GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone

BACKGROUND In the heart,aldosterone(Aldo)binds the mineralocorticoid receptor(MR)to exert damaging,adverse remodeling-promoting effects.We recently showed that G protein-coupled receptor-kinase(GRK)-5 blocks the cardiac MR by directly phosphorylating it,thereby repressing its transcriptional activity.MR antagonist(MRA)drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure.Non-steroidal MRAs,such as finerenone,may provide better cardio-protection against Aldo than classic,steroidal MRAs,like spironolactone and eplerenone.AIM To investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade.METHODS We used H9c2 cardiomyocytes,which endogenously express the MR and GRK5.RESULTS GRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone.Unlike eplerenone,finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity,thus displaying inverse agonism.GRK5 is necessary for finerenone’s inverse agonism,since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity.Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels.Finally,GRK5 is necessary for the antiapoptotic,anti-oxidative,and anti-fibrotic effects of both finerenone and eplerenone against Aldo,as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis,oxidative stress,and fibrosis.CONCLUSION Finerenone,but not eplerenone,induces GRK5-dependent cardiac MR inhibition,which underlies,at least in part,its higher potency and efficacy,compared to eplerenone,as an MRA in the heart.GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium.

Renin-angiotensin system blockers-SGLT2 inhibitorsmineralocorticoid receptor antagonists in diabetic kidney disease:A tale of the past two decades!

Several pharmacological agents to prevent the progression of diabetic kidney disease(DKD)have been tested in patients with type 2 diabetes mellitus(T2DM)in the past two decades.With the exception of renin-angiotensin system blockers that have shown a significant reduction in the progression of DKD in 2001,no other pharmacological agent tested in the past two decades have shown any clinically meaningful result.Recently,the sodium-glucose cotransporter-2 inhibitor(SGLT-2i),canagliflozin,has shown a significant reduction in the composite of hard renal and cardiovascular(CV)endpoints including progression of end-stage kidney disease in patients with DKD with T2DM at the top of reninangiotensin system blocker use.Another SGLT-2i,dapagliflozin,has also shown a significant reduction in the composite of renal and CV endpoints including death in patients with chronic kidney disease(CKD),regardless of T2DM status.Similar positive findings on renal outcomes were recently reported as a top-line result of the empagliflozin trial in patients with CKD regardless of T2DM.However,the full results of this trial have not yet been published.While the use of older steroidal mineralocorticoid receptor antagonists(MRAs)such as spironolactone in DKD is associated with a significant reduction in albuminuria outcomes,a novel non-steroidal MRA finerenone has additionally shown a significant reduction in the composite of hard renal and CV endpoints in patients with DKD and T2DM,with reasonably acceptable side effects.

Glucocorticoid and mineralocorticoid receptor expression in critical illness:A narrative review

The glucocorticoid receptor(GCR)and the mineralocorticoid receptor(MR)are members of the steroid receptor superfamily of hormone-dependent transcription factors.The receptors are structurally and functionally related.They are localized in the cytosol and translocate into the nucleus after ligand binding.GCRs and MRs can be co-expressed within the same cell,and it is believed that the balance in GCR and MR expression is crucial for homeostasis and plays a key role in normal adaptation.In critical illness,the hypothalamic-pituitary-adrenal axis is activated,and as a consequence,serum cortisol concentrations are high.However,a number of patients exhibit relatively low cortisol levels for the degree of illness severity.Glucocorticoid(GC)actions are facilitated by GCR,whose dysfunction leads to GC tissue resistance.The MR is unique in this family in that it binds to both aldosterone and cortisol.Endogenous GCs play a critical role in controlling inflammatory responses in critical illness.Intracellular GC concentrations can differ greatly from blood levels due to the action of the two 11β-hydroxysteroid dehydrogenase isozymes,type 1 and type 2.11β-hydroxysteroid dehydrogenases interconvert endogenous active cortisol and intrinsically inert cortisone.The degree of expression of the two isozymes has the potential to dramatically influence local GC availability within cells and tissues.In this review,we will explore the clinical studies that aimed to elucidate the role of MR and GCR expression in the inflammatory response seen in critical illness.

