内皮素受体拮抗剂在肺动脉高压治疗中的作用

肺动脉高压(PAH)是常见的临床疾病,内皮素(ET)在PAH的发生机制中发挥了重要的作用,临床研究显示,ET受体拮抗剂治疗PAH疗效良好,该类药物可能成为治疗PAH的有效药物.     

内皮素受体拮抗剂治疗肺动脉高压的临床应用进展

内皮素（ET）-1是强有力的内源性血管收缩剂，在肺动脉高压的发病机制中发挥重要作用。ET受体分为两种类型：ETA和ETB。本文综述近年来非选择性ET受体拮抗剂和选择性ETA受体拮抗剂治疗肺动脉高压的临床应用进展。证明ET受体拮抗剂可以改善肺动脉高压患者的运动耐量，降低肺血管阻力，增加心输出量，改善心功能。其主要副作用是血清转氨酶增高。     

内皮素系统在肺动脉高压中的作用

内皮素（ET）具有强力而持久的血管收缩作用，同时促进细胞的生长和促有丝分裂。ET-1与内皮素受体（ETR）结合发挥作用，ET-1过度表达引起多种心脑血管疾病。广泛的临床前和临床试验表明，ETR拮抗剂具有预防和治疗肺动脉高压（PAH）的作用，使患者的血流动力学改善，运动耐力和功能分级提高，提高了生存率。目前，非选择性ETR拮抗剂波生坦经FDA批准用于治疗休息或者轻微运动（WHO功能分级评为Ⅲ和Ⅳ级）PAH。     

内皮素受体拮抗剂用于肺动脉高压的治疗进展

肺动脉高压（PAH）是一类以肺血管阻力进行性升高为主要特征的心肺血管疾病,最终可导致右心衰竭甚至死亡。早期发现PAH患者中内皮素明显高于正常,可引起肺血管的持续收缩及重构。内皮素受体拮抗剂可阻断该通路进而起到降低肺高压的作用。但目前国内临床上对于该类药物了解甚少。本文参考国内外文献对内皮素受体拮抗剂在PAH中的作用机制及临床应用作简要综述,旨在指导临床用药,使更多患者获益。     

内皮素受体拮抗剂治疗肺动脉高压症临床评价

目的：伴随对肺动脉高压症发病机制的解释，一类内皮素受体桔抗剂于近期问市，本文阐述其在治疗肺动脉高压症的进展与临床评价，方法：采用国内、外文献综述方法。结果及结论：内皮素受体拮抗剂近年来进展迅猛，其抑制ET-1的收缩血管和促进细胞增殖作用，使动脉高压和心力衰竭问题已不再难于逾越，成为解脱肺动脉高压症之门一把金“药匙”．     

内皮素受体拮抗剂治疗肺动脉高压的研究进展

近年来肺动脉高压的药物治疗多从调控内源性血管收缩因子（如内皮素-1、血栓素A2）和增殖介质（前列腺素和一氧化氮）的失衡入手。本文综述了基于内皮素-1途径的内皮素受体拮抗剂,如波生坦、安立生坦以及新近上市的macitentan,该类药物具有全身副作用小和口服优势,日益受到关注。     

内皮素受体拮抗剂在肺动脉高压治疗中的应用

内皮素是强的缩血管因子,肺动脉高压患者内皮素表达明显增加,内皮素受体拮抗剂已经作为靶向药物治疗肺动脉高压,其疗效及前景备受瞩目。波生坦、安立生坦分别为口服的双重和选择性内皮素受体拮抗剂(ERAs),均能显著降低肺动脉高压,改善患者的生存,Macitentan是一种新型的口服非肽类双重ERAs,现已完成Ⅲ期临床研究,疗效可观;西他生坦是选择性的内皮素受体拮抗剂,因其肝脏毒性已经退市。对于这些双重或选择性内皮素受体拮抗剂的选择问题至今仍存在分歧,长期疗效、联合用药及肝脏安全性等问题都需要更多循证医学证实。     

