

醛固酮受体不仅存在于肾脏，也存在于心脏、血管及脑中。许多研究发现，醛固酮与其受体结合可导致心血管系统损害。醛固酮拮抗剂螺内酯对心血管系统具有保护作用，可预防和治疗醛固酮对血管及靶器官的损害，但存在性激素等相关不良反应使之不宜广泛应用于临床。新一代选择性醛固酮受体拮抗剂依普利酮可特异性阻断醛固酮受体，而对雄激素和孕酮受体的亲和力极低，可替代螺内酯用于心血管疾病的治疗。     

Modulation of aldosterone levels by −344 C/T CYP11B2 polymorphism and spironolactone use in resistant hypertension

Interindividual variability in plasma aldosterone levels comprises environmental and genetic sources. Increased aldosterone levels have been associated with higher risk of hypertension and target-organ damage related to hypertension. Aldosterone excess and intravascular volume expansion are implicated in pathophysiology of resistant hypertension (RH). We sought to investigate whether −344 C/T polymorphism (rs1799998) in aldosterone synthase gene (CYP11B2) is associated with plasma aldosterone levels in patients with resistant hypertension. Sixty-two patients with resistant hypertension were enrolled in this cross-sectional study. Genotypes were obtained by allelic discrimination assay using real time polymerase chain reaction. Multivariable linear regression was used to identify whether TT genotype was a predictor of aldosterone levels. No differences in clinical and laboratorial parameters were found among genotype groups. We found an additive effect of the T allele on plasma aldosterone concentration in RH. Also, there was higher aldosterone levels in TT homozygous under use of spironolactone compared with C carriers and compared with TT subjects who was not under use of spironolactone. TT genotype and the use of spironolactone were significant predictors of aldosterone levels in RH subjects. Plasma aldosterone concentration is significantly associated with −344 C/T CYP11B2 polymorphism and with the treatment with spironolactone in resistant hypertensive subjects.     

The Diagnostic Value of the 24 Hour Integrated Concentration of Plasma Aldosterone

The 24-hour urinary excretion rate of aldosterone, the 24-hour integrated concentration of plasma aldosterone (IC-ALDO) and the morning plasma aldosterone levels from a single, discrete venipuncture of 92 subjects (30 normal subjects, 62 patients with mild, essential hypertension) were compared, using the variance ratio method, to 12 patients with primary aldosteronism.

The variance of the IC-ALDO was significantly lower than the respective variances of the 24-hour urinary excretion of aldosterone (P < 0.01) and of the discrete, morning plasma levels of aldosterone (P < 0.01).

The clinical usefulness of this diagnostic procedure depends on its ability to discriminate between healthy subjects and various hypertensive patients. Because of its narrower variance and enhanced discriminatory ability, the 24-hour IC-ALDO may have useful application in diagnosis of various disorders of aldosterone secretion. We have found the IC-ALDO completely separated 11 of 12 primary aldosteronism patients (mean 36±17) from essential hypertensive controls (mean 9.6±4.1)(P < 0.01). When IC-ALDO was combined with integrated concentration of plasma renin activity in an ALDO/RENIN ratio, all 12 primary aldosteronism patients were diagnosed.     

醛固酮合酶基因多态性与原发性高血压及血浆醛固酮水平的关系

目的　探索武汉地区汉族人群中醛固酮合酶 (CYP11B2 )基因 3 44C/T多态性与原发性高血压 (EH)的相关性 ,及高血压人群醛固酮合酶CYP11B2基因 3 44C/T多态性与血浆醛固酮(pAldo)水平的相关性。方法　应用PCR RELP技术对 2 0 4例CYP11B2基因 3 44C/T多态性进行分析 ,应用放射免疫法测定 10 6例EH组的血浆醛固酮水平。结果　CYP11B2基因 3 44C/T多态性以TT和CT为主要基因型 ,与EH无明显相关性 (P >0 .0 5 )。高血压患者血浆醛固酮水平在CYP11B2基因 3 44C/T的 3个不同基因型组比较差异有显著性 (P <0 .0 1)。结论　武汉地区汉族人群CYP11B2基因 3 44C/T多态性频率与EH没有明显相关性。高血压人群的血浆醛固酮水平与CYP11B2基因 3 44C/T多态性相关     

Autonomic Effects of Spironolactone and MR Blockers in Heart Failure

Neurohormonal dysfunction is an important and potentially modifiable part of the disease process of heart failure. In this review we will discuss the ways in which the autonomic system is deranged in congestive cardiac failure and the different ways we have of monitoring these abnormalities i.e.: heart rate variability, plasma norephinephrine activity, MIBG scanning, heart rate turbulence, baroreceptor function and briefly, microneurographic techniques and QT interval analysis. We will then discuss the direct effects of aldosterone and of aldosterone blockade on some of these parameters. We conclude that neurohormonal dysfunction is an important component of chronic heart failure, which is affected by aldosterone and can be modified by the use of aldosterone receptor blockade.     