Effects of mineralocorticoid receptor antagonists on responses to hemorrhagic shock in rats

AIM To evaluate the effects of mineralocorticoid receptor(MR) antagonists on mortality and inflammatory responses after hemorrhagic shock(HS) in rats.METHODS One hundred and two male Sprague–Dawley rats were randomly assigned to one of the following three groups: Control, spironolactone (SPL), and eplerenone(EP) groups. HS was induced by the removal of blood. One half of rats were evaluated to determine mortality, hemodynamics, plasma tumor necrosis factor-alpha(TNF-α) concentrations, and arterial blood gas at 8 h afterHS recovery. In the remainder of rats, the expression levels of genes encoding cytokines were evaluated in liver tissue samples at 1 h after HS recovery. RESULTS The survival rates 8 h after HS recovery were 71%, 94%, and 82% in the control, SPL, and EP groups, respectively. There were no significant differences in survival rates among the three groups (P = 0.219). Furthermore, there were no significant differences in gene expression levels in the liver or plasma TNF-α concentrations among the three groups(P = 0.888).CONCLUSION Pretreatment with MR antagonists did not improve mortality or cytokine responses in the liver after HS recovery in rats.

MicroRNA-155 mediates endogenous angiotensin II type 1 receptor regulation:implications for innovative type 2 diabetes mellitus management

Type 2 diabetes mellitus(T2DM)is a lifelong condition and a threat to human health.Thorough understanding of its pathogenesis is acutely needed in order to devise innovative,preventative,and potentially curative pharmacological interventions.MicroRNAs(miRNA),are small,non-coding,one-stranded RNA molecules,that can target and silence around 60%of all human genes through translational repression.MiR-155 is an ancient,evolutionarily well-conserved miRNA,with distinct expression profiles and multifunctionality,and a target repertoire of over 241 genes involved in numerous physiological and pathological processes including hematopoietic lineage differentiation,immunity,inflammation,viral infections,cancer,cardiovascular conditions,and particularly diabetes mellitus.MiR-155 Levels are progressively reduced in aging,obesity,sarcopenia,and T2DM.Thus,the loss of coordinated repression of multiple miR-155 targets acting as negative regulators,such as C/EBPβ,HDAC4,and SOCS1 impacts insulin signaling,deteriorating glucose homeostasis,and causing insulin resistance(IR).Moreover,deranged regulation of the renin angiotensin aldosterone system(RAAS)through loss of Angiotensin II Type 1 receptor downregulation,and negated repression of ETS-1,results in unopposed detrimental Angiotensin II effects,further promoting IR.Finally,loss of BACH1 and SOCS1 repression abolishes cytoprotective,anti-oxidant,anti-apoptotic,and anti-inflam matory cellular pathways,and promotesβ-cell loss.In contrast to RAAS inhibitor treatments that further decrease already reduced miR-155 Levels,strategies to increase an ailing miR-155 production in T2DM,e.g.,the use of metformin,mineralocorticoid receptor blockers(spironolactone,eplerenone,finerenone),and verapamil,alone or in various combinations,represent current treatment options.In the future,direct tissue delivery of miRNA analogs is likely.

