内皮素阻断对糖尿病高血压大鼠肾脏AT1受体表达的影响

目的 观察糖尿病高血压大鼠肾脏AT1受体的改变以及内皮素受体阻断剂波生坦的影响。方法 将自发性高血压大鼠建成链脲佐菌素诱导的糖尿病模型（SHR－DM）,设柳平舒组、波生坦＋氨氯地平（络活喜）组、络活喜组和非治疗组,4 一采用免疫组织化学、Western印迹法及逆转录－聚合酶链式反应（RT－PCR）方法检测肾脏AT1受体基因和蛋白表达。结果 与WKY大鼠对照组相比,SHR－DM大鼠存在明显的蛋白尿和肾功能减退,肾脏AngⅡ水平明显升高,ＡＴ１受体的mRNA和蛋白表达则显著下降。波生坦能使上述异常显著减轻。结论 糖尿病高血压大鼠肾脏ＡＴ１受体表达明显下调;波生坦可减轻ＳＨＲ－ＤＭ大鼠肾脏损害并防止ＡＴ１受体表达下调。     

Effect of endothelin receptor antagonist bosentan on plasma leptin concentration in acute myocardial infarction in rats

The aim of the study was to evaluate the effect of endothelin receptor antagonism on plasma leptin level after myocardial infarction (MI). In Wistar rats under chloral hydrate anesthesia, MI was performed by ligation of the left coronary artery. The animals were divided into the following groups: control-sham (thoracotomy only), and two MI groups with or without bosentan treatment. Bosentan was given daily by gavage at the dose of 100 mg/kg. Treatment of animals started 2 days before MI and continued up to the fifth day. Concentration of leptin was measured by radioimmunoassay by means of ¹²⁵I labeled antigen in the following time intervals: before MI or sham operation, 4, 24 and 48 h after surgery. Electrocardiogram (ECG), blood pressure, heart rate, arterial pO₂, pCO₂ and pH were periodically monitored. Two days after the MI animals were perfused retrograde into descending aorta with 2% triphenyltetrazolium chloride (TTC) and hearts were fixed by immersion in formalin for microscopic examination. Hearts were sectioned transaxially and size of MI was quantitated with morphometric methods. ECG, TTC staining and microscopic results confirmed development of MI. Morphometric methods did not show significant differences in infarct size between bosentan treated and untreated groups. Concentration of leptin in plasma in untreated group significantly increased already 4 h after MI. In bosentan treated animals this increase appeared only after 24 h. In animals treated with bosentan also a significant diminution of MI mortality was observed. Our results indicate that bosentan has an important effect on leptin concentration in ischemic cardiovascular pathology.     

PDCD4在野百合碱诱导肺动脉高压大鼠的表达及波生坦的干预机制

目的研究凋亡相关基因程序性细胞死亡因子4（PDCD4）蛋白在野百合碱诱导肺动脉高压大鼠中的表达并探讨波生坦对其干预机制。方法 SD大鼠正常对照组（N组,n=9）,不做任何处理。14只SD大鼠通过腹腔内注射野百合碱（60mg/kg）两周后,随机将大鼠分成2组,肺动脉高压模型对照组（M组,n=7）和波生坦组（B组,n=7）,分别通过胃管予以安慰剂或波生坦[200mg/（kg.d）]治疗,每天1次,共3周。测量血流动力学参数,观测肺血管和右室组织病理学改变,Western blot法测定肺组织中PDCD4和p-ERK1/2蛋白的表达。结果与N组相比,M组大鼠肺组织PDCD4蛋白表达明显减少、p-ERK1/2蛋白表达明显增加（P均〈0.001）。与M组相比,B组的平均肺动脉压和肺小动脉中膜平滑肌厚度均明显减少,肺组织PDCD4蛋白表达明显增加、p-ERK1/2蛋白表达明显减少（P均〈0.01）。结论 PDCD4蛋白在野百合碱诱导肺动脉高压大鼠中的表达减少,而波生坦可能经p-ERK1/2信号途径增加PDCD4蛋白表达从而降低肺动脉高压、减轻血管平滑肌细胞增殖,逆转肺血管重构的发生。     

波生坦治疗肺动脉高压疗效与安全性评价的Meta分析

目的根据现有随机对照临床试验,综合评价波生坦治疗肺动脉高压的疗效与安全性。方法在数据库中检索以肺动脉高压患者为研究对象,并进行了波生坦治疗(治疗组)与安慰剂(安慰剂组)比较的随机对照试验(RCT)研究,对其短、长期疗效和安全性进行Meta分析。结果(1)有2项研究进行了短期疗效与安全性评价。与安慰剂组比较,治疗组患者:①6min步行距离平均增加了47.71m(95%CI为26.09~69.33,P<0.0001);②WHO心功能分级改善率的合并比数比(OR)值为1.84(95%CI为1.06~3.18,P=0.03);③呼吸困难明显改善,Borg呼吸困难评分平均下降0.71分(95%CI为0.19~1.23,P=0.007);④病死率差异无统计学意义,其合并OR值为2.45(95%CI为0.28~21.35,P=0.42);⑤肝损害的发生率差异无统计学意义,其合并OR值为1.78(95%CI为0.66~4.81,P=0.26);⑥临床病情恶化率明显改善,其合并OR值为0.26(95%CI为0.11~0.60,P=0.002)。(2)有2项研究评价了波生坦治疗的长期疗效与安全性:与安慰剂组比较,治疗组患者1年生存率明显改善,其合并OR值为2.57(95%CI为1.59~4.17,P=0.0001);肝损害的发生情况:2项研究均报道了治疗组患者转氨酶明显升高的病例,由于缺乏安慰剂组的资料,未对其进行Meta分析。结论波生坦治疗可以提高肺动脉高压患者的运动能力,改善心功能和呼吸困难的症状,提高患者1年生存率。肝损害可能是其主要副作用。     

