血管紧张素转换酶抑制剂在小儿心力衰竭治疗中的应用进展

心力衰竭是常见的小儿心血管危重症,血管紧张素转换酶抑制剂在治疗小儿心力衰竭中起着重要作用.本文从血管紧张素转换酶抑制剂的药理学机制、药代动力学及治疗小儿心力衰竭的作用和使用方法作一介绍,以对临床使用起到一定的参考作用.     

血管紧张素转换酶基因多态性与儿童肾脏疾病研究进展

血管紧张素转换酶(angiotensin convertjng enzyme,ACE)基因是肾脏疾病遗传易患性的主要候选基因之一,但ACE基因多态性与肾脏疾病的相关性还存在着争议.该文就近年来有关ACE基因多态性与儿童肾脏疾病相关性的研究进行综述.     

血管紧张素转换酶基因多态性与儿童原发性高血压的关系

目的：探讨血管紧张素转换酶(ACE)基因第16内含子中287 bp的插入/缺失（I/D）多态性与儿童原发性高血压的关系。方法：应用聚合酶链式反应（PCR）技术检测105例原发性高血压儿童（高血压组）及105例正常健康儿童（对照组）的ACE基因第16内含子中287 bp的I/D多态性。结果：高血压组及对照组儿童的ACE基因第16内含子均有I/D多态性,分为II、ID、DD 3种形态。高血压组DD型、ID型、II型基因型频率分别为30.5%、47.6%、21.9%,对照组DD型、ID型、II型基因型频率分别为14.3%、46.7%、39.1%,两组比较,DD型、II型基因型频率差异有统计学意义（P＜0.01）。高血压组D等位基因的基因频率明显高于对照组（54.3% vs 37.6%,P<0.01）;而I等位基因的基因频率明显低于对照组（45.7% vs 62.4%,P<0.01）。结论：ACE基因存在II型、ID型、DD型多态性。儿童原发性高血压的发生可能与ACE基因中第16内含子287 bp的缺失相关。     

Unintentional paediatric ingestions of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists

AIMS: There is limited information on safety of angiotensin converting enzyme (ACE) inhibitors and angiotensin II (AII) receptor antagonists in unintentional paediatric ingestions. This study was conducted with the aim of developing referral guidelines for poison information centres. METHODS: Calls to the NSW poison information centre from January 2002 to July 2004 regarding paediatric ingestion of ACE inhibitors and AII receptor antagonists were recruited and prospectively followed up. Information collected included: demographics (age, gender, weight), type of exposure (unintentional, therapeutic error), ingested dose and clinical effects. Dose was reported in defined daily doses (DDD) to compare across and within the two drug classes with respect to the normal adult dose. RESULTS: Nineteen cases of paediatric ingestion of ACE inhibitors and AII receptor antagonists were included. The median age was 2 years (Interquartile range (IQR): 20-33 months) and the median dose ingested was 1 DDD (IQR: 1-2). There were nine ACE inhibitor ingestions and 10 AII receptor antagonist ingestions. One of nine children (11%) observed in hospital developed transient hypotension but required no treatment and recovered without complication. This child ingested an ACE inhibitor and ingested >3 DDD. CONCLUSION: Unintentional paediatric ingestions of ACE inhibitors and AII receptor antagonists resulted in the majority of children remaining asymptomatic. ACE inhibitor ingestions under 2 DDD can be observed at home provided the child is asymptomatic and there is a responsible adult to observe the child. The dose required for observation in AII receptor antagonist ingestions is less clear.     

Angiotensin I converting enzyme and angiotensinogen gene polymorphisms related to 24-h blood pressure in paediatric type I diabetes mellitus

The aim of this study was to evaluate two putative predictive genetic markers for hypertension in children and adolescents with diabetes mellitus. Ambulatory blood pressure measurements were performed in 199 patients with type I diabetes mellitus (mean age 16.5 years, mean duration of diabetes 7.7 years) and compared to those of 1141 healthy children. The local allele frequencies were established based on a control population consisting of 181 healthy subjects. The allele frequencies of the angiotensinogen gene M235T polymorphism was nearly identical in insulin-dependent diabetes mellitus patients (MM 33%, MT 51%, TT 16%) and controls (MM 35%, MT 49%, TT 16%). In contrast, the genotype distribution of the angiotensin I converting enzyme gene insertion/deletion (I/D) polymorphism was different between patients with type I diabetes mellitus (DD 26%, ID 49%, II 25%) and the control group (DD 37%, ID 44%, II 19%) (P = 0.04). Relative nocturnal systolic and diastolic pressures in patients with diabetes were higher than in healthy age- and height-matched controls; no association was found with the angiotensinogen gene M235T polymorphism. Relative nocturnal diastolic blood pressure was higher in patients homozygous for the I allele of the angiotensin I converting enzyme gene. Conclusion Nocturnal systolic and diastolic blood pressure is higher in patients with type I diabetes than in healthy children. The formerly described, but controversial, association of the M235T polymorphism with arterial hypertension could not be confirmed in this study. Received: 4 February 1998 / Accepted: 15 June 1998     

Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists

The renin-angiotensin system plays an important role in the regulation of blood pressure. The use of angiotensin converting enzyme inhibitors or angiotensin receptor blockers both control hypertension by interruption of the production or action of angiotensin II, the major end-product of the renin-angiotensin system. The use of angiotensin converting enzyme inhibitors in pregnant women revealed serious and deleterious effects on fetal development including renal failure, renal dysplasia, hypotension, oligohydramnios, pulmonary hypoplasia, and hypocalvaria. The fetal effects of angiotensin converting enzyme inhibitors seem to be greatest during the 2nd and 3rd trimesters of pregnancy. The fetal effect of angiotensin converting enzyme inhibitors during the 1st trimester is controversial. These effects may represent the effect of hypoperfusion in the fetus and not a teratogenic effect. The effect of angiotensin receptor blockers is similar to converting enzyme inhibitors. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers should be avoided in all pregnant women. Alternative antihypertensive medications should be considered for use in women of childbearing years.     

Cardiovascular drugs in children: Angiotensin-converting enzyme inhibitors

Summary Angiotensin-converting enzyme inhibitors are potent vasodilators acting by inhibition of production of the vasoconstrictor angiotensin II. In adults, they are used for treatment of systemic hypertension and congestive heart failure and investigated for treatment of primary pulmonary hypertension.In infants and children, saralasin and captopril were found to be useful in treatment of systemic arterial hypertension, especially when associated with high plasma renin activity. Captopril has failed in the treatment of congestive heart failure associated with complex congenital heart diseases and in most cases of primary pulmonary hypertension. It has a clear beneficial effect in coarctation of the aorta and may have such an effect in endomyocardial diseases and ventricular septal defect.In adults, serious side effects have limited the use of captopril. New converting enzyme inhibitors, devoid of a sulfhydryl group, are expected to have a better safety profile.     

Serum level and gene polymorphism of angiotensin I converting enzyme in Japanese children

The aim of the present study was to determine the distribution of the insertion/deletion polymorphism of angiotensin I converting enzyme (ACE) gene in Japanese children. In addition, the relationship between this polymorphism and serum ACE levels in the same population were analyzed. Insertion/deletion polymorphism located in intron 16 of the ACE gene was examined by polymerase chain reaction in Japanese children aged 10–15 years. Allele frequencies were 0.64 for the insertion allele and 0.36 for the deletion allele in 122 subjects. No association was found between genotypes in this polymorphism and the level of systolic or diastolic blood pressure. A significant relationship between this polymorphism and serum ACE activity was observed. These results suggest that interindividual variability of serum ACE level is strongly influenced by the ACE genotype as early as in childhood.     

小儿原发性膀胱输尿管反流的临床研究

目的　探讨小儿原发性膀胱输尿管反流的发病机制、临床特点、肾损害评价、治疗及预后。方法　回顾性研究 1990～ 2 0 0 2年复旦大学附属儿科医院 5 0例小儿原发性膀胱输尿管反流 ,对反流程度、尿路感染、肾疤痕形成、尿液分析及血管紧张素转化酶 (ACE)基因型进行了分析 ,并将药物和手术治疗组的随访结果进行比较。结果　 5 0例中双侧反流者 2 2例 (44 % ) ,单侧反流者 2 8例 (5 6 % ) ;39例行膀胱尿道造影检查发现反流Ⅰ度2 9 5 % (2 3/ 78) ,Ⅱ度 7 7% (6 / 78) ,Ⅲ度 14 1% (11/ 78) ,Ⅳ度 4 1 0 % (32 / 78) ,Ⅴ度 7 7% (6 / 78)。尿液 β2 微球蛋白、尿视黄醇结合蛋白、N乙酰半胱氨酸异常升高与肾疤痕形成相关 (P <0 0 5 ) ,血ACE基因型ID或DD型与肾疤痕形成相关 (P <0 0 5 )。药物与手术治疗组尿路感染复发率、肾疤痕形成率及反流有效控制率无显著差别。结论　小儿原发性膀胱输尿管反流需要及早诊断 ,同时通过对尿液微量蛋白及血ACE基因型检测 ,对肾损害作出预测 ,建立个体化的有效的治疗方案     

Angiotensin converting enzyme activity in children with congenital heart disease

Serum angiotensin converting enzyme (ACE) activity was determined in 46 children with congenital heart disease with normal and abnormal lung perfusion: (1) congenital heart disease with normal pulmonary blood flow (12 patients); (2) congenital heart disease with increased pulmonary blood flow (18 patients); (3) congenital heart disease with decreased pulmonary blood flow (16 patients). There was no significant difference in serum ACE activity between the three groups. In group 2 serum ACE activity had a tendency to correlate inversely with both mean pulmonary arterial pressure (r=–0.43;P0.05) and pulmonary vascular resistance (r=–0.48;P=0.05). No further correlations between serum ACE activity and age, serum electrolytes, creatinine nor other haemodynamic data could be established.     

