血管紧张素Ⅱ受体拮抗剂对雌性大鼠激素水平影响

目的探讨血管紧张素Ⅱ受体拮抗剂(ARB)-氯沙坦对雌性大鼠的雌二醇E2,促卵泡激素FSH,黄体生成素LH水平的影响,为临床妊高征患者选药提供动物实验依据。方法随机选择18只雌性SD大鼠分为对照组和实验组,灌胃21d后取血。采用酶联免疫方法,测定血清中E2,FSH,LH的含量。结果实验组的E2激素水平显著高于对照组(P<0.005),FSH、LH激素水平两组无显著性差别(P>0.05)。结论氯沙坦可提高雌性大鼠的E2水平,可能对妊娠高血压患者有治疗和妊娠的保护作用;对FSH、LH影响不大,则不会增加其流产风险。     

卡托普利对左心室心肌血管紧张素Ⅱ—1型受体mRNA及其受体蛋白的影响

目的观察卡托普利对左室心肌血管紧张素Ⅱ-1型受体mRNA表达及其受体蛋白的影响,探讨卡托普利逆转左室重构的机制。方法36只大鼠分为假手术组、模型组和卡托普利组,每组12只。采用RT—PCR方法检测心肌组织AT1 mRNA的表达,采用免疫组织化学染色方法观察心肌组织AT1受体蛋白的改变。结果模型组大鼠左心室心肌组织AT1 mRNA表达较假手术组升高（P〈0．01）,卡托普利组左心室心肌组织AT1 mRNA表达较模型组显著下降（P〈0．01）。模型组大鼠左心室心肌组织AT1受体蛋白较假手术组升高（P〈0．01）,卡托普利组左心室心肌组织AT1受体蛋白较模型组显著下降（P〈0．01）。结论压力负荷所致心肌肥厚大鼠左心室心肌中AT1基因转录与AT1蛋白合成水平是升高的;卡托普利对压力负荷所致心肌肥厚大鼠左心室心肌AT1基因转录与翻译水平均有影响。     

卡托普利和氯沙坦对心力衰竭病人血管内皮功能影响的比较

目的 比较卡托普利和氯沙坦对心力衰竭病人疗效和对血管内皮功能的影响。方法：80例心力衰竭病人随机分为卡托普利组（40例）和氯沙坦组（40例）。卡托普利组口服卡托普利12．5mg，tid。氯沙坦组每日口服氯沙坦50mg。均连续用药8wks。结果 卡托普利治疗心力衰竭的总有效率为77．5％，氯沙坦治疗心力衰竭的总有效率为67．5％。两药均有减慢心率、降低血压、减少心肌氧耗、改荐心肌缺血、改善心肌收缩功能的作用。两组血管内皮功能均明显改善。结论 卡托普利和氯沙坦在治疗心力衰竭的同时可改善血管内皮功能。     

氯沙坦对糖尿病大鼠肾脏AT2受体及细胞因子mRNA表达的影响

目的研究氯沙坦对糖尿病大鼠肾脏AT2受体及细胞因子mRNA表达影响.方法SD大鼠随机分成3组对照组、糖尿病组、氯沙坦治疗组(30 mg·kg-1·d-1,ig).实验第8周,应用RT-PCR技术检测大鼠肾皮质血管紧张素Ⅱ2型受体(AT2)、转化生长因子-β1(TGF-β1)、血小板衍化生长因子-B(PDGF-B)、肿瘤坏死因子-α(TNF-α)及Ⅳ型胶原的mRNA表达.同时用放免法检测大鼠肾皮质血管紧张素II(Ang II)含量.结果糖尿病大鼠尿蛋白排泄率(P＜0.01)、肾皮质Ang II水平(P＜0.05)较对照组明显升高;糖尿病组大鼠肾皮质TGF-β1、PDGF-B、TNF-α及Ⅳ型胶原的mRNA表达较对照组大鼠显著增加(P＜0.01);然而,糖尿病组大鼠肾皮质AT2mRNA表达却较对照组显著下降(P＜0.05),氯沙坦治疗能明显降低糖尿病大鼠肾皮质TGF-β1、PDGF-B、TNF-α及Ⅳ型胶原的mRNA表达(均P＜0.05).治疗组AT2的mRNA表达则明显高于对照组(P<0.05)与糖尿病组(P＜0.01).结论糖尿病大鼠肾皮质AT2受体mRNA表达的下调可能与肾组织TGF-β1、PDGF-B、TNF-α及血管紧张素Ⅱ表达的增加有关.氯沙坦激活AT2受体的表达的机制可能与下调肾脏系列细胞生长因子的表达有关.     