Retrospective analysis of the frequency of centrofacial telangiectasia in systemic sclerosis patients treated with bosentan or ilomedin

Background

Bosentan is a dual endothelin receptor antagonist initially introduced for the treatment of pulmonary arterial hypertension and recently approved for the treatment of digital ulcers in patients with systemic sclerosis (SSc). Our clinical observations indicate that bosentan therapy may be associated with an increased frequency of centrofacial telangiectasia (TAE). Here, we sought to analyze the frequency of TAE in patients with SSc who were treated with either bosentan or the prostacyclin analog iloprost.

Methods

We conducted a retrospective analysis in 27 patients with SSc undergoing therapy with either bosentan (n = 11) or iloprost (n = 16). Standardized photodocumentations of all patients (n = 27) were obtained at a time point ten months after therapy initiation and analyzed. A subgroup of patients (bosentan: n = 6; iloprost: n = 6) was additionally photodocumented prior to therapy initiation, enabling an intraindividual analysis over the course of therapy.

Results

After ten months of therapy patients with SSc receiving bosentan showed a significantly (P = 0.0028) higher frequency of centrofacial TAE (41.6 ± 27.8) as compared to patients with SSc receiving iloprost (14.3 ± 13.1). Detailed subgroup analysis revealed that the frequency of TAE in the bosentan group (n = 6 patients) increased markedly and significantly (P = 0.027) by 44.4 after ten months of therapy (TAE at therapy initiation: 10.8 ± 5.1; TAE after ten months of therapy: 55.2 ± 29.8), whereas an only minor increase of 1.9 was observed in the iloprost group (n = 6 patients; TAE at therapy initiation: 18.3 ± 14.5; TAE after ten months of therapy: 20.2 ± 15.5), yet without reaching statistical significance (P = 0.420).

Conclusions

The use of bosentan may be associated with an increased frequency of TAE in patients with SSc. Patients should be informed about this potential adverse effect prior to therapy. Treatment options may include camouflage or laser therapy.     

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疗效观察

目的探讨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。方法选取2013年1月—2015年1月在聊城市第二人民医院心胸外科接受治疗的先天性心脏病术后肺动脉高压患者76例,随机分为对照组和治疗组,每组各38例。对照组口服盐酸伐地那非片,20 mg/次,1次/d。治疗组在对照组的基础上口服波生坦片,根据患者体质量给药,体质量10 kg:15.625 mg/次;体质量10~20 kg:31.25 mg/次;体质量21~40 kg:62.5 mg/次,1次/d。两组患儿均治疗6个月。观察两组的临床疗效,同时比较治疗前后两组呼吸困难评分(Borg评分)、脑钠尿肽(BNP)、心脏功能分级(NYHAFC)、血氧饱和度(SpO_2)、6 min步行实验距离(6 MWTD)及右心导管检查结果变化情况。结果治疗后,对照组和治疗组的总有效率分别为73.68%、92.11%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者Borg评分、BNP及NYHAFC均明显降低,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的下降幅度优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者肺动脉收缩压(s PAP)、肺动脉平均压(mPAP)、肺动脉收缩压/体循环动脉收缩压(Pp/Ps)均明显降低,而肺循环血流量/体循环血流量(Qp/Qs)明显增高,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者Sp O2和6 MWTD均明显增加,同组治疗前后比较差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度优于对照组,两组比较差异具有统计学意义(P0.05)。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具有较好的临床疗效,可提高患者的运动能力,改善患者的心脏功能,缓解呼吸困难症状,具有一定的临床推广应用价值。     

波生坦治疗肺动脉高压42例临床疗效观察

目的 观察波生坦治疗肺动脉高压临床疗效.方法 42例患者口服波生坦14d前、后观察6min步行距离(6MWD),彩色多普勒超声心动图(UCG)测定肺动脉收缩压(PAP)、动脉血气分析,评估心功能的变化.结果 治疗后相关结果均有明显改善,6MWD增加37-139.5(72.3±39.5)m,肺动脉压下降8-37(16.5±8.2)mmHg(1mmHg=0.133kPa),动脉血氧分压(PaO2)上升16-31(22.3±5.8)mmHg;二氧化碳分压(PaCO2)平均下降8-23(14.8±6.7)mmHg,心功能改善提高1级.结论 口服波生坦可以显著改善患者耐力及降低肺动脉压.