苯那普利对糖尿病大鼠肾脏细胞凋亡及Fas和Fas-L表达的影响

目的 探讨血管紧张素转换酶抑制剂(ACEI)对糖尿病肾脏细胞凋亡及凋亡相关蛋白的影响。方法 单侧肾切除大鼠腹腔注射STZ(65mg/kg)诱发糖尿病模型，每日灌胃给予ACEI苯那普利(10mg/kg)，共12周。采用原位末端标记法检到肾脏细胞凋亡情况，流式细胞术和免疫组化检到肾皮质Fas和Fas-L表达。结果 糖尿病组较对照组肾小球、肾小管凋亡细胞数明显增多，Fas和Fas-L的表达亦显著增强，苯那普利治疗组较糖尿病组凋亡细胞数减少，Fas和Fas-L的表达减弱。结论 苯那普利可能通过影响凋亡相关蛋白Fas和Fas-L的表达而抑制肾脏细胞凋亡，从而发挥肾脏保护作用。     

苯那普利对2型糖尿病肾病的疗效观察

目的：观察血管紧张素转换酶抑制剂－苯那普利,对2型糖尿病肾病,降低血压、尿蛋白及延缓轻、中度慢性肾功能衰竭（CRF）进展的疗效。方法：根据内生肌酐清除率（Ccr）,将90例糖尿病患者分为无CRF组、轻度CRF、中度CRF组,每组病人再随机分为治疗组和对照组,治疗组加服苯那普利,剂量每天2．5－20mg,服用8周,对照组不用苯那普利。两组分别于治疗前、治疗后8周测血尿素氮（BUN）、血清肌酐（Scr)、Ccr、尿蛋白及24h动态血压。结果：治疗组的收缩压、舒张压、平均动脉压、尿蛋白、BUN、Scr下降,Ccr升高,均明显优于对照组。结论：苯那普利有良好的降低血压及尿蛋白,改善及延缓慢性肾功能衰竭进展的作用。     

培哚普利对实验性糖尿病大鼠肾小管上皮细胞凋亡的影响

目的探讨培哚普利对实验性糖尿病大鼠肾小管上皮细胞凋亡的影响。方法链脲佐菌素（Streptozotocin,STZ）诱导的糖尿病大鼠模型,随机分为糖尿病组和培哚普利治疗组,另以正常大鼠作为对照组,共观察24周。于24周末检测各组大鼠血糖,血压,24 h尿白蛋白定量,肾重/体重。TUNEL检测小管细胞凋亡。免疫组织化学检测肾组织葡萄糖调节蛋白（glucose-reg-ulated protein-78,GRP78）蛋白的表达。结果糖尿病组和治疗组血糖明显高于正常组,但治疗组和糖尿病组差异无显著性。糖尿病模型组尿白蛋白水平均显著高于正常组,培哚普利治疗组尿白蛋白水平较模型组降低。糖尿病模型大鼠肾脏内TUNEL阳性细胞数、内质网应激相关蛋白GRP78的表达水平均较正常组明显升高。培哚普利能明显减少糖尿病大鼠肾脏内TUNEL阳性细胞数并降低内质网应激相关蛋白的表达。结论血管紧张素转换酶抑制剂可以减少实验性糖尿病大鼠肾小管上皮细胞凋亡,可能与其减少内质网应激的激活有关。     

苯那普利对糖尿病肾病患者肾脏保护作用的机制

目的探讨苯那普利对糖尿病肾病慢性肾衰患者血清一氧化氮(NO)、血浆超氧化物歧化酶(SOD)、血浆脂质过氧化物丙二醛(MDA)的影响。方法24例糖尿病肾病慢性肾衰患者分别在使用苯那普利治疗前后检测患者血清NO、SOD、MDA的含量,并比较各指标的变化。结果糖尿病肾病慢性肾衰患者经苯那普利治疗后,血清NO、SOD水平较治疗前增加(P<0.05),MDA水平减少(P<0.05)。结论苯那普利可能通过影响慢性肾衰患者血清NO、SOD、MDA的水平来发挥其保护肾脏,延缓肾衰进展的作用。     

贝纳普利对糖尿病大鼠肾脏中ICAM-1 mRNA和尿微量白蛋白的影响

目的探讨血管紧张素转换酶抑制剂贝纳普利对糖尿病肾脏病变的保护作用和对细胞间粘附分子(ICAM-1)mRNA及蛋白表达的影响.方法STZ诱发大鼠糖尿病,实验设正常组,糖尿病对照组,贝纳普利组和胰岛素治疗组,贝纳普利1.1mg·kg-1·d-1治疗2月,观察肾脏肥大、尿蛋白变化以及用免疫组化和RT-PCR方法检测ICAM-1在肾组织的定位、半定量表达.结果与糖尿病组相比,贝纳普利能显著降低肾重/体重,24h尿微量白蛋白(P<0.01).免疫组化和RT-PCR半定量结果显示贝纳普利能显著降低ICAM-1表达(P<0.01).结论贝纳普利能够降低STZ诱发糖尿病大鼠肾脏组织ICAM-1 mRNA和蛋白表达,对糖尿病肾脏病变有保护作用.     