血管紧张素Ⅱ受体抑制剂对人卵巢癌细胞抑制作用的研究

目的探讨血管紧张素Ⅱ1型受体拮抗剂(氯沙坦)对人卵巢癌HO89101细胞的体外生长的影响。方法采用体外实验的方法将不同浓度的Losartan作用于HO8910细胞后,运用四甲基偶氮唑蓝(MTT)法观察氯沙坦对HO8910细胞增殖的抑制作用,并采用流式细胞仪分析氯沙坦对HO8910细胞增殖周期的影响。结果①不同浓度的氯沙坦对HO8910细胞有抑制其生长的作用(P<0.05),并呈现剂量依赖性关系;②细胞周期分析显示氯沙坦使HO8910 G0/G1期细胞明显增加,而S和G2/M期的细胞减少,说明细胞被阻滞在G0/G1期,细胞增殖被抑制。结论氯沙坦可以抑制HO8910细胞的体外增殖,细胞被阻滞在G0/G1期,诱导细胞进行程序性死亡。     

卡托普利对糖尿病大鼠心肌组织肾素─血管紧张素系统的影响

在链脲霉素所致糖尿病大鼠模型（链脲霉素７０ｍｇ·ｋｇ－１，ｉＰ）观察了大鼠心肌组织肾素血管紧张素系统（ＲＡＳ）的变化以及血管紧张素转换酶抑制剂卡托普利的治疗作用（４．６ｍｍｏｌ·Ｌ－１卡托普利饮水给药４ｗｋ）。结果表明，糖尿病大鼠较正常大鼠心肌组织ＲＡ、ＡＣＥ活性显著升高（Ｐ＜０．０１），ＡｎｇⅠ、ＡｎｇⅡ、ＡＬＤ含量均明显增加（Ｐ＜０．０１）。卡托普利治疗组大鼠较糖尿病大鼠上述各项指标均有不同程度的降低，其中ＡＣＥ活性和ＡｎｇⅠ、ＡＭⅡ含量的改变有显著性差异（Ｐ＜０．０５，Ｐ＜０．０１），ＲＡ和ＡＬＤ含量改变差异无显著性（Ｐ＞０．０５）。提示：心肌组织ＲＡＳ功能亢进参与了糖尿病性心肌病发病过程。卡托普利对心肌组织ＲＡＳ的抑制作用可能是其减轻糖尿病心肌损害的主要作用机制。     

卡托普利对糖尿病大鼠心肌组织肾素─血管紧张素系统的影响

在链脲霉素所致糖尿病大鼠模型（链脲霉素７０ｍｇ·ｋｇ－１，ｉＰ）观察了大鼠心肌组织肾素血管紧张素系统（ＲＡＳ）的变化以及血管紧张素转换酶抑制剂卡托普利的治疗作用（４．６ｍｍｏｌ·Ｌ－１卡托普利饮水给药４ｗｋ）。结果表明，糖尿病大鼠较正常大鼠心肌组织ＲＡ、ＡＣＥ活性显著升高（Ｐ＜０．０１），ＡｎｇⅠ、ＡｎｇⅡ、ＡＬＤ含量均明显增加（Ｐ＜０．０１）。卡托普利治疗组大鼠较糖尿病大鼠上述各项指标均有不同程度的降低，其中ＡＣＥ活性和ＡｎｇⅠ、ＡＭⅡ含量的改变有显著性差异（Ｐ＜０．０５，Ｐ＜０．０１），ＲＡ和ＡＬＤ含量改变差异无显著性（Ｐ＞０．０５）。提示：心肌组织ＲＡＳ功能亢进参与了糖尿病性心肌病发病过程。卡托普利对心肌组织ＲＡＳ的抑制作用可能是其减轻糖尿病心肌损害的主要作用机制。     