Angiotensin-converting enzyme genotype distribution in familial vesicoureteral reflux

 Vesicoureteric reflux (VUR) is known to occur in families. In siblings of index patients with VUR, there is a much higher incidence (16% to 46%) than in the general population. The renin-angiotensin system plays an important role in renal development. Recently, it has been reported that angiotensin-converting enzyme (ACE) I/D gene polymorphism is a risk factor for renal parenchymal damage in patients with congenital urological abnormalities. The aim of this study was to investigate the ACE I/D genotype pattern in familial VUR patients. Blood samples were obtained from 86 families in which two or more members had VUR. Samples of DNA were extracted from 407 blood samples (183 affected patients and 224 non-affected family members). To detect ACE I/D polymorphism, polymerase chain reaction (PCR) amplification was performed using specific primers for the ACE gene. PCR products were electrophoresed with 2% agarose gel containing ethidium bromide. Among 224 non-affected family members the ACE genotype distribution of DD, ID, and II was 23%; 56% and 21%, respectively. The ACE genotype distribution of 183 affected patients was 28%, 47% and 25%, respectively. There was no significant difference in ACE I/D distribution between affected patients and their non-affected families. Both the ACE genotype distribution of affected patients and that of non-affected family members were not significantly different from the previously reported genotype distribution of the normal Caucasian population. This study demonstrates that ACE genotype frequencies are similar in index patients with VUR and their unaffected siblings, thus suggesting that the ACE gene is not involved in the development of familial VUR.     

Deletion allele of angiotensin-converting enzyme is associated with increased risk and severity of bronchopulmonary dysplasia

OBJECTIVE: To explore whether the deletion (D) allele of angiotensin-converting enzyme (ACE) is associated with the risk or severity of bronchopulmonary dysplasia (BPD) among very low birth weight (BW) infants. STUDY DESIGN: Infants with a BW < or = 1250 g were prospectively recruited. The D and I (insertion) alleles of ACE were determined using a polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULTS: Infants with DD/DI genotype of ACE had a (mean +/- SD) birth weight (938 +/- 204 g vs 925 +/- 196 g) and gestational age (28 +/- 3 weeks vs 28 +/- 2 weeks), similar to infants with II genotype of ACE (P > .05). Infants with DD/DI genotype of ACE were more likely to have BPD than infants with II genotype (47% vs 22%, P = .025). Among infants with BPD, ACE DD/DI genotype was more common among infants with moderate or severe BPD compared with infants with mild BPD (74% vs 26%, P = .012). The number of D alleles of ACE correlated directly and positively with the severity of BPD (R = 0.23, P = .045). CONCLUSION: The D allele of ACE is associated with an increased risk and severity of BPD among preterm infants.     

肾病幼鼠肾组织尿激酶型纤溶酶原激活物及其抑制物mRNA与蛋白表达的特点和ACEI干预的影响

目的　探讨肾病幼年大鼠肾组织尿激酶型纤溶酶原激活物 (uPA)及其特异性抑制物(PAI 1)mRNA与蛋白质表达的特点 ,及予血管紧张素转换酶抑制剂 (ACEI)苯那普利治疗的影响。方法　采用阿霉素诱导的肾病大鼠为动物模型 ,予ACEI治疗 12周后测大鼠体重、血压、尿蛋白及血生化各项指标的变化 ,同时用Northern杂交及免疫组化染色等方法 ,检测肾组织uPA和PAI 1的mRNA及蛋白表达情况 ,并比较各组间的变化特点。结果　肾病大鼠肾组织PAI 1mRNA吸光度值为 1 6 ,蛋白质组化半定量为 (6 5 3± 10 2 ) % ,uPAmRNA吸光度值为 0 4 ,蛋白组化半定量为 (30 3± 4 2 ) % ;正常对照组PAI 1mRNA吸光度值为 0 5 ,蛋白质组化半定量为 (10 6± 2 4 ) % ,uPAmRNA吸光度值为0 7,蛋白组化半定量为 (85 3± 3 0 ) % ,两组两指标比较差异均有显著意义。经治疗后肾组织PAI 1mRNA吸光度值 0 9,蛋白组化半定量为 (2 0 7± 6 5 ) % ,趋于下降 ,uPAmRNA吸光度值为 0 8,蛋白组化半定量为 (93 1± 5 1) % ,趋于增高 (P <0 0 1)。结论　肾病病变进展中可出现纤溶系统的平衡紊乱 ,ACEI治疗可改善PA/PAI 1的异常表达 ,防止细胞外基质的异常沉积 ,阻止肾小球硬化和间质纤维化病变的进展     