苯那普利在肾脏病领域中的应用

血管紧张素转换酶抑制剂（ACEI）的出现带来了肾脏病治疗的新时代,它不仅能有效地控制肾性高血压,还能减轻肾脏病变的进展,有效地延缓慢性肾衰（CRF）及防止糖尿病肾病（DN）的发生与ACEI制剂的不断发展,又为临床更加合理地、有选择地应用不同类型ACEI提供了保障,     

苯那普利治疗原发性高血压40例

我们用苯那普利治疗原发性高血压40例,获得满意疗效,现报告如下。1　资料与方法1.1　一般资料　40例中男29例,女11例;年龄44～75岁,平均51岁。病程2～18年,平均6.5年。高血压病期15例,期21例,期4例。合并冠心病6例,高血压心脏病、高脂血症各8例,心衰3例。所有病例排除下列情况:2周内服过降压药,继发性、恶性或进行性高血压,双肾动脉狭窄伴肾功能不全,已知对血管紧张素转换酶(ACEI)类药物过敏或有禁忌,孕妇及服过避孕药的妇女。1.2　诊断标准　按1978年WHO关于高血压病的诊断标准。1.3　治疗与观察方法　所有病例均先停用影响血压的药物,…     

苯那普利治疗糖尿病肾病临床研究

目的：探讨苯那普利(洛汀新)对糖尿病肾病(DN)患者尿蛋白排泄和肾功能的影响。方法：60例DN患者在抗糖尿病的基础上，加洛汀新10—l5mg／d，短期观察10—l5周。结果：10—l5周后，24h尿蛋白及血压明显降低(P＜0.01)，尿蛋白排泄的降低与血压的下降无显著相关，血Cr，BUN，血钾，空腹血糖和24h尿糖无明显变化。结论：洛汀新对DN有较好的保护作用。     

苯那普利对血压正常的早期糖尿病肾病患者尿蛋白及肾功能的评价

苯那普利是非巯基的新一代长效血管紧张素转换酶抑制剂(ACEI)。临床研究证实ACEI有降低尿蛋白及延缓慢性肾功能不全进展的作用。近年有学者提出对正常血压的早期糖尿病患者长期使用ACEI治疗可有效降低尿蛋白而保护肾功能,本研究对苯那普利在正常血压早期糖尿病肾病患者中减少尿蛋白及保护肾功能的长期疗效观察及评价。1资料与方法1.1一般资料:自1999年7月至2007年6月在我院门诊及病房选择血压正常的早期糖尿病肾病患者46例,男性21例,女性25例,年龄37～68岁,平均(49±8)岁。根据1997年世界卫生组织糖尿病诊断标准进行诊断和分型[2],1型2…     

苯那普利对糖尿病大鼠胰岛细胞功能的影响

目的研究苯那普利对糖尿病大鼠胰岛细胞功能的影响。方法采用长期高脂饮食加小剂量链脲菌素（STZ,30mg/kg）腹腔注射建立2型糖尿病大鼠模型,以苯那普利10mg·kg^-1·d^-1进行干预,2个月后行口服葡萄糖耐量试验（OGTT）检测胰岛细胞功能,试剂盒检测胰腺组织丙二醛（MDA）含量及超氧化物歧化酶（SOD）活性,HE染色和免疫组化对胰腺形态学及十二指肠同源框蛋白-1（PDX-1）进行观察。结果DM组大鼠葡萄糖刺激的胰岛素分泌明显延迟,MDA含量（7.10±0.21）nmol/mg较NC组（3.25±0.12）nmol/mg显著升高（P〈0.01）,SOD活性（38.9±2.1）U/mg较NC组（51.01±1.47）U/mg显著降低（P〈0.01）,免疫组化胰岛素染色阳性面积（12.8±2.2）%及PDX-1平均光密度0.240±0.051显著低于NC组[（42.6±2.7）%,（0.648±0.087）nmol/mg]（P〈0.01）,苯那普利干预后胰岛素释放曲线基本接近正常形态,MDA含量（5.87±0.19）nmol/mg较DM组显著降低（P〈0.01）,SOD活性（45.3±1.7）较DM组显著升高（P〈0．01）,免疫组化胰岛素染色阳性面积（18．8±2．7）％及PDX-1平均光密度0．40±0．044较DM组显著增高（P〈0．01）。结论苯那普利可以减轻糖尿病大鼠氧化应激反应,并上调PDX-1的表达,改善胰岛细胞功能。     

