心肌钠氢交换抑制药在心血管疾病治疗中的应用

心肌钠氢交换抑制药通过抑制心肌细胞内外钠氢交换,从而防止或减少心肌细胞内钙超负荷。研究表明心肌钠氢交换抑制药对心肌缺血、再灌注损伤、心肌肥厚和心力衰竭有明确的治疗作用。     

Nampt对ERK1/2的调控在病理性心肌肥大中的作用研究

目的研究烟酰胺磷酸核糖基转移酶(Nampt)调控细胞外调节蛋白激酶(ERK1/2)在病理性心肌肥大中的作用和机制。方法采用苯肾上腺素(PE)刺激原代心肌细胞24 h,在细胞水平上建立心肌细胞肥大模型;SD大鼠连续3周皮下注射ISO,或进行腹主动脉结扎(AAC)8周诱导心肌肥大或心衰模型。采用Western blot检测蛋白变化;RT-qPCR检测mRNA变化;采用质粒瞬时转染过表达Nampt;而加入干扰RNA降低其表达,或使用FK866来抑制其酶活性。结果在细胞水平成功建立心肌肥大模型,在整体动物水平成功诱导心肌肥大和心衰模型,均发现Nampt的mRNA和蛋白表达水平上调;过表达Nampt可缓解PE导致的NAD⁺含量降低、ERK1/2磷酸化水平增加及心肌细胞肥大反应;敲低Nampt或抑制其酶活性则显示相反的效应。结论Nampt可能通过上调NAD⁺并抑制ERK1/2磷酸化,从而发挥抗心肌肥大的作用。     

Neuregulin-1β在慢性左心衰患者中的表达及其临床意义

心力衰竭(心衰)是各种心脏结构或功能性疾病导致心室充盈及(或)射血能力受损而引起的一组综合征,在临床中以慢性左心衰常见。从分子生物角度研究认为心衰本质是心肌组织细胞中某些相关基因表达与调控异常而引起的疾病,而越来越多研究显示Neuregulin-1以旁分泌方式与心肌细胞表面其受体结合,参与到心衰的发生发展中。本文选择检测Neuregulin-1中的一个亚型β观察其在体内的改变并与     

硝普钠治疗难治性心衰的观察与护理

目的观察微泵注射硝普钠治疗难治性心衰的效果。方法硝普钠12.5mg或25mg加5%葡萄糖50ml避光泵入难治性心衰患者118例。结果 110例患者临床症状基本消失,心功能明显改善,总有效率达93.2%。结论微泵注射硝普钠治疗难治性心衰优于其他血管扩张剂;微泵操作简单、安全。     

钠钙交换器抑制药在心律失常治疗中的应用

心肌钠钙交换在调节心肌细胞内外钠、钙平衡中发挥重要作用。钠钙交换分为前向型和逆向型2种。在心力衰竭、心肌缺血、心肌再灌注等病理情况下,通过钠钙交换器的离子交换可产生致心律失常性的一过性内向电子流,引起延迟后除极和非折返激动型的室性心动过速。钠钙交换器抑制药在预防这些病理情况下的心律失常具有潜在的作用。     

赖诺普利致高血压患者心肌纤维化消退

高血压时 ,除由心肌细胞肥大致左心室肥大(ＬＶＨ)外 ,尚可发生进行性心肌纤维化 ,从而导致左室舒张功能不全。体内外实验已证实肾素 血管紧张素 醛固酮系统的效应器激素、血管紧张素Ⅱ和醛固酮可刺激成纤维细胞介导的胶原蛋白合成。血管紧张素Ⅱ尚可抑制胶原蛋白酶活性 ,使心肌间质组织中胶原蛋白进行性积聚。本研究旨在评定有ＬＶＨ、心肌纤维化和左室舒张功能不全的高血压患者 ,经ＡＣＥ抑制剂赖诺普利治疗后能否使心肌纤维化消退。35例原发性高血压患者随机接受赖诺普利 ( 1 8例)和氢氯噻嗪 (ＨＣＴＺ ,1 7例 ) ,口服赖诺普利和ＨＣＴＺ…     

长正五聚蛋白3与慢性心力衰竭的关系

慢性心力衰竭(chronic heart failure,CHF)是由于任何原因的初始心肌损伤而引起心肌结构和功能改变,最后导致心室泵血和(或)充盈功能下降。CHF为各种心脏病的严重阶段,其发病率高,5年存活率与恶性肿瘤相仿。有资料显示,人群中心衰的患病率高达1.5%～2.0%,65岁以上可达6%～10%,心衰导致的死亡比40年前增加了6倍[1]。慢性心衰的发病机理     