Mineralocorticoid receptor: a critical player in vascular remodeling

Vascular remodeling is a pathological condition with structural changes of blood vessels.Both inside-out and outside-in hypothesis have been put forward to describe mechanisms of vascular remodeling.An integrated model of these two hypotheses emphasizes the importance of immune cells such as monocytes/macrophages,T cells,and dendritic cells.These immune cells are at the center stage to orchestrate cellular proliferation,migration,and interactions of themselves and other vascular cells including endothelial cells(ECs),vascular smooth muscle cells(VSMCs),and fibroblasts.These changes on vascular wall lead to inflammation and oxidative stress that are largely responsible for vascular remodeling.Mineralocorticoid receptor(MR)is a classic nuclear receptor.MR agonist promotes inflammation and oxidative stress and therefore exacerbates vascular remodeling.Conversely,MR antagonists have the opposite effects.MR has direct roles on vascular cells through non-genomic or genomic actions to modulate inflammation and oxidative stress.Recent studies using genetic mouse models have revealed that MR in myeloid cells,VSMCs and ECs all contribute to vascular remodeling.In conclusion,data in the past years have demonstrated that MR is a critical control point in modulating vascular remodeling.Studies will continue to provide evidence with more detailed mechanisms to support this notion.

An alternative splicing variant of mineralocorticoid receptor discovered in preeclampsia tissues and its effect on endothelial dysfunction

The pathophysiology of preeclampsia(PE)remains unclear.PE spiral artery remodeling dysfunction and PE offspring cardiovascular future development has been a worldwide concern.We collected placental and umbilical artery samples from normotensive and PE pregnancies.Mineralocorticoid receptor(MR)and its alternative splicing variant(ASV)expression and their biological effects on PE were examined.An MR ASV was found to be highly expressed in all PE samples and slightly expressed in about half of the normotensive samples(umbilical artery,~57.58%;placenta,~36.84%).The MR ASV expression was positively associated with blood pressure in both groups.The MR ASV protein changed the aldosterone-induced expression pattern of MR target genes related to ion exchanges and cell signaling pathways.The MR ASV can also impair the proliferation,migration,and tube formation ability of endothelial cells.These findings indicate that MR ASV in PE placenta plays a pathogenic role in PE pathophysiology,especially in endothelial dysfunction,and the existence of the MR ASV in PE umbilical artery provides a new direction in the study of PE offspring with increased risk of cardiovascular diseases.

非奈利酮对2型糖尿病患者心肾保护作用的研究进展

盐皮质激素受体拮抗剂是心力衰竭患者的指南推荐治疗药物。然而,高钾血症和激素副作用的相关风险限制了其在2型糖尿病合并中晚期慢性肾脏病及心血管疾病高风险患者中的广泛使用。非奈利酮是一种新型非甾体类盐皮质激素受体拮抗剂,用于与2型糖尿病相关的心血管疾病和慢性肾脏病患者,达到心肾保护的作用。本文对非奈利酮在治疗2型糖尿病中心肾保护的作用机制、药理特性、安全性等进行综述,旨在为2型糖尿病合并心力衰竭及肾脏损伤患者的临床治疗提供帮助。

Expression of hippocampal corticosteroid receptors,as well as corticotrophin-releasing hormone and vasopressin in the hypothalamic paraventricular nucleus,in fornix transected rats

BACKGROUND： The hippocampus regulates the hypothalamic-pituitary-adrenal axis through negative feedback. The hypothalamic paraventricular nucleus receives neuronal input from the hippocampus via the fomix, OBJECTIVE： To explore whether the negative feedback effect of the hippocampus on the hypothalamic-pituitary-adrenal axis is contributed to the inhibitory effect of mineralocorticoid receptor （MR） and glucocorticoid receptor （GR） in the hippocampus on the paraventricular nucleus via the fornix. DESIGN, TIME AND SETTING： Randomized, controlled, animal experiment. The study was performed at the Department of Histology and Embryology, China Medical University between September 2006 and September 2008. MATERIALS： Rabbit anti-rat anti-MR and rabbit anti-rat anti-GR antibodies were purchased from Santa Cruz Biotechnology, USA. Rabbit anti-rat anti-corticotrophin releasing hormone （CRH） and rabbit anti-rat anti-arginine vasopressin antibodies were purchased from Wuhan Boster. METHODS： A total of 90 male, Wistar rats were randomly divided into model and sham-surgery groups （n = 45）. Fornix transection was performed in the model group, while the sham-surgery group underwent surgery, but no fornix transection. MAIN OUTCOME MEASURES： Immunohistochemistry was used to examine MR and GR expression in the hippocampus, as well as CRH and anti-arginine vasopressin in the paraventricular nucleus. Western blot was used to measure alterations in MR, GR, and CRH protein expression following fomix transection. RESULTS： Compared with the sham-surgery group, there were no obvious changes in MR and GR expression in the hippocampus, or CRH and anti-arginine vasopressin expression in the paraventdcular nucleus within 4 days of fornix transection. However, after 7-10 days, significantly decreased MR and GR expression in the hippocampus, and increased CRH and anti-arginine vasopmssin expression in the paraventricular nucleus were observed （P 〈 0.05-0.01）. CONCLUSION： Negative feedback from the hippocampus on the hypothalamic-pituitary-adrenal axis might be mediated through the fornix, and the corticosterene actions mediated by hippocampal corticosteroid receptors indirectly modulated the hypothalamic-pituitary-adrenal axis.