肺动脉高压治疗药

内皮索受体（ETA和ETB）拮抗剂约于10年前首次被提出可用于治疗充血性心力衰竭、高血压及其他心血管疾病，最初的内皮素受体拮抗剂为非选择性ETA和ETB双重拮抗荆。然而，更多的最新研究表明，单一拮抗ETA可产生临床血管舒张疗效，避免了对非血管巩产生阻断作用，并能保护由内源性内皮素ET-1结合巩而产生的血管舒张作用。     

新型内皮素受体拮抗剂CPU0214与正常大鼠心肌ET受体结合特点及对清醒DOCA-盐型高血压大鼠的降压作用

目的　研究新型内皮素受体拮抗剂CPU0 2 1 4与正常大鼠心肌内皮素 (ET)受体结合特点 ,对血管收缩的拮抗作用及对高血压大鼠血压的降低作用。方法　采用放射配体竞争抑制结合法和ET 1引起的胸主动脉环收缩法分别研究CPU0 2 1 4与正常大鼠心肌ET受体结合的特性和对血管收缩功能的拮抗作用 ;采用放射配体结合法观察注射醋酸脱氧皮质酮 (DO CA)和饮用盐水造成的高血压模型大鼠的心肌ET受体的改变及其股动脉平均动脉压的变化 ,研究CPU0 2 1 4的降压作用。结果　CPU0 2 1 4在正常心肌膜上竞争性结合1 2 5I ET1 ,其IC50 为1 6nmol·L-1 ;抑制ET 1所致胸主动脉环收缩。DOCA 盐型高血压大鼠表现内皮素受体的Bmax值和Kd 值升高 ;CPU0 2 1 4使清醒高血压大鼠的平均动脉压明显降低 ,在 6 0～ 90min时最为明显。结论　CPU0 2 1 4在正常大鼠竞争结合内皮素受体、拮抗血管收缩 ,在内皮素异常高血压大鼠可降低其血压 ,表明CPU0 2 1 4对治疗高血压有良好的研究价值     

肺动脉高压治疗药Macitentan关键性Ⅲ期临床试验获得阳性结果

Actelion公司近日宣称,其研发的新型内皮素受体拮抗剂macitentan在一项名为SERAPHIN的Ⅲ期临床研究中达到主要考察指标。     

新化合物Ⅲ21对大鼠心肌内皮素受体(ETAR,ETBR)亚型的亲和力和选择性

目的研究新化合物Ⅲ21与大鼠心肌内皮素受体(Endothelin receptor,ETR)的亲和力及结合特点.方法采用放射配体受体结合分析方法,通过125I-ET1与大鼠左心室膜受体结合,观察新化合物Ⅲ21对ETR的亲和力及对ETAR,ETBR两种亚型的选择性,分别求IC50值.结果Ⅲ21对125I-ET1与ETR的结合有较强的抑制作用,在10-7mol·L-1浓度时,使其结合率降为原来的(43.1±13.7)%.Ⅲ21抑制125I-ET1与ETAR和ETBR结合的IC50值分别为10.21 nmol·L-1和1.65μmol·L-1,两者比值(ETAR的选择性)为161.76.结论新化合物Ⅲ21与ETR有较强的亲和力,并且对ETAR具有较高的选择性,可能是一种选择性ETA受体拮抗剂.     

CPU0507, an endothelin receptor antagonist, improves rat hypoxic pulmonary artery hypertension and constriction in vivo and in vitro