联合硝普钠、多巴胺微量泵治疗肺结核肺心病心衰疗效观察

目的联合硝普钠、多巴胺微量泵治疗肺结核肺心病患者慢性心力衰竭（CHF）疗效观察。方法 71例CHF患者随机分为36例硝普钠、多巴胺微量泵治疗组和35例常规治疗对照组。治疗组在对照组的基础上用NS50ML,硝普钠20mg,多巴胺200mg,微量泵恒速注射,平均剂量1h 5mL,每天1次。结果治疗组中有29例心衰症状改善,总有效率91.67%,心衰症状改善平均5.8d。血压无明显变化,心率减慢;对照组有25例心衰症状改善,总有效率71.43%,心衰症状改善平均10.4d,两者比较差异显著（P〈0.05）。结论联合硝普钠、多巴胺微量泵治疗肺结核肺心病心力衰竭有明显疗效,且能控制输液量,使用方便,经济、安全。     

微量泵输入硝普钠治疗顽固性心衰的观察护理

心力衰竭是各种心脏疾病导致心功能不全的一种综合征状,绝大多数情况下是指心肌收缩力下降心排血量不能满足机体代谢的需要,器官组织血液灌注不足,同时出现肺循环和体循环的淤血表现。数十年来,心衰的治疗一直延续着应用强心剂、利尿剂、血管扩张剂,及增加心肌能量的方法。对顽固性心衰,我们一直在探索着更理想的治疗方案。应用微量泵输入硝普钠治疗顽固性心衰效果很好。现介绍如下:     

心衰的早期呼救信号

<正>心衰是器质性心脏病共同的临床结局,由于心肌梗死、心肌病等引起的心肌损伤,造成心肌结构和功能的变化,最后导致心室泵血或充盈功能低下。很多人以为,心衰的症状就是过度疲劳、呼吸困难、心律失常。其实并不完全正确,心力衰竭的危险性在于     

Targeting the myocardial sodium-hydrogen exchange for treatment of heart failure

Although the past number of years have seen a substantial improvement in the therapeutic approaches for the treatment of heart failure, mortality rates continue to be high. Moreover, the incidence of heart failure is expanding rapidly. Sodium-hydrogen exchange (NHE) is a key target for the treatment of heart failure. NHE is a major mechanism for intracellular pH regulation in most cell types, including the cardiac cell. Seven isoforms of NHE have been identified so far although cardiac cells possess primarily the ubiquitous NHE-1 subtype. NHE-1 is a major contributor to ischaemic and reperfusion injury and NHE-1 inhibitors exert marked cardioprotective effects, particularly when administered before ischaemia, findings which have now been extended to clinical trials. It is emerging that NHE-1 also contributes to chronic maladaptive myocardial responses to injury (myocardial remodelling) and may contribute to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in terms of inhibition of hypertrophy in response to various stimuli as well as inhibiting heart failure after coronary artery ligation. These effects occurred independently of any infarct size reducing effects of NHE-1 inhibitors or on any direct effects on afterload thus indicating a direct effect on the myocardial remodelling process. In fact, it appears that NHE-1 may represent a common downstream mediator for various hypertropic factors such as angiotensin II, endothelin-1 and beta(1) adrenergic receptor activation. NHE-1 inhibition, therefore, represents a potentially effective new therapeutic approach for the treatment of heart failure.     

Therapeutic potential of Na-H exchange inhibitors for the treatment of heart failure

The Na-H exchanger (NHE) represents a family of transporters which regulate intracellular pH by removing protons in exchange for sodium influx in an electroneutral 1:1 stoichiometric relationship. Six isoforms have thus far been identified with the NHE-1 subtype representing the primary isoform in the cardiac cell. It is well-established that NHE-1 contributes to cardiac injury produced by ischaemia and reperfusion and inhibitors of the antiporter exert excellent cardioprotection. More recent evidence suggests that NHE-1 may also be important for cell growth and may contribute to the maladaptive remodelling which contributes to heart failure particularly the early hypertrophic responses. Evidence from in vitro studies suggest that NHE-1 inhibitors attenuate cardiomyocyte hypertrophy in response to various stimuli whereas in vivo studies report substantial attenuation of both hypertrophy and heart failure by these agents, especially after myocardial infarction. Accordingly, NHE-1 inhibitors could emerge as important therapeutic tools for the attenuation and treatment of heart failure.     