Aldosterone Receptor Blockade in the Management of Heart Failure

Mounting evidence suggests that increased circulating aldosterone levels, despite angiotensin-converting-enzyme inhibitors therapy, may exert deleterious cardiovascular effects in heart failure, leading to clinical deterioration and poor prognosis. In the past decades, a number of experimental investigations have provided major insight into the mechanism(s) of action and the biological effects of aldosterone on the cardiovascular system, indicating that aldosterone participates in the structural and functional remodeling of cardiac and vascular tissue. In particular, it has emerged that aldosterone plays a key role in the regulation of myocardial extracellular matrix composition and endothelial function with important pathophysiological implications. Such evidence, coupled with the recent beneficial effects of spironolactone, a competitive aldosterone receptor antagonist, in reducing cardiac mortality and morbidity in patients with severe chronic heart failure treated with angiotensin-converting-enzyme inhibitors and loop diuretics, highlights the importance of aldosterone in the pathophysiology of human heart failure.The purpose of this review is to provide an overview of the regulation of aldosterone production and metabolism in heart failure, the basic mechanism of aldosterone action, and the pathophysiological implications of aldosterone in heart failure, and to discuss recent evidence supporting the efficacy of aldosterone receptor blockade in the treatment of chronic heart failure in humans.     

Association Between Increased Plasma Levels of Aldosterone and Decreased Systemic Arterial Compliance in Subjects With Essential Hypertension

We previously observed that, in subjects with essential hypertension, acute ouabain constricts the brachial artery diameter in the presence of spironolactone treatment, a finding that is not observed in the absence of aldosterone antagonist and therefore suggests a specific effect of aldosterone on the arterial wall. To evaluate whether aldosterone excess may contribute to modulate arterial function, we investigated 56 patients with sustained essential hypertension in comparison with 36 normotensive controls. Systemic arterial compliance was measured from intraarterial blood pressure and cardiac output measurements using a classical Windkessel model to determine the elasticity of the proximal arterial tree. Radial artery compliance was determined using a previously described echo tracking technique. In hypertensive, but not in normotensive, subjects, systemic arterial compliance was strongly and negatively correlated with plasma aldosterone. The correlation was observed even after adjustment for age and blood pressure. Plasma potassium and renin activity did not interfere in the correlation. Acute administration of diltiazem did not change systemic compliance but significantly decreased plasma aldosterone, suggesting that, in the presence of calcium blockade, the same compliance was achieved for a lower plasma aldosterone level. Taken together, these findings strongly suggest that significant interactions exist between aldosterone and central conduit arteries and that aldosterone might modulate arterial function in subjects with essential hypertension.     

醛固酮合成酶及基因

近年来 ,醛固酮在维持人体正常生理功能及在心血管、肝脏和肾脏等疾病发病中的作用日益受到重视 ,其合成酶成为研究的重点。本文综述了近年来醛固酮合成酶在基因、结构、调控以及临床相关疾病方面研究的新进展。     

醛固酮拮抗剂在顽固性高血压治疗中的地位

对于顽固性高血压患者,无论是否伴有明显的血醛固酮增多,在监测血钾及药物不良反应的条件下,加用小剂量醛固酮拮抗剂可得到意想不到的降压效果以及保护靶器官的作用。现将通过近年多项相关临床试验,探讨醛固酮拮抗剂在顽固性高血压治疗中的地位。     

Central Infusion of Aldosterone Increases Blood Pressure by Mechanisms Independent of Na Retention

Experiments were performed to test the hypothesis that Na retention and Na in the diet are not required to initiate central aldosterone induced hypertension. Rats were fed either standard rat chow or Na-deficient diet and infused intracerebroventricularly (i.c.v.) with aldosterone (28 ng/h) dissolved in artificial cerebrospinal fluid (vehicle) or vehicle alone. In Na-replete rats the central infusion of aldosterone did not promote Na or water retention, prior to increases in systolic blood pressure (SBP). Infusion of aldosterone in Na-deficient rats also initiated a rise in SBP, although the response was delayed. In neither group of rats did aldosterone infusion significantly change plasma Na, K, renin, norepinephrine (NE) or vasopressin (AVP) concentrations. There was no significant increase in plasma aldosterone concentration in Na replete rats centrally infused with aldosterone. Infusion of vehicle had no effect on SBP. We conclude that central aldosterone infusion initiates an increase in blood pressure by a mechanism independent of Na retention. Furthermore, increased concentrations of systemic renin, vasopressin, and activation of the sympathetic nervous system do not appear to be involved in maintaining hypertension.