1. The Aim Of The Present Study Was To Test The Efficacy Of The Novel Endothelin (Et) Receptor Antagonist CPU0507 In Treating Rat Hypoxic Pulmonary Hypertension (Ph) In Vivo And In Vitro And To Explore The Role Of The Et-1 System In The Disease. 2. Male Sprague-dawley Rats (220 +/- 20 G) Were Divided Into Four Groups: (I) Control; (Ii) Untreated Hypoxic (28 Days Hypoxia); (Iii) Hypoxic Rats Treated In The Last 5 Days Of Hypoxia With Nifedipine(5 Mg/kg Per Day, P.o.); And (Iv) Hypoxic Rats Treated In The Last 5 Days Of Hypoxia With CPU0507 (20 Mg/kg Per Day, S.c.). Effects Of Treatments On Haemodynamics And Biochemical Data, As Well As Functional Assessments Of The Isolated Pulmonary Artery, Were Determined In Vivo And In Vitro. 3. It Was Found That CPU0507 Reduced The Elevated Pulmonary Arterial Pressure And Right Heart Weight Index And Restored Abnormalities In Nitric Oxide (No), Malondialdehyde And No Synthase (Nos) In The Serum And Superoxide Dismutase, Hydroxyproline And Nos In Pulmonary Homogenates. In Addition, CPU0507 Restored Altered Pulmonary Vasoconstrictor And Vasodilator Responses. Vascular Constriction And Dilatation Of Untreated Pulmonary Arteries Were Reverted Effectively Towards Normal Following Exposure Of Artery Rings To CPU0507 In Vitro. 4. In Conclusion, The Results Indicate That Hypoxic Ph Is Relieved Significantly By CPU0507 In Vivo And In Vitro And The Effects Are Presumed To Be Mediated By Suppression Of The Et-reactive Oxygen Species Axis.     

Protective effects of vasonatrin peptide against hypobaric hypoxia-induced pulmonary hypertension in rats

1. The aim of the present study was to investigate the in vivo effects of vasonatrin peptide (VNP) on hypoxia-induced pulmonary hypertension (HPH).
2. The HPH model was developed by subjecting rats to hypobaric hypoxia. The HPH rats were then treated with either VNP (50 μg/kg per day, i.p.) or saline (0.5 mL, i.p.) every day for 7 days. Haemodynamic indices, right ventricular hypertrophy (RVH) and remodelling of the pulmonary arteries were evaluated. In addition, plasma levels of atrial natriuretic peptide (ANP), endothelin (ET)-1 and angiotensin II (AngII) were determined, as was natriuretic peptide receptor-C (NPR-C) mRNA expression in the right ventricle.
3. Hypobaric hypoxia induced severe HPH compared with the normoxic control group. Treatment of HPH rats with VNP for 1 week significantly reduced mean pulmonary arterial pressure, pulmonary vascular resistance, RVH and muscularization of the pulmonary arteries, although pulmonary blood flow was increased in this group. In addition, significantly lower levels of plasma ET-1 and AngII and cardiac NPR-C mRNA expression were observed in VNP-treated compared with saline-treated HPH rats, whereas higher plasma concentrations of ANP were found in the former group. Acute intravenous administration of 50 μg/kg VNP significantly ameliorated pulmonary haemodynamics in HPH rats.
4. Taken together, the date indicate that VNP has certain preventative and therapeutic effects against HPH.     

Ambrisentan,an endothelin receptor type A-selective endothelin receptor antagonist,for the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a disease of the pulmonary vasculature characterized by vasoconstriction and vascular proliferation, which leads to right heart failure and death. Prostacyclin, NO and endothelin are felt to be key mediators in the development of PAH. We present the available published and presented data about ambrisentan, an ET_A-selective endothelin receptor antagonist (ERA) and newest ERA agent to be approved by the FDA for the treatment of PAH in patients with WHO functional class II and III symptoms. Randomized, placebo-controlled trials have demonstrated a significant improvement in exercise capacity and decrease in time to clinical worsening, along with evidence to support an improvement in WHO functional class and quality of life for patients receiving ambrisentan. Long-term data have shown a 1-year survival of 95%; of the survivors, 94% remained on ambrisentan monotherapy. Endothelin receptor antagonists as a drug class have previously been associated with peripheral edema, aminotransferases abnormalities and a teratogenic risk to a developing fetus. Peripheral edema was observed in patients receiving ambrisentan; however, a greater percentage was experienced in patients aged > 65 years. In contrast, significant aminotransferase abnormalities were not observed with ambrisentan treatment in the placebo-controlled trials, and in all clinical trials combined the 1-year risk seems to be low (< 3%). Despite these data, the FDA requires monthly liver function tests monitoring. As with other ERAs, monthly pregnancy testing is required in all women of child bearing potential.     