急性压力超负荷后大鼠心肌损伤与血管紧张素Ⅱ的关系

观察大鼠腹主动脉狭窄后心肌形态学动态变化及其与心肌血管紧张素Ⅱ（ＡｎｇⅡ）含量的关系． 结果表明腹主动脉狭窄形成急性压力超负荷后,大鼠心肌出现明显的缺氧性损伤,线粒体数密度减小,肿胀变性,心肌中ＡｎｇⅡ含量迅速升高,一氧化氮（ＮＯ）含量迅速降低． 卡托普利（３０ ｍ ｇ·ｋｇ－ １·ｄ－ １,术前ｐｏ ２ ｄ）可明显抑制急性压力超负荷引起的心肌中ＡｎｇⅡ含量升高和ＮＯ 含量降低,减轻心肌缺氧性损伤． 提示急性压力超负荷所致心肌缺氧性损伤可能与心肌血管紧张素系统活化有关．     

血管紧张素Ⅱ受体拮抗剂的临床应用现状

血管紧张素Ⅱ(AngⅡ)受体(AT)拮抗剂是一类新型降压药.它在受体水平拮抗循环和局部AngⅡ作用,成为当今抗高血压药物治疗的新观念和新方法。据Dotamonitor报道,本世纪抗高血压药的市场将由AT拮抗剂支配。 AT拮抗剂分肽类和非肽类,早期的AT拮抗剂为肽类,如肌丙抗压素(Saralasin),由于必须静脉注射,半衰期极短,因而临床应用受限,目前应用的多为非肽类。AngⅡ有AT1和AT2两种受体,AT1受体与AngⅡ结合产生血管收缩、水钠潴留等有害效应;相反,AT2受体与AngⅡ结合产生血管扩张、促尿钠排泄及利尿等有益效应。目前,临床上应用的或开发中     

Efficacy of angiotensin II type 1 receptor blockade on reperfusion-induced arrhythmias and mortality early after myocardial infarction is increased in transgenic rats with cardiac angiotensin II type 1 overexpression

Angiotensin II induces ischemia/reperfusion (I/R)-induced arrhythmias and blockade of the angiotensin II type 1 receptor (AT1R) may therefore be beneficial in preventing arrhythmias and decreasing mortality after myocardial infarction (MI). Because the AT1R is upregulated after myocardial ischemia, it was hypothesized that the level of AT1R expression would mediate the response to AT1R blockade. Transgenic (TGR) rats that overexpress the human AT1R and Sprague-Dawley rats were used as controls. Total duration of arrhythmia (seconds) after I/R injury was similar in TGR and SD rats (433 +/- 109 vs. 376 +/- 117, p = n.s.). AT1R blockade with losartan decreased total duration of arrhythmia in the TGR rats (433 +/- 110 s-164 +/- 48 s; p < 0.05), whereas it caused a nonsignificant increase in the SD rats (376 +/- 117 s-497 +/- 97). In vivo, survival in the first 24 hours after MI was impaired in TGR rats (39%; SD, 63%). Losartan improved survival significantly in TGR rats (from 39% to 80%, p < 0.05). A smaller, nonsignificant effect was observed in SD rats (63% to 81%). AT1R blockade is beneficial only when the AT1R was overexpressed, both in reducing the reperfusion-induced arrhythmias and mortality early after MI.     