盐皮质激素受体拮抗剂治疗糖尿病足细胞损伤的研究进展

糖尿病肾脏疾病(DKD)可经多重机制损伤肾小球足细胞,足细胞病变进一步促进DKD进展。盐皮质激素通过作用于盐皮质激素受体(MR)调节人体水盐平衡、体液容量和血压。MR表达于足细胞、内皮细胞、系膜细胞等肾小球固有细胞,其活化将影响足细胞的结构和功能,损坏滤过屏障,导致蛋白尿。糖尿病状态下MR过度活化提高足细胞内氧化应激水平,损伤细胞超微结构,抑制足细胞自噬、促进凋亡,导致蛋白尿和肾脏局部炎症,阻断MR可避免足细胞结构受损、功能障碍和数量减少,有助于修复滤过屏障。本文将综述糖尿病导致足细胞损伤的病理生理机制,MR拮抗剂(MRA)保护足细胞的基础和临床研究,为MRA治疗DKD足细胞病变、减少蛋白尿、改善肾脏预后提供理论依据。

慢性肾脏病氧化应激发生机制的研究进展

氧化应激是慢性肾脏病(CKD)的一个重要特征。其可促进CKD进展,并加速肾性高血压、动脉粥样硬化和肾性贫血等相关并发症的发生发展,是重要的预后因素。CKD氧化应激的发生机制复杂,涉及肾脏线粒体功能障碍、氧化酶激活、肠源性尿毒症毒素蓄积、抗氧化能力下降、铁代谢紊乱、肾素-血管紧张素-醛固酮系统激活等多方面因素。针对以上机制的干预措施对改善氧化应激具有良好的治疗前景。未来深入研究CKD氧化应激的发生机制,有助于寻找特异性治疗靶点,改善CKD患者的预后。

盐皮质激素受体与代谢相关心血管疾病的研究进展

盐皮质激素受体(MR)通过与醛固酮结合发挥多种生理作用,参与全身多种系统性疾病的发病过程。MR可在多种细胞中表达,如免疫细胞、代谢细胞等,在这些细胞中MR可通过参与炎症、氧化应激及内皮细胞功能障碍等过程调节机体免疫、代谢和应激反应。本文就MR与代谢相关心血管疾病之间的关系进行简要回顾,研究免疫细胞和代谢细胞MR参与调节心肌肥厚、心肌纤维化、动脉粥样硬化、肝脏脂肪变性、胰岛素抵抗、心肌重构及高血压等的关键作用及机制,以期为代谢相关心血管疾病的防治提供证据和思路。

Advances in Medical Treatment of Primary Aldosteronism

Primary aldosteronism(PA)is the most common form of secondary hypertension,with its main manifestations including hypertension and hypokalemia.Early identification of PA is extremely important as PA patients can easily develop cardiovascular complications such as atrial fibrillation,stroke,and myocardial infarction.The past decade has witnessed the rapid advances in the genetics of PA,which has shed new light on PA treatment.While surgery is the first choice for unilateral diseases,bilateral lesions can be treated with mineralocorticoid receptor antagonists(MRAs).The next-generation non-steroidal MRAs are under investigations.New medications including calcium channel blockers,macrophage antibiotics,and aldosterone synthase inhibitors have provided a new perspective for the medical treatment of PA.

