Update on apelin peptides as putative targets for cardiovascular drug discovery

Introduction: The physiological importance of GPCR/ligand pathways is highlighted by the fact that numerous pathologies are attributed to their signaling dysfunction. Over 50% of the pharmaceutical drugs currently used to treat human disease are based on compounds that interact with GPCRs. Apelin/APJ constitutes a novel endogenous peptide/GPCR system proposed to be involved in a wide range of physiological functions. Early evidence suggests that apelin/APJ may hold promise as a target for development of novel therapeutic agents which may counteract a number of pathologies including cardiovascular disease. Despite advances in treatment of cardiovascular disease, incidence, prevalence, morbidity and economic costs remain high necessitating the development of new treatment paradigms. Areas covered: This review summarizes apelin/APJ structure, distribution and regulation; presents evidence for a role of apelin in pressure/volume homeostasis and in the pathophysiology of cardiovascular disease; summarizes data on beneficial effects of apelin in preclinical, animal models of cardiovascular disease and measurement of plasma levels of apelin across the full spectrum of cardiovascular disease in humans; and notes the first studies describing bioactivity of apelin peptides in human healthy volunteers and patients with heart failure. Expert opinion: More clarity is needed on the precise physiological/pathophysiological role of the apelin/APJ system in human health and disease. Nonetheless, preclinical studies and initial studies in humans show that APJ antagonism may represent a novel therapeutic target for patients with cardiovascular disease. Development of appropriately validated assays for apelin will clarify circulating levels of the peptide in health and disease. Development of suitable agonists/antagonists will pave the way for much needed future studies essential for advancing this promising field of drug discovery.     

The role of apelin in central cardiovascular regulation in rats with post‐infarct heart failure maintained on a normal fat or high fat diet

Based on the available literature, it can be assumed that in cases of post‐infarct heart failure (HF) and obesity, a significant change in the central regulation of the cardiovascular system takes place with, among others, the involvement of the apelinergic system. The main objective of the present study was to clarify the role of apelin‐13 in the central regulation of the cardiovascular system in Sprague Dawley rats with HF or sham operated (SO) and fed on a normal fat (NFD) or a high fat diet (HFD). The study was divided into two parts: Part I, hemodynamic studies; and Part II, biochemical and molecular studies. The animals were subjected to the following research procedures. Part I and II: feeding NFD or HFD; experimental induction of HF or SO; Part I: intracerebroventricular (ICV) infusion of the examined substances, monitoring of mean arterial blood pressure (MABP) and heart rate (HR); Part II: venous blood and tissue samples collected. ICV infusion of apelin‐13 caused significantly higher changes in ΔMABP in the SO NFD group. No changes were noted in ΔHR in any of the studied groups. Apelin and apelin receptor (APJ) mRNA expression in the brain and adipose tissues was higher in the HF rats. HFD causes significant increase in expression of apelin and APJ mRNA in the left ventricle. In conclusion, HF and HFD appear to play an important role in modifying the activity of the central apelinergic system and significant changes in mRNA expression of apelin and APJ receptor.     

Natriuretic peptides as therapeutic targets

Natriuretic peptides (atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide) are cardiac and vascular peptides with vasodilatory, diuretic, natriuretic, anti-inflammatory, antifibrotic and antimitogenic actions. Natriuretic peptides are implicated in normal pressure and volume homeostasis and in the defence against excessive increases in overload-related factors, vasopressive and cardiotoxic factors and their impact on the heart, blood vessels and brain. Genetic manipulation studies confirmed the importance of natriuretic peptides in these functions. Natriuretic peptides are metabolised by NPR-C (clearance receptors) and by enzymatic degradation by neutral endopeptidase. Natriuretic peptide levels (mainly brain natriuretic peptide) correlate with left ventricular hypertrophy and with the severity of heart failure, and are reduced by effective treatment, thus used as diagnostic and prognostic tools. Based on the multiple protective effects of natriuretic peptides, pharmacological therapy has been approved and includes potentiating natriuretic peptide levels by intravenous infusion or by inhibition of endogenous natriuretic peptide degradation. Because each approach has its limitations, the field remains open for improvement.     

