Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.     

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.     

Concerns and hopes for stem cell therapy in cardiology: focus on endothelial progenitor cells

The crucial role played by the endothelium in cardiovascular disorders has been repetitively recognised. Endothelium injury has been implicated in atherosclerosis, thrombosis, hypertension and other cardiovascular diseases. Recently, however, research has undertaken a new avenue. As mature endothelial cells posses limited regenerative capacities, the interest has been switched to the circulating endothelial progenitor cells (EPCs). Indeed, the scientific community has made progress in understanding the role of EPCs in the maintenance of endothelial integrity and function as well as post natal neovascularisation. It has been suggested that these cells are able to home in the site of heart injury / damage and that they might take part in angiogenesis, giving hope for new treatment opportunities. There is evidence that reduced availability of EPCs or impairment of their function is associated with more severe CV disease and to comorbid risk factors. Different current drug regimes are able to influence bone marrow production and release of EPCs and several growth factors are considered for possible useful new therapeutic approaches. Thus, many studies into the potential use of EPCs in the clinical setting have recently been conducted with conflicting results. The goal of this review article is to discuss current therapies to regenerate new vessels and therefore to enhance myocardial function. The article overviews the search strategy and the pathophysiological aspects behind this therapy, consider the target currently under investigation and set the stage for new ideas.     

Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.     

The effects of growth hormone and insulin-like growth factor-1 on the aging cardiovascular system and its progenitor cells

Aging is a major risk factor for the development of cardiovascular disease. Aging is also associated with a decline in the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis. This axis impacts endothelial and vascular smooth muscle cell biology, as well as cardiac function. The number of endothelial progenitor cells (EPCs) also decreases with age and is emerging as a surrogate measurement of vascular senescence. Studies suggest that EPCs impact vascular health by modulating vascular repair and function. Current evidence demonstrates that EPC number and function is restored with a GH-mediated increase in serum IGF-1. Modulation of the GH and IGF-1 system may therefore provide a useful therapy in the prevention of age-associated changes in the cardiovascular system and in future regenerative cell-based therapies.     

Therapeutic Potential for Endothelin Receptor Antagonists in Cardiovascular Disorders

The endothelins are synthesized in vascular endothelial and smooth muscle cells, as well as in neural, renal, pulmonal, and inflammatory cells. These peptides are converted by endothelin-converting enzymes (ECE-1 and -2) from ‘big endothelins’ originating from large preproendothelin peptides cleaved by endopeptidases. Endothelin (ET)-1 has major influence on the function and structure of the vasculature as it favors vasoconstriction and cell proliferation through activation of specific ET_A and ET_B receptors on vascular smooth muscle cells. In contrast, ET_B receptors on endothelial cells cause vasodilation via release of nitric oxide (NO) and prostacyclin. Additionally, ET_B receptors in the lung are a major pathway for the clearance of ET-1 from plasma. Indeed, ET-1 contributes to the pathogenesis of important disorders as arterial hypertension, atherosclerosis, and heart failure. In patients with atherosclerotic vascular disease (as well as in many other disease states), ET-1 levels are elevated and correlate with the number of involved sites. In patients with acute myocardial infarction, they correlate with 1-year prognosis. ET receptor antagonists have been widely studied in experimental models of cardiovascular disease. In arterial hypertension, they prevent vascular and myocardial hypertrophy. Experimentally, ET receptor blockade also prevents endothelial dysfunction and structural vascular changes in atherosclerosis due to hypercholesterolemia. In experimental myocardial ischemia, treatment with an ET receptor antagonist reduced infarct size and prevented left ventricular remodeling after myocardial infarction. Most impressively, treatment with the selective ET_A receptor antagonist BQ123 significantly improved survival in an experimental model of heart failure. In many clinical conditions, such as congestive heart failure, both mixed ET_A/B as well as selective ET_A receptor antagonism ameliorates the clinical status of patients, i. e. symptoms and hemodynamics. A randomized clinical trial showed that a mixed ET_A/B receptor antagonist effectively lowered arterial blood pressure in patients with arterial hypertension. In patients with primary pulmonary hypertension or pulmonary hypertension related to scleroderma, treatment with a mixed ET_A/B receptor antagonist resulted in an improvement in exercise capacity. ET receptor blockers thus hold the potential to improve the outcome in patients with various cardiovascular disorders. Randomized clinical trials are under way to evaluate the effects of ET receptor antagonism on morbidity and mortality.     

Heart regeneration: what cells to use and how?