“川芎-当归”药对主要活性成分的网络药理学研究

目的应用网络药理学方法探究川芎-当归药对的主要活性成分、靶点和药理作用机制。方法研究时间为2020年9—12月。首先以“川芎”“当归”为关键词,在TCMSP 2.3数据库中检索药材的成分、靶点和对应疾病数据,构建“药物-成分靶点-疾病”网络,进行基因本体(gene ontology,GO)分类富集分析、京都基因和基因组百科全书(kyoto encyclopedia of genes and genomes,KEGG)通路富集分析,探究“川芎-当归”药对作用机制。结果“药物-成分-靶点-疾病”网络包含2个药物、10个活性成分,71个作用靶点,191种疾病。关键靶点涉及环氧化酶2(PTGS2)、过氧化物酶体增生激活受体γ(PPARG)、雌激素受体(ESR1)、β2肾上腺素能受体(ADRB2)、周期蛋白依赖激酶2(CDK2)、热休克蛋白90(HSP90)、促分裂原活化蛋白激酶14(MAPK14)、胆碱能受体2(CHRM2)、5羟色胺受体2A(HTR2A)、凝血因子Ⅱ受体(F2R)、盐皮质激素受体(NR3C2)、内皮型一氧化氮合酶(NOS3)等,关键疾病涉及疼痛、心血管疾病、乳腺癌、阿尔茨海默病、炎症、癌症、焦虑症、精神分裂症、前列腺癌、实体肿瘤、脑损伤等。GO富集分析得到237个条目,包括生物过程178个,分子功能26个,细胞组成33个。通路富集分析包含66条通路,主要涉及神经活性配体-受体相互作用、钙离子信号通道、癌症通路、5-羟色胺能突触、大肠癌、雌激素信号通路、心肌细胞的肾上腺素能信号、甲状腺激素信号通路、cAMP信号通路、血管内皮生长因子信号通路等。结论“川芎-当归”药对中多个成分作用于多个靶点和通路,对疼痛、心血管疾病、乳腺癌、阿尔茨海默病、炎症、癌症等多种疾病均一定的治疗作用。

依达拉奉对心肌重构小鼠AT1R/StAR/MR信号通路的影响

目的探究依达拉奉治疗小鼠压力超负荷致心肌重构与血管紧张素1型受体(AT1R)/类固醇合成急性调节蛋白(StAR)/盐皮质激素受体(MR)的关系。方法SPF级C57小鼠18只,4周龄,体重22~24 g,根据随机数字表法将其分为对照组、血管紧张素Ⅱ组、依达拉奉组,每组6只。采用皮下埋置渗透泵持续灌注血管紧张素Ⅱ1500 ng/(kg·min)28 d的方法制备小鼠心肌重构模型。对照组埋置预先充填0.9%氯化钠的渗透泵;依达拉奉组皮下埋置预先充填血管紧张素Ⅱ的渗透泵后,每日给予腹腔注射依达拉奉10 mg/kg,连续28 d。于模型制备成功后,处死小鼠取心脏,称重后计算心重/体重(HW/BW)比值;取心肌石蜡组织切片,采用苏木精-伊红染色法测定心肌细胞横截面积,采用Masson’s染色法测定胶原容积分数(CVF),采用免疫组织化学染色法测定心肌细胞血管紧张素1型受体(AT1R)、StAR、MR、转化生长因子-β_(1)(TGF-β_(1))、α-平滑肌肌动蛋白(α-SMA)表达。结果血管紧张素Ⅱ组小鼠HW/BW比值、MSA和CVF高于对照组,差异有统计学意义(P<0.05);依达拉奉组小鼠HW/BW比值、MSA和CVF低于血管紧张素Ⅱ组,差异有统计学意义(P<0.05)。血管紧张素Ⅱ组小鼠AT1R、StAR、TGF-β_(1)、α-SMA、MR蛋白表达高于对照组,差异有统计学意义(P<0.05);依达拉奉组小鼠AT1R、StAR、TGF-β_(1)、α-SMA、MR蛋白表达低于血管紧张素Ⅱ组,差异有统计学意义(P<0.05)。结论依达拉奉治疗小鼠压力超负荷致心肌重构与抑制AT1R/StAR/MR有关。