Efficacy,safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension

Introduction: Macitentan is a novel dual endothelin receptor antagonist (ERA) showing sustained receptor occupancy. In vitro and in vivo animal studies have demonstrated its potency in antagonizing endothelin-induced disorders. A large morbidity/mortality study in patients with pulmonary arterial hypertension (PAH) taking macitentan has been completed recently.

Areas covered: This drug evaluation reviews the efficacy, safety and clinical pharmacology of macitentan in the treatment of PAH.

Expert opinion: The large Phase III study (SERAPHIN) tested macitentan in more than 700 PAH patients and has provided unique long-term outcome data for this ERA, not available for other members of this class. The effect on a composite clinically relevant morbidity/mortality end point was highly significant at a 10 mg/day dose. The safety profile of macitentan appears to be superior with respect to hepatic safety and edema/fluid retention than bosentan and ambrisentan, respectively, and is similar when considering decrease in hemoglobin concentration. The drug has a low propensity for drug–drug interactions and has one circulating pharmacologically active metabolite. The pharmacokinetics of macitentan in patients with renal or hepatic impairment does not require dose adjustments. Based on its characteristics, macitentan is an important addition to the therapeutic armamentarium in the long-term treatment of PAH. Its potential use in other disorders is under investigation.     

Safety and efficacy evaluation of ambrisentan in pulmonary hypertension

Introduction: Pulmonary arterial hypertension (PAH) is characterized by an increase in pulmonary vascular resistance, which can lead to right heart failure and death. Endothelin-1 binding ETA and ETB receptors seem to play a critical role in the pathogenesis and progression of the disease, and oral endothelin receptor antagonists (ERAs) have been shown to be an effective treatment. Bosentan and ETA-selective ambrisentan are the ERAs currently available for PAH treatment.

Areas covered: On the basis of the analysis of the literature, this paper addresses the efficacy and safety of ambrisentan in the treatment for PAH.

Expert opinion: Ambrisentan has shown an efficacy comparable with other ERAs. Compared with bosentan, ambrisentan seems to have a better safety profile with regards to hepatic safety and drug–drug interactions. On the other hand, ambrisentan shows a higher rate of other adverse events, such as nasal congestion and peripheral edema. Ambrisentan is a viable option for PAH treatment. However, there is still a need for more robust data about long-term mortality, treatment in non-PAH pulmonary hypertension (PH) (such as PH due to left heart disease and PH due to chronic hypoxic lung diseases) and combination therapy.     

Therapeutic potential of endothelin receptor antagonists and nitric oxide donors in pulmonary hypertension

Pulmonary hypertension can occur idiopathically as a primary disorder of the pulmonary circulation or more commonly, it can exist as a haemodynamic manifestation of a wide variety of pulmonary and cardiovascular diseases, including acute lung injury, chronic obstructive lung disease, congenital heart disease, mitral stenosis, chronic left-sided congestive heart failure and connective tissue diseases such as scleroderma. Pulmonary hypertension is associated with changes in vascular tone as well as vascular structure, with the relative contribution of each dependent upon the aetiology of the increased pulmonary vascular resistance. Most currently available treatments utilise anticoagulants as well as vasodilator drugs that only attenuate the vasoconstrictive component of the disease. The latter category includes oral calcium channel blockers, iv. and aerosolised prostacyclin analogues and inhaled nitric oxide but all three classes of vasodilators have disadvantages and limitations. Treatment with vasodilators is often ineffective in patients with longstanding pulmonary hypertension in which structural changes contribute significantly to the pulmonary hypertension, blood flow obstruction and right heart failure. In view of the immense clinical need, new therapies are being developed by pharmaceutical companies to treat pulmonary hypertension. This update will focus on the current development status of endothelin receptor antagonists and nitric oxide donors for the treatment of pulmonary hypertension.