Coronary artery disease (CAD) is the leading cause of death in modern societies. Recent achievements in the treatment of CAD including statins, ACE inhibitors, beta blockers, and interventional procedure improved the outcome of patients with CAD, but this conventional approach failed to control cardiovascular mortality. Nowadays, cells (stem cells) and their potential role in managing patients with heart disease is a field of intensive research. Various types of cells have been used for transplantation targeting heart regeneration, including bone marrow cells (BMCs), cardiac stem cells (CSCs), endothelial progenitor cells (EPCs), skeletal myoblasts (SMs), adipose stroma tissue cells (ATSCs), mesenchymal cells (MCs), and embryonic stem cells (ESCs). Several routes have been used to deliver these cells to human myocardium or to the coronary circulation such as, intracoronary injection, intravenous infusion, direct injection into the ventricular wall, or transepicardial/transendocardial infusions. Although the results of the recent clinical trials in this area are rather conflicting, these therapeutic approaches seem to be promising for the treatment of ischemic heart disease.     

Effects of metoprolol,methyldopa, and nifedipine on endothelial progenitor cells in patients with gestational hypertension and preeclampsia

Endothelial progenitor cells (EPCs) are critical for vascular regeneration and function, but are reduced in hypertensive disorders of pregnancy. We aimed to determine the possible effects of antihypertensive drugs, such as metoprolol, methyldopa, and nifedipine, on EPC number and functions in patients with gestational hypertension and preeclampsia. We collected blood samples from 30 normal pregnant women, 67 patients with gestational hypertension and 48 patients with preeclampsia. The patients received no drug or an antihypertensive drug, such as metoprolol, methyldopa, or nifedipine, between 20 and 24 weeks of gestation. The number of EPCs and circulating endothelial cells (CECs) in the blood was measured by flow cytometry. Moreover, colony formation and migration assays were performed on the isolated EPCs. Both the systolic and diastolic blood pressure (BP) increased, while the percentage of flow‐mediated vasodilatation (FMD) decreased in patients with gestational hypertension and preeclampsia, compared to the healthy controls at 20 weeks of gestation. CEC number increased in the patients, whereas EPC counts decreased. Furthermore, EPC colony formation and migration abilities were also impaired in the patients. However, administration of metoprolol, methyldopa, or nifedipine effectively restored the systolic and diastolic BP, FMD%, EPCs, and CEC numbers, as well as EPC migration capacity. Endothelial progenitor cells colony formation ability selectively improved with methyldopa and nifedipine. In patients receiving no drugs, most of these indexes worsened within 4 weeks (study duration). This study revealed a new pharmacological action of these antihypertensive drugs against gestational hypertension and preeclampsia, thus supporting their clinical use.     

Eplerenone: a selective aldosterone blocker

Recent studies suggest that aldosterone may play a larger role than once appreciated in normal physiologic function and cardiovascular disease. Some of the adverse cardiovascular effects that have been described include cardiac and vascular fibrosis, vascular necrosis and inflammation, impaired endothelial function, reduced fibrinolysis, hypertension, left ventricular hypertrophy (LVH), congestive heart failure, and cardiac arrhythmias. In light of these findings, the ability to block the actions of aldosterone has gained increased therapeutic importance. Eplerenone is a selective aldosterone receptor blocker that displays little interaction with androgen and progesterone receptors. Eplerenone has already been approved for the treatment of systemic hypertension and has been evaluated in numerous hypertension subgroups, including patients with low plasma renin activity; diabetes; LVH; uncontrolled blood pressure while receiving monotherapy with angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium channel blockers, or beta-blockers; and in black patients. Results of these trials indicate that eplerenone lowers blood pressure and reduces end-organ damage. Further proof of the therapeutic importance of mineralocorticoid receptor blockade comes from the eplerenone post acute myocardial infarction survival and efficacy study (EPHESUS). In this large-scale clinical outcome trial, eplerenone was shown to reduce total mortality by 15% as well as the combined endpoint of cardiovascular mortality/cardiovascular hospitalization by 13% when administered at a mean of 7.3 days post myocardial infarction to patients with evidence of systolic left ventricular dysfunction and symptoms of heart failure. Eplerenone is well tolerated, with an adverse effect profile comparable to placebo. The advent of selective aldosterone blockers, such as eplerenone, should prove to be of great therapeutic value in hypertension control and prevention of cardiovascular disease and associated end-organ damage.     