Novel targets for antibiotics - an update

Despite the improvements in survival with angiotensin-converting enzyme inhibitors and β-blockers, the clinical events for patients with heart failure remain elevated. New therapies for heart failure are required to improve the functional capacity, quality of life and prognosis. Growth hormone exerts both direct and indirect effects on cardiac structure and function. Experimental models of heart failure and small studies have demonstrated significant improvements in cardiac function, haemodynamical parameters, functional capacity and quality of life. The results from randomised controlled studies have been mixed with others showing benefit and some that do not. The randomised studies showing benefit consistently used growth hormone every other day. Further studies are needed to assess the potential role of this adjuvant therapy in patients with heart failure.     

Update on the safety of testosterone therapy in cardiac disease

Introduction: Testosterone has been used for decades in the treatment of men with hypogonadism and women with low libido. More recently, it has been used in patient populations with cardiac disease and, in particular, in those patients with heart failure. The benefits of testosterone supplementation have been demonstrated in the literature, but there is also concern that testosterone supplementation may not be benign, especially when administered to achieve supraphysiological levels, e.g., to improve athletic performance.

Areas covered: This review seeks to address the link between testosterone levels and cardiac disease while discussing the safety concerns of testosterone supplementation in clinical practice. Randomized controlled trials, systematic reviews and meta-analyses that were obtained through a literature search of the Medline database are discussed in this paper.

Expert opinion: Ultimately, the definitive role of testosterone in cardiovascular disease remains contentious, but testosterone may have niche roles in certain conditions, such as advanced heart failure and cardiac cachexia. Testosterone has been used safely, and we believe may continue to be used safely, in men with cardiac disease when achieving physiological levels, with adequate monitoring of prostate specific antigen and hematocrit levels during the course of treatment per established clinical guidelines. Testosterone might exert beneficial effects on physical capacity and functioning as well as overall outcomes in patients with chronic heart failure.     

NSFC资助下的阿尔采末病药物作用靶点的研究

阿尔采末病(Alzheimesdisease,AD)是一种神经退行性病变,最近几年对AD的研究主要集中在其两个标志性的病理改变上即β样淀粉蛋白和神经纤维缠结。该文主要是根据国内外对AD的研究进展,结合国家自然科学基金委员会(NationalNatureScienceFoundationofChina,NSFC)近10年来资助的有关AD的基金项目,针对AD的药物治疗靶点作一综述。     

经络腧穴给药治疗心血管系统疾病的研究概况

基于近15年经络腧穴给药治疗心血管疾病的文献,介绍经络腧穴给药的常用方法、穴位选择,并对经络腧穴治疗充血性心力衰竭、心绞痛、心律失常、高血压以及其他心血管疾病进行综述。     

基于靶点的抗新型冠状病毒病COVID-19药物发现

新型冠状病毒(SARS-CoV-2)引发的新冠病毒病(COVID-19),采取对症治疗不失为可行有效的治疗方案,但治疗药物大多缺乏针对性。基于病毒复制过程中的关键蛋白和病毒引发的病理机制,研制有针对性的治疗药物,将为临床提供更加有效的治疗方案。此外,由于新型冠状病毒是RNA病毒,而RNA病毒基因易于变异,因此针对新冠病毒病的新药研发将是一项长期而艰巨的任务。本文基于新型冠状病毒从吸附、进入宿主细胞到病毒复制过程中的关键蛋白及病毒感染引发的致病因素等多个环节的潜在靶点,利用分子模拟和机器学习等算法,探讨防治COVID-19新药发现的研究思路,并简述本课题组所开展的相关工作,为促进不同作用机制的新药发现提供可行性研究方法和策略。     

注射用益气复脉（冻干）对心血管系统的药理及临床研究进展

注射用益气复脉（冻干）来源于生脉散,经现代工艺提取而制成的无菌冻干粉针,具有益气复脉、养阴生津的功效。药理研究表明其能改善线粒体功能、抑制心肌重塑、减轻心肌细胞炎性反应等,临床上主要用于冠心病劳累型心绞痛及慢性心功能不全等心血管系统疾病的治疗。归纳总结了近年来注射用益气复脉（冻干）在抗心力衰竭、冠心病心绞痛、心肌梗死和调节血压方面的药理作用及临床应用,为其基础研究及临床应用提供参考。     