奶牛亚临床酮病血液生化指标分析及糖皮质激素影响肝细胞糖异生作用分子机制的研究

为探究围产期奶牛亚临床酮病血清中生化指标的变化特征,本研究选取2~4胎次荷斯坦围产期奶牛45头,分别在分娩前7 d、分娩当天晨饲前经尾根静脉采血,以血酮检测值<1.2 mmol/L为健康组,≥1.2 mmol/L为酮病组。采用ELISA试剂盒测定分娩前7 d、分娩当天、分娩后7 d、14 d健康组和酮病组奶牛血液中的生化指标。结果显示,酮病组奶牛分娩前7 d和分娩当天血清中皮质醇含量显著高于健康组(P<0.05);并且酮病组奶牛分娩前7 d血清中β-羟丁酸(BHBA)、高密度脂蛋白(HDL-C)含量显著高于健康组(P<0.05);酮病组奶牛分娩前后血清中葡萄糖(Glu)、甘油三脂(TG)、极低密度脂蛋白(VLDL-C)、游离脂肪酸(FFA)含量较健康组虽无显著差异,但均高于健康组。分别以0、1×10^(-7)mmol/L、1×10^(-8)mmol/L、1×10^(-9)mmol/L浓度的糖皮质激素(GC)刺激原代分离培养的犊牛肝细胞,作用0、1 h、3 h、6 h、24 h后采用荧光定量PCR检测肝细胞中糖异生相关受体及其相关酶编码基因的相对转录水平,并以皮尔森相关系数对糖异生相关受体及其相关酶编码基因的转录水平进行相关性分析。q PCR结果显示:高浓度GC促进原代犊牛肝细胞中糖皮质激素受体(GR)NR3CI的转录水平,低浓度GC促进盐皮质激素受体(MR)NR3C2的转录水平。糖异生相关限速酶PC、PEPCK-C、PCK2、11β-HSD1、11β-HSD2编码基因的相对转录水平随GC浓度和其作用时间而变化。皮尔森(Pearson)相关性分析结果显示:PC、PCK2、11β-HSD1基因的相对转录水平与NR3C1极显著相关(P<0.01),PEPCK-C、11β-HSD1、11β-HSD2与NR3C2的相对转录水平显著相关(P<0.05)。上述结果表明酮病奶牛分娩前GC水平升高,而GC可能通过结合其受体GR/MR提高奶牛肝细胞中糖异生关键酶PC、PEPCK-C、PCK2、11β-HSD1和11β-HSD2编码基因m RNA的转录,从而促进糖异生作用。本研究为酮病奶牛体内糖脂代谢相关激素GC的内分泌调节作用及其分子机制和GC的临床应用奠定实验基础。

原发性醛固酮增多症与糖代谢紊乱的研究进展

原发性醛固酮增多症作为内分泌性高血压中最常见的类型伴有相当比例的糖代谢异常,是内分泌性糖尿病的一种病因,可能机制包括自主醛固酮过量分泌并通过盐皮质激素受体及非盐皮质激素受体等导致外周组织和肝脏等胰岛素敏感性下降、胰岛功能受损。近期研究表明,原发性醛固酮增多症合并皮质醇共分泌发生率较高,皮质醇作为一种糖皮质激素,可以通过糖皮质激素受体及盐皮质激素受体发挥作用,促进糖异生、抑制糖原合成、降低胰岛素敏感性及胰岛素分泌等途径影响糖代谢。盐皮质激素受体拮抗剂对糖代谢的影响目前仍存在争议,针对合并皮质醇共分泌且不宜手术的原发性醛固酮增多症患者,盐皮质激素受体拮抗剂联合糖皮质激素受体拮抗剂或许对糖代谢发挥作用。