Endothelial dysfunction and chronic kidney disease: treatment options

Endothelial cells detect physical and chemical changes in the blood vessels, and release various factors to counter these changes to maintain homeostasis. Traditional cardiovascular disease risk factors, such as hypertension, dyslipidemia and diabetes, cause endothelial dysfunction characterized by off-balanced vasodilation/vasoconstriction, increased oxidative stress and inflammation, deregulation of thrombosis and fibrinolysis, abnormal smooth muscle cell proliferation, and a deficient repair mechanism. Patients with chronic kidney disease (CKD) have a much higher risk of cardiovascular disease and mortality than the general population. Endothelial dysfunction is commonly observed in CKD, likely preceding other cardiovascular complications. Lipid-lowering agents, such as statins, improve endothelial functions and are effective in reducing cardiovascular disease risk in the general population, but have not demonstrated comparable efficacy in the CKD patient population. Similarly, antidiabetic agents, such as thiazolidinediones, that improve endothelial function in the general population are less efficacious than expected in slowing disease progression and reducing cardiovascular disease risk in CKD patients. Interestingly, agents that activate the vitamin D receptor (VDR) for the treatment of hyperparathyroidism secondary to CKD are associated with a survival benefit in CKD patients that is likely mediated through the effects of the VDR on modulating key components involved in endothelial dysfunction. However, a randomized, clinical study is required to confirm the survival benefit of VDR activation therapy for CKD patients. Results from clinical studies suggest that managing hypertension alone may not be adequate in slowing CKD progression and its related cardiovascular complications. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers that target the renin-angiotensin system slow CKD progression, possibly due to their effects on improving endothelial function, independent of controlling blood pressure.     

糖尿病患者血管内皮祖细胞研究进展

血管内皮祖细胞(EPC)来源于骨髓,是具有修复内皮和新生血管功能的干细胞。糖尿病患者外周血EPC数量和功能均出现下降,EPC已成为糖尿病及其并发症治疗的一个新靶点。本文综述EPC在糖尿病病理生理中的作用和药物干预机理的研究进展。     

Therapeutic applications of sildenafil citrate in the management of paediatric pulmonary hypertension

Pulmonary hypertension is characterised by a progressive increase in pulmonary vascular resistance and a poor prognosis. The exact underlying mechanisms are still poorly understood; however, it is hypothesised that pulmonary medial hypertrophy and endothelial dysfunction lead to impaired production of vasodilators such as nitric oxide (NO) and prostacyclin, and increased expression of vasoconstrictors such as endothelin-1. The current treatment modalities for pulmonary hypertension include conventional supportive therapies and more specific pharmacological therapies that are targeted at abnormalities of endothelial function. NO and phosphodiesterase type 5 (PDE5) inhibitors induce pulmonary vasodilation by increasing intracellular cyclic guanosine monophosphate (cGMP) concentrations.Sildenafil citrate is a highly selective inhibitor of PDE5. Investigations in animal models and recent clinical case reports with some studies in the paediatric population suggest that sildenafil may be a promising agent in treating pulmonary hypertension. The effect of sildenafil on pulmonary vasculature appears to be independent of the underlying cause, thereby providing a role in idiopathic pulmonary arterial hypertension (PAH), PAH associated with congenital heart disease, pulmonary hypertension secondary to lung disease or persistent pulmonary hypertension of the newborn. It may also be beneficial in postoperative pulmonary hypertension and in neonates who are difficult to wean from inhaled NO. It is easily administered and effective, and has minimal systemic adverse effects. Although the reported results in children with pulmonary hypertension are promising, it is an experimental drug and large-scale randomised controlled studies are required to validate the safety, efficacy and dosage in the paediatric population.     

波生坦联合伐地那非治疗先天性心脏病术后肺动脉高压的临床疗效及对血管内皮功能的影响

目的 探究波生坦联合伐地那非治疗先天性心脏病术后肺动脉高压的临床疗效及对血管内皮功能的影响。方法 2011年11月-2015年12月郑州市第七人民医院重症医学科收治的80例先天性心脏病术后肺动脉高压患者为研究对象。根据术后拔除气管插管顺序随机分为观察组（40例）和对照组（40例）。两组患者均给予持续吸氧、利尿等常规治疗。在此基础上,对照组口服盐酸伐地那非片;观察组在对照组的基础上加服波生坦,两组均治疗6个月。比较两组患者临床有效率、临床症状缓解情况、心脏功能的情况。结果 治疗后对照组的临床总有效率为80.0%,观察组的临床总有效率为90.0%,观察组的临床总有效率显著高于对照组,差异有统计学意义（P<0.05）。与治疗前比较,治疗后两组患者的肺动脉收缩压（sPAP）、肺动脉平均压（mPAP）均大幅下降（P<0.05）,肺循环血流量/体循环血流量明显升高（P<0.05）;且观察组的变化较对照组更为显著,差异有统计学意义（P<0.05）。与治疗前比较,治疗后两组患者的呼吸困难评分（Borg）、心脏功能分级（NYHAFC）评分均大幅下降（P<0.05）,且观察组上述指标评分显著低于对照组,差异有统计学意义（P<0.05）。治疗后,两组患者血管内皮生长因子（VEGF）水平均治疗前大幅下降（P<0.05）,且观察组下降幅度较对照组更为明显,差异有统计学意义（P<0.05）。两组在不良反应方面比较,差异无统计学意义。结论 波生坦联合伐地那非治疗先天性心脏病术后肺动脉高压的临床效果显著,可显著改善患者呼吸困难等临床症状,改善心脏功能,值得临床推广。     