亚临床甲状腺功能减退症与心血管疾病相关性的研究进展

摘要： 亚临床甲状腺功能减退症 （亚临床甲减） 是一种仅有促甲状腺素水平升高而甲状腺素水平正常的代谢性疾病。国内外已有大量研究表明, 亚临床甲减可能与动脉粥样硬化以及左室舒张功能障碍相关, 从而导致心血管疾病的发生率和死亡率增加。亚临床甲减会影响脂质代谢异常、 高血压、 凝血功能异常、 血管内皮功能损伤及糖代谢异常等, 并与同型半胱氨酸、 C 反应蛋白及脂蛋白等存在相关性, 从而加速动脉粥样硬化的形成。近年来亚临床甲减与心血管疾病之间的关系越来越受到关注, 本文就有关两者相关性的研究进行综述。     

注射用益气复脉（冻干）对心衰合并药物性低血压大鼠的作用研究

目的 探究注射用益气复脉（冻干）（YQFM）对心衰合并低血压大鼠的血压、心功能以及相应生化指标的影响。方法 将SD大鼠进行冠状动脉左前降支手术结扎制备心衰模型,饲养2周后,用小动物超声仪检测大鼠心功能筛选造模成功的大鼠,假手术组进行开胸手术不结扎。心衰大鼠血压最低（均低于90 mmHg）的10只挑选出来作为非药物性低血压-YQFM（470 mg/kg）组,其余大鼠进行呋塞米（53.35 mg/kg）低血压造模1周（与给药前比较,血压下降幅度在20 mmHg左右）后,随机分为模型组（呋塞米53.35 mg/kg）,联合给药：呋塞米（53.35 mg/kg）+YQFM低、高剂量（470、940 mg/kg）组,YQFM低、高剂量（470、940 mg/kg）组,各给药组分别ig呋塞米或（和）iv YQFM,给药2周。超声诊断仪检测大鼠的心功能;检测大鼠心脏指数（HWI）;从术后1周开始至给药结束监测大鼠血压变化;ELISA法检测各组大鼠血清脑钠肽（BNP）、心钠素（ANP）、血管紧张素Ⅱ（AngⅡ）、白介素-6（IL-6）、肌酸激酶同工酶（MB）、β1肾上腺素受体（β1AR）含量变化。结果 模型组大鼠心脏有明显的前壁运动异常,而给药各组心室收缩功能障碍具有不同程度的减轻。与模型组比较,给药组的E/A值>1.2的大鼠占比明显上升;与模型组比较,非药物性低血压-YQFM组,YQFM低、高剂量组,呋塞米+YQFM低、高剂量组LVEF、LVFS均显著升高,差异有统计学意义（P<0.05、0.01）。与模型组比较,各给药组HWI均显著降低（P<0.05、0.01）。低血压造模实验后,各组血压显著降低（P<0.01）,治疗给药后,各给药组的血压显著升高（P<0.01）。与模型组比较,给药组的BNP、ANP、IL-6、MB和AngⅡ水平显著下降（P<0.01）,而β1AR水平显著升高（P<0.01）。结论 YQFM可以有效升高心衰大鼠血压,也能有效地减轻呋塞米用药引起的低血压;YQFM能显著改善心衰大鼠生化指标水平,抑制肾素-血管紧张素系统（RAS）的过度激活,改善炎症症状,从而改善大鼠的心衰症状。     

Dose-response effects of sotalol on cardiovascular function in conscious, freely moving cynomolgus monkeys