Effects of angiotensin II type 1 receptor antagonist,YM358, on cardiac hypertrophy and dysfunction after myocardial infarction in rats

This study was undertaken to investigate the effects of an angiotensin II type 1 receptor antagonist, YM358 (2,7-diethyl-5-[[2'(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-5H-pyrazolo [1,5-b] [1,2,4]triazole potassium salt monohydrate), on cardiac hypertrophy and dysfunction in rats with heart failure after myocardial infarction (MI). One day after the coronary ligation, rats were randomized, and administered YM358 or vehicle for 2, 4 or 8 weeks. In MI rats, mean blood pressure, left ventricular (LV) systolic pressure, and the first derivative of LV pressure significantly decreased, and LV end-diastolic pressure (LVEDP) markedly increased after 2 to 8 week treatment of YM358. From 2 weeks after the ligation, ratios of cardiac weight and lung weight to body weight (BW) significantly increased, which indicated the progression of cardiac hypertrophy and lung congestion in MI rats. Two weeks after the ligation, YM358 did not improve LV function, although it decreased the elevated LVEDP and cardiac weights/BW ratios 8 weeks after the ligation. These results indicated that long-term treatment with YM358 improves the reduced cardiac function and reduces cardiac hypertrophy after MI, and may be useful for the treatment of congestive heart failure.     

AT1受体拮抗剂和ACEI对大鼠心肌肥厚时AT1mRNA表达的影响

目的探讨血管紧张素lI（AngⅡ）及其受体AT。在心肌肥厚中的作用,研究DMP811（AT,受体拈抗剂）、培哚普利（ACEI）对AngⅡ诱导的心肌肥厚大鼠心肌AT,mRNA表达水平的影响。方法24只6周龄的SD雄性大鼠随机分为4组：正常对照组、AngII组、AngⅡ＋DMP811组、AngⅡ＋培哚普利组,每组6只。分别皮下埋藏装有生理盐水或AngⅡ的渗透微泵。1周后观察心脏质量、心脏质量／体质量的变化,采用反转录聚合酶链反应（RT—PCR）检测心肌AT1mRNA表达情况,并进行比较。结果①输注AngII7d不会明显影响大鼠的体质量,但可使大鼠的心脏质量、心脏质量／体质量显著增加。AngⅡ组较正常对照组心脏质量、心脏质量,体质重明显增加（P〈0．05）;与AngⅡ＋DMP811组、AngⅡ＋培哚普利组相比．AngⅡ组心脏质量、心脏质量／体质量也明显增加,差异具有统计学意义（P〈0．05）,而AngⅡ＋DMP811组、AngII＋培哚普利组的心脏质量、心脏质量／体质量差异无统计学意义（P〉0．05）。②AngⅡ组的ATlmRNA水平较对照组上调（84．5＋3．0）％（P〈0．01）,DMP811、培哚普利药物干预,可使AngⅡ诱导的ATlmRNA的转录上调有效阻断。而AngⅡ＋DMP811组、AngU＋培哚普利组的AT,mRNA水平差异无统计学意义（P〉O．05）。结论心肌肥厚时AT1mRNA的表达水平明显增加,且AngⅡ诱导了AT。mRNA的转录上调。而AngII导致的上述改变能被DMP811、培哚普利有效阻断。为以后防治心肌肥厚提供了重要依据。     

Effects of cimetidine on pharmacokinetics and pharmacodynamics of losartan,an AT1-selective non-peptide angiotensin II receptor antagonist

This was a 2-period randomized, crossover study in 8 healthy males to determine the effects of cimetidine (400 mg q.i.d. for 6 days) on the pharmacokinetics and pharmacodynamic effects of the angiotensin II receptor antagonist, losartan (100 mg). Cimetidine increased the AUC for losartan 18% without affecting the AUC for E-3174, the active metabolite of losartan. The increase in plasma renin activity following losartan was not affected by cimetidine (maximum mean increases 12.6 and 12.1 ng Ang I·ml^–1·h^–1 without and with cimetidine, respectively). These results indicate that cimetidine does not appear to alter the pharmacokinetics or pharmacodynamics of losartan to a clinically significant extent.     