Endothelial progenitor cells: therapeutic target for cardiovascular diseases

Circulating endothelial progenitor cells (EPCs) derived from bone marrow were isolated for the first time in 1997 and characterized. Recent evidence has indicated that EPCs contribute to re-endothelialization of injured vessels as well as neovascularization of ischemic lesions and that a decrease in the number of EPCs is an independent predictor of morbidity and mortality of cardiovascular diseases. These finding suggest that EPCs play a major role in the pathogenesis of atherosclerosis and cardiovascular diseases. Interestingly, the number and function of EPCs are regulated by not only various kinds of angiogenic cytokines and cardiovascular risk factors per se but also some interventions, including lifestyle modification (aerobic exercise, body weight loss, and smoking cessation) and pharmacological therapy (e.g., renin-angiotensin system inhibitor, statin, and erythropoietin). It is thought that regulation of the number and function of EPCs directly influences the maintenance and development of atherosclerosis. Therefore, it is clinically important to estimate the degree of EPC bioactivity and to increase the EPC bioactivity by appropriate interventions. In this review, we focus on the relationship between EPCs and cardiovascular risk factors and the role of EPCs in cardiovascular diseases.     

Atenolol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders.

Atenolol is a selective beta 1-adrenoceptor antagonist with a duration of activity of at least 24 hours. The scope of therapeutic use of the drug has been expanded and become better defined since it was first reviewed in the Journal in 1979. Atenolol is effective and generally well tolerated in patients with all grades of hypertension. Data from comparative studies show that when administered orally, atenolol reduces blood pressure to a similar extent, and in a similar proportion of patients, as usual therapeutic doses of other beta-adrenoceptor antagonists (such as acebutolol, celiprolol, betaxolol, indenolol, metoprolol, nadolol, pindolol, propranolol, tertatolol), angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril and lisinopril), calcium antagonists (e.g. amlodipine, diltiazem, felodipine, isradipine, nitrendipine, nifedipine, verapamil), doxazosin, ketanserin and alpha-methyldopa. Atenolol effectively lowers blood pressure in elderly patients with hypertension and in women with hypertension associated with pregnancy, and improves objective and subjective indices in patients with stable angina pectoris. Oral atenolol is used for preventing recurrence of supraventricular arrhythmias once control is achieved by intravenous administration of atenolol. Early intervention with intravenous atenolol followed by oral maintenance therapy reduces infarct recurrence and cardiovascular mortality in patients with known or suspected myocardial infarction. There is also encouraging evidence of reduced mortality from cardiovascular disease during long term therapy with atenolol in patients with hypertension. Atenolol is well tolerated in most patients. Increases in plasma levels of both total triglycerides and very low density lipoprotein (VLDL) triglycerides have accompanied atenolol therapy although the clinical relevance, if any, of longer term metabolic effects has yet to be determined. Its low lipid solubility and limited brain penetration results in a lower incidence of central nervous system effects than that associated with propranolol. After many years of clinical usage atenolol is a well established treatment option in several areas of cardiovascular medicine such as mild to moderate hypertension and stable angina pectoris. Furthermore, it has also shown potential in the treatment of some cardiac arrhythmias and has been associated with reduced cardiovascular mortality in patients with hypertension and in patients with myocardial infarction.     