BACKGROUND AND PURPOSE: The non-selective beta-adrenoceptor antagonist, D,L-sotalol (sotalol) is commonly employed as a positive control during preclinical cardiovascular safety pharmacology testing, mainly because of its ability to prolong QT interval duration. However, no information appears in the literature, except in abstract form, regarding the dose-response effects of sotalol in unanesthetized monkeys. The current study was conducted to determine the dose- and plasma-response effects of orally administered sotalol on cardiovascular function in conscious non-human primates. EXPERIMENTAL APPROACH: Male cynomolgus monkeys were implanted with telemetry devices and the effects of sotalol hydrochloride (5, 10 and 30 mg kg(-1) of body weight, p.o.) on arterial blood pressure, heart rate, body temperature and electrocardiogram waveform were continuously monitored for 6 h after dosing. Blood was sampled for the measurement of plasma concentrations of sotalol. KEY RESULTS: Sotalol dose dependently decreased heart rate and prolonged RR, PR, QT and corrected QT intervals, while having little or no effects on the QRS complex, arterial pressure or body temperature, over the dose range tested. When the data were related to plasma concentrations of sotalol, it was clear that the cardiovascular effects occurred in a similar pattern and to a comparable degree as those reported in human studies. CONCLUSIONS AND IMPLICATIONS: The current study helps demonstrate the validity of utilizing telemetry-instrumented non-human primates for the cardiovascular safety pharmacology assessment of drugs prior to first-in-human testing, and its findings may serve as a reference source for the dose- and plasma-response effects of orally administered sotalol in conscious monkeys.     

Nitric oxide as a metabolic regulator during exercise: effects of training in health and disease

1. Accumulating animal and human data suggest that nitric oxide (NO) is important for both coronary and peripheral haemodynamic control and metabolic regulation during performance of exercise. 2. While still controversial, NO of endothelial origin is thought to potentiate exercise-induced hyperaemia, both in the peripheral and coronary circulations. The mechanism of release may include both acetylcholine derived from the neuromuscular junction and vascular shear stress. 3. A splice variant of neuronal nitric oxide synthase (NOS), nNOSmicro, incorporating an extra 34 amino acids, is expressed in human skeletal muscle. In addition to being a potential modulator of blood flow, skeletal muscle-derived NO is an important regulator of muscle contraction and metabolism. In particular, recent human data indicate that NO modulates muscle glucose uptake during exercise, independently of blood flow. 4. Exercise training in healthy individuals promotes adaptations in the various NO systems, which can increase NO bioavailability through a variety of mechanisms, including increased NOS enzyme expression and activity. Such adaptations likely contribute to increased exercise capacity and protection from cardiovascular events. 5. Cardiovascular risk factors, including hypercholesterolaemia, hypertension, diabetes and smoking, as well as established disease, are associated with impairment of the various NO systems. Given that NO is an important signalling mechanism during exercise, such impairment may contribute to limitations in exercise capacity through inadequate coronary or peripheral blood delivery and via metabolic effects. 6. Exercise training in individuals with elevated cardiovascular risk or established disease can increase NO bioavailability and may represent an important mechanism by which exercise training provides benefit in the setting of secondary prevention.     

miRNAs as potential therapeutic targets and diagnostic biomarkers for cardiovascular disease with a particular focus on WO2010091204

Introduction: A number of miRNAs have been reported to be critically involved in the regulation of cardiovascular disease (CVDs). Therefore, the development of potent analogues/inhibitors for miRNAs have thus become a key focus in the present drug discovery. In this review, we discuss the basic research and clinical use of miRNAs as the early diagnosis and therapeutic targets for CVD. We have also focused on the efficiency of therapeutically targeting miR-499, which is considered as one of the most promising molecules for treating CVDs.

Areas covered: In this review, we have discussed the patents and patent applications related to miRNAs detected in CVD patients published in recent years. This review also covers the expression pattern of miR-499, as well as it highlights functions of its inhibitors in CVD. We used Google and Pubmed search engines to find relevant patents.

Expert opinion: Although a massive number of miRNAs are patented as CVD biomarkers, further work is absolutely required to evaluate the reliable diagnostic values and therapeutic potential of these candidates. Overall, targeting miRNAs is definitely a promising strategy to be investigated for diagnosis and treatment of CVDs in future, however, the delivery system and off-targets effects are still a difficult challenge need to be elucidated.     