Regulation and role of the presynaptic and myocardial Na+/H+ exchanger NHE1: effects on the sympathetic nervous system in heart failure

In acute myocardial ischemia and in chronic heart failure, sympathetic activation with excessive norepinephrine (NE) release from and reduced NE reuptake into sympathetic nerve endings is a prominent cause of arrhythmias and cardiac dysfunction. The Na(+)/H(+) exchanger NHE1 is the predominant isoform in the heart. It contributes to cellular acid-base balance, and electrolyte, and volume homeostasis, and is activated in response to intracellular acidosis and/or activation of guanine nucleotide binding (G) protein-coupled receptors. NHE1 mediates its signaling via protein kinases A (PKA) or C (PKC). In cardiomyocytes, NHE1 is restricted to specialized membrane domains, where it regulates the activity of pH-sensitive proteins and modulates the driving force of the Na(+)/Ca(2+) exchanger. During acute ischemia/reperfusion and in heart failure the activity/amount of NHE1 is increased, leading to intracellular Ca(2+) overload and promoting structural (apoptosis, hypertrophy) and functional (arrhythmias, hypercontraction) myocardial damage. In sympathetic nerve endings, increased NHE1 activity results in the accumulation of axoplasmic Na(+) that diminishes the inward and/or favors the outward transport of NE via the neuronal norepinephrine transporter (NET). The increased NE levels within the nerve-muscle junction facilitate the sustained stimulation of myocardial alpha- and beta-adrenoceptors (ARs), which in turn aggravate the increases in myocardial NHE1 activity and the associated deleterious effects. Furthermore, the responsiveness of the beta-AR declines overtime, which results in further release of NE, initiating a vicious cycle. Accordingly, NHE1 is a potential candidate for targeted intervention to suppress this feedback loop.     

No positive association between adrenergic receptor variants of alpha2cDel322-325, beta1Ser49, beta1Arg389 and the risk for heart failure in the Japanese population

AIMS: We investigated the correlation of adrenergic receptor polymorphisms, alpha(2c)Del322-325, beta(1)Ser49Gly and beta(1)Arg389Gly, with the risk of heart failure in the Japanese population. METHODS: These polymorphisms were analysed by polymerase chain reaction-restriction fragment length polymorphism in patients with chronic heart failure due to idiopathic dilated cardiomyopathy (DCM) and compared with the control group. RESULTS: There were no differences or any trends in the allele and genotype frequencies of the beta(1)Ser49Gly and beta(1)Arg389Gly polymorphisms. The allele frequency of the alpha(2c)Del322-325 variant was lower in patients than in controls (0.11 vs. 0.04, P = 0.011 < 0.017, by Bonferroni correction), while the genotype frequency just failed to reach significance (P = 0.022 > 0.017, by Bonferroni correction). CONCLUSIONS: In this population, the variants beta(1)Ser49, beta(1)Arg389, and alpha(2c)Del322-325 do not appear to be risk factors for chronic heart failure due to DCM. The alpha(2c)Del322-325 variant may in fact confer some protection.     

The myocardial Na+/H+ exchanger: a potential therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and attenuation of postinfarction heart failure

The myocardial Na+/H+ exchange (NHE) represents a major mechanism for pH regulation during normal physiological processes but especially during ischaemia and early reperfusion. However, there is now very compelling evidence that its activation contributes to paradoxical induction of cell injury. The mechanism for this most probably reflects the fact that activation of the exchanger is closely coupled to Na+ influx and therefore to elevation in intracellular Ca2+ concentrations through the Na+/Ca2+ exchange. The NHE is exquisitely sensitive to intracellular acidosis; however, other factors can also exhibit stimulatory effects via phosphorylation-dependent processes. These generally represent various autocrine and paracrine as well as hormonal factors such as endothelin-1, angiotensin II and alpha1-adrenoceptor agonists, which probably act through receptor-signal transduction processes. Thus far, 6 NHE isoforms have been identified and designated as NHE1 through NHE6. All except NHE6, which is located intracellularly, are restricted to the sarcolemmal membrane. In the mammalian myocardium the NHE1 subtype is the predominant isoform, although NHE6 has also been identified in the heart. The predominance of NHE1 in the myocardium is of some importance since, as discussed in this review, pharmacological development of NHE inhibitors for cardiac therapeutics has concentrated specifically on those agents which are selective for NHE1. These agents, as well as the earlier nonspecific amiloride derivatives have now been extensively demonstrated to possess excellent cardioprotective properties, which appear to be superior to other strategies, including the extensively studied phenomenon of ischaemic preconditioning. Moreover, the salutary effects of NHE inhibitors have been demonstrated using a variety of experimental models as well as animal species suggesting that the role of the NHE in mediating injury is not species specific. The success of NHE inhibitors in experimental studies has led to clinical trials for the evaluation of these agents in high risk patients with coronary artery disease as well as in patients with acute myocardial infarction (MI). Recent evidence also suggests that NHE inhibition may be conducive to attenuating the remodelling process after MI, independently of infarct size reduction, and attenuation of subsequent postinfarction heart failure. As such, inhibitors of NHE offer substantial promise for clinical development for attenuation of both acute responses to myocardial as well as chronic postinfarction responses resulting in the evolution to heart failure.     