外周血CD34^＋水平与高血压病患者动脉血管功能的关系

目的探讨能否根据外周血内皮祖细胞（endothelial progenitor cells,EPCs）CD34^＋水平评价高血压病患者动脉血管病变程度。方法高血压病患者组62例,对照组20例。高血压病患者采用Framingham心血管危险因素积分分层心血管危险因素,分为低危组18例,中危组14例,高危组17例,极高危组13例。作外周血循环EPCsCD34^＋水平、内皮依赖性血管舒张功能（flow—mediated dialation,FMD）测定并作EPCsCD34^＋水平与Framingham心血管危险因素积分、FMD的相关性分析。结果高血压病患者外周循环EPCsCD34^＋水平随着其心血管危险程度的增加,逐步下降,各组间比较川差异均有显著性（P〈0．05）.高血压病患者肱动脉FMD随着其心血管危险程度的增加显著下降（P〈0．01）。各研究组高血压病患者循环EPCs CD34^＋水平与Framingham心血管危险因素积分呈负相关（r=-0．875,P〈0．01）,与肱动脉FMD呈正相关r=0．859,P〈0．01）.结论高血压病患者循环EPCs CD34^＋水平下降与心血管危险因素、动脉血管功能损伤有显著的相关性。说明循环EPCs CD34^＋水平可以作为评价高血压病患者动脉血管病变的指标.     

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.     

Perindopril: a review of its use in patients with or at risk of developing coronary artery disease

Perindopril (Coversyl) is a prodrug ester of perindoprilat, an ACE inhibitor. This agent has shown pharmacodynamic effects beyond those responsible for lowering blood pressure (BP), including the improvement of endothelial function and the normalisation of vascular and cardiac structure and function. Perindopril has a well established role in the treatment of patients with hypertension or heart failure. In the EUROPA trial, once-daily perindopril 8 mg prevented cardiovascular events in patients with stable coronary artery disease (CAD) without any apparent heart failure receiving standard recommended therapy. In the ASCOT-BPLA trial, a calcium channel antagonist +/- perindopril regimen demonstrated significant cardiovascular benefits compared with a conventional beta-blocker +/- diuretic regimen in patients with hypertension who were at risk of developing cardiovascular events. These trials demonstrate that while perindopril, in addition to standard recommended therapy, has a potential role in preventing cardiovascular events in hypertensive patients, its role in the management of patients with stable CAD is clearly established.     

Vasopeptidase inhibition for blood pressure control: emerging experience

Vasopeptidase inhibition is a novel treatment approach in cardiovascular disease such as hypertension and heart failure. Since the inhibition of the angiotensin-converting enzyme (ACE) turned out to represent a very successful principle in the treatment of hypertension in numerous large scale clinical studies, their results encouraged attempts to inhibit other key enzymes in the regulation of vascular tone as well--such as the neutral endopeptidase (NEP). Similar to ACE, NEP is an endothelial cell surface metalloproteinase, which is involved in the degradation of several regulatory peptides including the natriuretic peptides and thus augments vasodilatation and natriuresis through increased levels of atrial natriuretic peptide (ANP). By simultaneous inhibition of the RAS and potentiation of the natriuretic peptide system, combined NEP/ACE inhibitors--the so called vasopeptidase inhibitors--reduce vasoconstriction and enhance vasodilatation, therefore, decreasing peripheral vascular resistance and blood pressure. Based on these considerations, numerous preclinicial studies with vasopeptidase inhibitors were performed and revealed promising results in experimental hypertension. Correspondingly, large scale clinical studies in patients with hypertension are on the way. Their preliminary results indicate that combined inhibition of ACE and NEP by vasopeptidase inhibitors represents an effective strategy in the treatment of hypertension and other cardiovascular disease such as heart failure. However, clinical data also suggest that the incidence of angioedema may increase on vasopeptidase inhibition. Therefore, careful evaluation of the safety of this promising therapeutic principle in large scale clinical studies is mandatory before vasopeptidase inhibition may be considered a novel option in the treatment of cardiovascular disease.     

伊洛前列素治疗儿童先天性心脏病并肺动脉高压临床研究

目的 探讨吸人伊洛前列素(万他维)对先天性心脏病(先心病)并肺动脉高压患儿心功能的影响.方法 选择一组先心病患儿术前用口含器或面罩吸入万他维,剂量为25～30 ng·kg-1·min-1,以2 ml0.9%氯化钠溶液稀释后,通过PARI Junior BOY N压缩机压缩雾化吸入,每3小时给药一次,吸入60 min、120 min、180 min后采用连续多普勒超声波技术,测量左右心每搏心排量等血流动力学参数变化.结果 在用药前和后60 min、120 min、180 min,除血流动力学有明显变化,还发现用药后左、右心排血量增加,用药后再行手术的患儿,呼吸机带管时间缩短,术后恢复顺利.结论 吸人伊洛前列素可以增加心输出量,改善心功能,提示该方法治疗先心病并肺动脉高压有效可行.