Drugs modulating adenosine receptors as potential therapeutic agents for cardiovascular diseases

Adenosine has a wide range of physiological activities arising from its interaction with the P₁ purinoceptor, which has been further subclassified into four types - A₁, A_2A, A_2B and A₃. Apart from adenosine itself and long-established antagonists such as theophylline and caffeine there are no new adenosine receptor agonist or antagonist drug molecules currently in clinical use. In view of the widespread actions of adenosine in the cardiovascular system and the possible role of adenosine in the pathogenesis of many diseases affecting the cardiovascular system, new agents that modulate adenosine’s actions have considerable therapeutic potential. The main diseases under consideration in this review of patents from 1997 - 2000 are hypertension, myocardial ischaemia (infarction), cerebral ischaemia (stroke), supraventricular tachycardia, renal failure, heart failure and peripheral ischaemia (intermittent claudication). Novel agonists and antagonists at each of the four receptor subtypes have been disclosed, except A_2B agonists, where a gap still remains. Agents that raise endogenous adenosine levels, namely inhibitors of adenosine transport, adenosine deaminase and adenosine kinase, are also disclosed. Claims are made for the potential use of all of the agents in the treatment of cerebral and myocardial ischaemia. The likely mechanisms for this protective action are not always clear and the final therapeutic outcome must remain uncertain until the underlying mechanisms are resolved. Applications in the treatment of renal dysfunction and as diuretics are claimed for novel adenosine A₁ receptor antagonists which appear to be more realistic. There is growing interest in the role of adenosine in inflammatory disorders as they relate to cerebrovascular and myocardial ischaemia and actions of adenosine receptor agonists and antagonists on neutrophil and mast cell function appear to show particular promise. The only established use of adenosine in the treatment of supraventricular arrythmias has received some additional support with the disclosure of several novel A₁ receptor agonists. A₁-selective agonists with potential for hyperlipidaemias, arrhythmias following myocardial infarction, heart failure and hypertension, are also disclosed.     

DHA derivatives of fish oil as dietary supplements: a nutrition-based drug discovery approach for therapies to prevent metabolic cardiotoxicity

Introduction: During the early 1970s, Danish physicians Jorn Dyerberg and colleagues observed that Greenland Eskimos consuming fatty fishes exhibited low incidences of heart disease. Fish oil is now one of the most commonly consumed dietary supplements. In 2004, concentrated fish oil was approved as a drug by the FDA for the treatment of hyperlipidemia. Fish oil contains two major omega-3 fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). With advancements in lipid concentration and purification techniques, EPA- or DHA-enriched products are now commercially available, and the availability of these components in isolation allows their individual effects to be examined. Newly synthesized derivatives and endogenously discovered metabolites of DHA exhibit therapeutic utility for obesity, metabolic syndrome and cardiovascular disease.

Areas covered: This review summarizes our current knowledge on the distinct effects of EPA and DHA to prevent metabolic syndrome and reduce cardiotoxicity risk. Since EPA is an integral component of fish oil, we will briefly review EPA effects, but our main theme will be to summarize effects of the DHA derivatives that are available today. We focus on using nutrition-based drug discovery to explore the potential of DHA derivatives for the treatment of obesity, metabolic syndrome and cardiovascular diseases.

Expert opinion: The safety and efficacy evaluation of DHA derivatives will provide novel biomolecules for the drug discovery arsenal. Novel nutritional-based drug discoveries of DHA derivatives or metabolites may provide realistic and alternative strategies for the treatment of metabolic and cardiovascular disease.     

The implications of a growing evidence base for drug use in elderly patients Part 2. ACE inhibitors and angiotensin receptor blockers in heart failure and high cardiovascular risk patients

Traditionally, angiotensin converting enzyme (ACE) inhibitors have been used for the management of patients with congestive cardiac failure. Studies performed over the last decade have demonstrated that (1) angiotensin receptor blockers (ARBs) are as effective as ACE inhibitors in reducing morbidity and mortality in cardiac failure; and (2) inhibition of the renin-angiotensin system provides beneficial effects in patients at high cardiovascular risk without cardiac failure. This review focuses on the applicability of the results of the main trials with ACE inhibitors and ARBs to the elderly population.