Therapeutic potential of Na-H exchange inhibitors for the treatment of heart failure

The Na-H exchanger (NHE) represents a family of transporters which regulate intracellular pH by removing protons in exchange for sodium influx in an electroneutral 1:1 stoichiometric relationship. Six isoforms have thus far been identified with the NHE-1 subtype representing the primary isoform in the cardiac cell. It is well-established that NHE-1 contributes to cardiac injury produced by ischaemia and reperfusion and inhibitors of the antiporter exert excellent cardioprotection. More recent evidence suggests that NHE-1 may also be important for cell growth and may contribute to the maladaptive remodelling which contributes to heart failure particularly the early hypertrophic responses. Evidence from in vitro studies suggest that NHE-1 inhibitors attenuate cardiomyocyte hypertrophy in response to various stimuli whereas in vivo studies report substantial attenuation of both hypertrophy and heart failure by these agents, especially after myocardial infarction. Accordingly, NHE-1 inhibitors could emerge as important therapeutic tools for the attenuation and treatment of heart failure.     

比索洛尔治疗充血性心力衰竭的早期反应及其药理特点

β-受体阻滞剂以衰竭心肌细胞的“生物修复剂”被用于治疗CHF，然其治疗早期的安全性依然是不容勿视的。本研究通过对23例充血性心力衰竭（CHF）患者比索洛尔治疗早期的观察，认为比索洛尔治疗CHF早期存在“首日敏感受现象”，对其观察和处理有利于提高B．受体阻滞剂治疗CHF早期耐受性、安全性及有助于初步估计药物剂量倍增时间间隔。     

卡维地洛在心力衰竭治疗中的应用

卡维地洛是一个非选择性的肾上腺素β受体(β受体)阻滞药,另具有肾上腺素α1受体(α1受体) 阻滞作用、抗氧化作用、抗增生作用、抗细胞凋亡作用。通过β受体阻滞作用和α1受体阻滞作用,卡维地洛对心力衰竭病人的血流动力学发挥有利的作用。慢性心力衰竭病人长期应用卡维地洛可使左室射血分数提高。大量临床研究结果表明卡维地洛在心力衰竭治疗中优于安慰药和其他β受体阻滞药,并可用于重度心力衰竭、心肌梗死后心力衰竭以及扩张性心肌病引起的心力衰竭。     

新生儿心力衰竭时血浆内皮素、降钙素基因相关肽和心钠素的变化及其临床意义

目的：了解血浆内皮素（ＥＴ－１）、降钙素基因相关肽（ＣＧＲＰ）和心钠素（ＡＮＦ）在新生儿心力衰竭的作用和地位。方法放射性同位素免疫分析法直接测定２８例心力衰竭新生儿不同病程时血浆中ＥＴ－１、ＣＧＲＰ和ＡＮＦ含量,并与２０例正常新生儿对比。结果心衰发生时ＥＴ－１、ＣＧＲＰ、ＥＴ－１ＣＧＲＰ、ＥＴ－１／ＡＮＦ均明显高于对照组（Ｐ〈０．０１、Ｐ〈０．０５、Ｐ〈０．０１、Ｐ〈０．０１）,ＡＮＦ水平两组间无     

Decreased Lithium Disposition to Cerebrospinal Fluid in Rats with Glycerol-induced Acute Renal Failure

PURPOSE: The lithium disposition to cerebrospinal fluid (CSF) was evaluated in rats with acute renal failure (ARF) to examine whether electrolyte homeostasis of the CSF is perturbed by kidney dysfunction. In addition, the effects of renal failure on choroid plexial expressions of the Na(+)-K(+)-2Cl(-) co-transporter (NKCC1) and Na(+)/H(+) exchanger (NHE1) were also studied. METHODS: After lithium was intravenously administered at a dose of 4 mmol/kg, its concentration profile in plasma was evaluated by collecting plasma specimens, while that in CSF was monitored with a microdialysis probe in the lateral ventricles. NKCC1 and NHE1 expressions were measured via the Western immunoblot method using membrane specimens prepared from the choroid plexus in normal and ARF rats. RESULTS: The lithium concentration in CSF of ARF rats was 30% lower than that of normal rats, while their plasma lithium profiles were almost the same, indicating that the lithium disposition to CSF was decreased in ARF rats. It was revealed that the choroid plexial expression of NKCC1 was increased by 40% in ARF rats, but that of NHE1 was unchanged. CONCLUSION: ARF decreases the lithium disposition to CSF, possibly by promoting lithium efflux from CSF due to increased NKCC1 expression in the choroid plexus.