Acute hemodynamic effects of converting enzyme inhibition in children with intracardiac shunts

Summary The short-term hemodynamic effects of intravenous enalaprilat were assessed in 26 infants and children, aged 6 months to 15 years, with intracardiac shunts undergoing cardiac catheterization. Pulmonary and systemic pressure, flow, and resistance indices were measured by the direct Fick method before and 30 min after enalaprilat at 0.06 mg/kg.Aortic and pulmonary artery pressure decreased 15 and 20%, respectively, by 10 min, with little further change at 30 min. The heart rate did not change significantly and there was no reduction in systemic flow. In those with a large ventricular septal defect and normal or near-normal pulmonary resistance (<3.5 u.m²,n=8), the mean pulmonary-systemic flow ratio decreased from 2.9±0.3 to 2.4±0.3 (p<0.05) and the mean left-to-right shunt from 7.4±0.8 to 5.9±0.7 L/min/m² (p<0.02). Those with an elevated pulmonary vascular resistance (>5 u.m²,n=8) showed a varied response. Two children, both with Down's syndrome, an atrioventricular canal defect, and reversible pulmonary hypertension (as assessed by an infusion of isoproterenol), had no decrease in pulmonary vascular resistance with enalaprilat. There were no adverse effects.Converting enzyme inhibitors may benefit heart failure associated with large ventricular septal defects and normal or mildy elevated pulmonary resistance.     

Polymorphism of angiotensin converting enzyme is associated with severe circulatory compromise in febrile neutropenic children with cancer

Angiotensin converting enzyme (ACE) gene insertion(I)/deletion(D) polymorphism influences the outcome of a number of cardiovascular diseases. ACE I/D polymorphism was investigated by PCR in 207 pediatric cancer patients and 144 controls. ACE I/D distribution of patients and controls was similar. The frequency of the D allele and the prevalence of the deletion (DD) genotype were significantly (P < 0.05) higher among patients with severe circulatory compromise requiring treatment in the intensive care unit (ICU) than among the other patients and controls. Patients with the DD and ID genotypes spent significantly (P < 0.05) longer time in the ICU than patients with the II genotype.     

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目的探讨血管紧张素转换酶(ACE)基因插入(I)/缺失(D)多态性与过敏性紫癜(HSP)及紫癜性肾炎(HSPN)的关系。方法检索PubMed、中国期刊全文数据库和万方数据库,时间从该数据库建立至2011-03-01。收集有关HSP/HSPN ACE I/D多态性的文献,根据文献纳入标准提取相关数据。应用Stata 11.0软件进行Meta分析,计数资料采用优势比(OR)及95%CI表示,对病例组、对照组I/D进行分析。各组中研究异质性无统计学意义(P≥0.1)时采用固定效应模式,否则采用随机模式分析。结果纳入针对HSP及HSPN研究的文献各5篇,通过对纳入的文献进行Meta分析发现,D等位基因与HSP易感性相关(OR=1.23,95%CI:1.04～1.46,P=0.001),并且与HSPN也存在相关(OR=1.49,95%CI:1.01～2.19,P<0.001)。结论 ACE基因I/D多态性与HSP/HSPN发病关系密切。     

偏头痛患儿发作间期血浆P物质、降钙素基因相关肽及ACE活性水平变化及其相关性研究

目的研究偏头痛患儿发作间期血浆P物质(SP)、降钙素相关基因肽(CGRP)和血管紧张素转换酶活性(SACE)的变化及其相关关系。方法分别检测2005年3月～2006年10月儿科门诊98例偏头痛患儿发作间期及50例正常健康儿童血浆SP、CGRP及SACE水平,比较正常组、偏头痛有先兆组(MA)及偏头痛无先兆组(MO)三者间的差异及其相关关系。结果SP和CGRP水平MA组较正常组和MO组高,而SACE水平MA组较正常对照组高,与MO组比较差异无统计学意义。SP与CGRP相关,r=0.281(P<0.05);SP与SACE水平相关,r=0.423(P<0.05);CGRP与SACE之间未发现明显相关性。结论SP、CGRP和ACE与偏头痛的发病机制密切相关,并且它们之间也相互作用。