Effects of a novel angiotensin AT(1) receptor antagonist, HR720, on rats with myocardial infarction

We examined the effects of (R)- and (S)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) on the monosynaptic spinal reflex in rats. In intact rats, (R)-8-OH-DPAT (10 microg/kg, i.v.) enhanced the amplitude of the monosynaptic reflex, whereas at 100 microg/kg, it reduced the amplitude. (S)-8-OH-DPAT enhanced the monosynaptic reflex dose-dependently. In spinalized rats, (R)-8-OH-DPAT produced dose-dependent inhibition, but the (S)-enantiomer did not affect the monosynaptic reflex. Pretreatment with spiroxatrine or 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190) inhibited (R)-8-OH-DPAT-induced monosynaptic reflex enhancement in intact rats, as did 5-hydroxytryptamine (5-HT) depletion. Ketanserin reduced the effect of (R)-8-OH-DPAT. These pretreatment regimens had no effect on the monosynaptic reflex depression produced by the (R)-enantiomer in intact and spinalized rats. Pretreatment with prazosin inhibited (S)-8-OH-DPAT-induced monosynaptic reflex enhancement in intact rats, as did noradrenaline and 5-HT depletion. These results suggest that supraspinal 5-HT1A receptors and the descending serotonergic system are involved in the stimulatory effect of (R)-8-OH-DPAT on the monosynaptic reflex, while both the descending serotonergic and noradrenergic systems, the latter acting via alpha1-adrenoceptors, are involved in the effect of the (S)-enantiomer on this reflex.     

Effects of captopril and losartan on myocardial ischemia-reperfusion induced arrhythmias and necrosis in rats.

Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 (AT (1)) receptor blockers improve ischemia-reperfusion induced arrhythmias and infarct size in several animal models. However, the effects of pretreatment with ACEIs or AT (1) receptor blockers on acute myocardial infarct size and arrhythmias are controversial. Thus, we sought to assess the comparative effects of pretreatment with ACEI captopril and AT (1)-receptor blocker losartan on myocardial infarct size and arrhythmias in a rat model of ischemia-reperfusion. We randomly assigned 92 male Wistar rats for arrhythmias ( n= 60) and necrosis ( n= 32) experiments. To produce arrhythmia, the left main coronary artery was occluded for 7 min, followed by 7 min of reperfusion and to produce necrosis, the the left main coronary artery was occluded for 30 min, followed by 120 min of reperfusion. Captopril (3 mg kg (-1)) and losartan (0.2 and 2 mg kg (-1)) were given intravenously 10 min before occlusion. Captopril reduced the incidences of ventricular fibrillation (VF) and mortality associated with irreversible VF, whereas the studied doses of losartan did not. Captopril also decreased the number of ventricular beats on reperfusion. Losartan 2 mg kg (-1) reduced both the number of ventricular premature beats and the incidence of ventricular tachycardia (VT) on reperfusion, while losartan at dose of 0.2 mg kg (-1) had no effect on these arrhythmias. Compared to the control group, both captopril and losartan reduced myocardial infarct size in the rat model of ischemia-reperfusion, but this was statistically significant for captopril only. In this experimental model, although captopril did not reduce the incidence of reperfusion-induced VT, it was more effective than the AT (1)-receptor blocker losartan at preventing mortality associated with irreversible VF and to reduce myocardial infarct size in rat model of ischemia-reperfusion.     

Pharmacological characteristics and clinical application of losartan, an orally active AT1 angiotensin II receptor antagonist]

Losartan is the first orally active angiotensin II receptor type 1 antagonist for a new class of cardiovascular therapeutic agent. Losartan is converted to an active metabolite (E3174) after oral administration in humans and rats. Both losartan and E3174 contribute to the net angiotensin II receptor blockade and produce anti-hypertensive effect. Losartan not only blocks the vasoconstrictive effect of angiotensin II but also inhibits its mitogenic effect; thus losartan is expected to protect against end-organ-damage-related hypertension and chronic heart failure. Unlike angiotensin-coverting-enzyme inhibitor, losartan does not elicit adverse effects of cough and angioneurotic edema by its blockade of angiotensin II receptor. It is also expected to reduce proteinuria in nephropathy. In addition to its blockade of angiotensin II receptor, losartan blocks thromboxane A2 receptor and facilitates excretion of uric acid, although therapeutic importance of these effects are under investigation. In summary, losartan, an angiotensin II type 1 receptor antagonist is a new class of antihypertensive agent and its therapeutic potentials are not merely reduction of blood pressure but total protection from end-organ damage resulting from activation of both the systemic and local renin-angiotensin system.