非类固醇盐皮质激素受体拮抗剂在糖尿病肾病中的研究进展

糖尿病肾病是糖尿病的重要微血管并发症之一,研究显示盐皮质激素受体在糖尿病肾病的发展中起到重要作用,然而,因高钾血症、男性乳腺发育等不良反应,传统盐皮质激素受体拮抗剂的临床应用受限,近年来非类固醇盐皮质激素受体拮抗剂作为新型糖尿病肾病治疗药物受到关注。本综述介绍了盐皮质激素受体参与糖尿病肾病的病理生理学机制,并简要概述了非类固醇盐皮质激素受体拮抗剂相关临床研究进展。

防治心力衰竭新药临床应用及研究进展

心力衰竭(heart failure,HF)是全球的公共卫生问题,是多种心血管疾病的终末阶段,HF患者面临着高死亡率的威胁,且因反复住院及活动耐受差,严重影响生活质量。一线药物如利尿剂、肾素血管紧张素醛固酮系统(renin-angiotensin-aldosterone system,RAAS)抑制剂和β受体拮抗剂(beta-receptor blockers,BB)等使各类HF患者获益,但临床应用时产生的电解质紊乱、干咳、血管性水肿、心律失常和肾功能损伤等不良反应时有发生;同时药物种类的局限为心力衰竭药物治疗带来桎梏。因此,国内外围绕HF的新药研发一直在开展。本文就近5年在中国上市的防治HF新药临床应用及其在各期临床研究取得的进展进行综述,旨在明确HF新药临床应用价值与前景,为临床HF药物治疗提供新的思路。

依普利酮对高盐诱导的高血压大鼠主动脉内皮型一氧化氮合酶表达及活性的影响

目的：探讨依普利酮对高盐诱导的高血压大鼠主动脉内皮型一氧化氮合酶（e NOS）的表达及活性的影响。方法：50~60 g 4周龄雄性Wistar大鼠随机分为3组：对照（control,C）组用普通饲料饲养16周,高盐饮食（high salt diet,HS）组及依普利酮（eplerenone,Epl）组用5%高盐饲料饲养16周,C组和HS组于末4周给予同等剂量生理盐水灌胃,而Epl组于末4周给予依普利酮40 mg·kg-1·d-1灌胃。每2周检测各组大鼠尾动脉收缩压,16周后处死大鼠,留取主动脉。ELISA法检测醛固酮含量,蛋白免疫印迹法检测盐皮质激素受体（MR）及e NOS蛋白表达水平,化学比色法测定一氧化氮合酶活性,免疫组化染色法观察主动脉e NOS、神经型一氧化氮合酶（n NOS）及MR蛋白表达与定位。结果：（1）高盐饲料饲养8周后,大鼠收缩压即明显升高,并逐渐上升,16周时HS组收缩压较同时点C组明显升高（P〈0.05）;依普利酮灌胃4周后,收缩压比灌胃前明显下降（P〈0.05）。（2）与C组比较,HS组、Epl组主动脉醛固酮含量明显增加（P〈0.05）,且MR表达明显增加（P〈0.05）。（3）HS组较C组e NOS蛋白表达减少（P〈0.05）、结构型一氧化氮合酶（c NOS）活性也降低（P〈0.05）;Epl组较HS组e NOS蛋白表达增加（P〈0.05）、c NOS活性增高（P〈0.05）。结论：（1）高盐诱导高血压大鼠的主动脉醛固酮含量明显增加,醛固酮可能通过激动MR降低主动脉e NOS蛋白表达及酶活性。（2）选择性MR拮抗剂依普利酮可恢复e NOS蛋白表达及活性,改善e NOS功能。