HIGH SALT DIET AMELIORATES EFFECTS OF ANGIOTENSIN CONVERTING ENZYME INHIBITION IN SPONTANEOUSLY HYPERTENSIVE STREPTOZOTOCIN DIABETIC RATS

1. To dissociate the effects on the development of diabetic renal injury of angiotensin converting enzyme (ACE) inhibition per se, and a reduction in systemic blood pressure, we have studied the effects of chronic ramapril treatment in streptozotocin diabetic spontaneously hypertensive rats, with modulation of the hypotensive effect by a high salt diet. 2. Three weeks following uninephrectomy and induction of diabetes with streptozotocin, spontaneously hypertensive rats were allocated to three treatment groups. Groups 1 and 2 received 1% sodium chloride and Group 3 water as drinking solution. Groups 2 and 3 received 0.4 mg/kg per day ramapril in drinking solution over the subsequent 2 month study period. 3. Sodium chloride drinking solution (1%) completely prevented any hypotensive effect of ramapril. Blood pressure was reduced in Group 3 rats over the entire period of study, when compared with Group 2 rats (P<0.001). 4. Urinary protein excretion progressively increased in Group 1 and 2 rats, and was significantly reduced (P<0.001) in Group 3. After 2 months treatment, urinary protein (expressed as mean and s.e.m.) was 160±30 mg/day in Group 1, 240±50 mg/day in Group 2, and 60±11 mg/day in Group 3. 5. Angiotensin converting enzyme inhibition per se was not associated with a reduced protein excretion in diabetic nephropathy, requiring concomitant control of systemic blood pressure to become renoprotective.     

SAR1-LEU8-ANGIOTENSIN II REVERSES THE EFFECTS OF CAPTOPRIL ON RENAL FUNCTION IN RATS

In Inactin-anaesthetized rats inhibition of angiotensin converting enzyme by captopril resulted in a small decrease in mean arterial blood pressure accompanied by increases in the rates of glomerular filtration, water and electrolyte excretion. Infusion (100 pmol/min) of sar1-leu8-angiotensin II (sar1-leu8-AII) during continuing converting enzyme blockade reversed these changes in renal function but had no effect on arterial blood pressure. The data indicate that sar1-leu8-AII has partial agonist activity in the kidney although it acts as an antagonist of AII in the systemic circulation. This supports the proposal that angiotensin receptors within the kidney differ from those in the peripheral circulation.     

EFFECTS OF ANGIOTENSINS II AND III ON GLOMERULOTUBULAR BALANCE IN RATS

1. The role of angiotensin as a modulator of proximal glomerulotubular (GT) balance was investigated in anaesthetized rats by examining the relationship between glomerular filtration rate (GFR) and absolute proximal reabsorption (APR) during removal of endogenous angiotensin II (AII) and III (AIII) with enalaprilat (CEI) and then during their subsequent replacement by intravenous infusions. 2. Enalaprilat lowered mean arterial blood pressure (MABP) and increased renal blood flow (RBF), GFR, urine flow rate and sodium excretion. Filtration fraction (FF) was not altered. Absolute proximal reabsorption, derived from fractional lithium clearance, increased by only 48% of the change expected for 'perfect' GT balance. 3. Angiotensin II replacement corrected MABP, GFR and plasma renin level, but reduced RBF and increased FF; APR was decreased and GT balance was restored. Urine flow and sodium excretion remained above control values with AII. 4. Replacement with AIII did not correct the hypotension but completely reversed the renal and renin responses to enalaprilat and restored GT balance without affecting FF. 5. It was concluded that the relation between proximal reabsorption and GFR is considerably modified by the intrarenal angiotensin concentration. The findings are best explained by a direct stimulation of proximal tubular sodium transport by angiotensin at the concentrations existing in anaesthetized rats.     

EFFECTS OF HEPARIN ON VASCULAR DYSFUNCTION IN DIABETIC RATS

1. Treatment with heparin has beneficial effects in diabetic nephropathy. The occurrence of increased urinary albumin excretion in diabetic patients reflects general vascular dysfunction, including increased transcapillary permeability of macromolecules. The aim of the present study was to evaluate the effects of heparin on vascular dysfunction in diabetic rats. 2. Male Sprague-Dawley rats were used in two studies. Diabetes was induced by 65 mg/kg, i.v., streptozotocin. In one study, diabetic rats were dosed subcutaneously with different heparin fractions for 8 months and the transcapillary escape rate of albumin (TERalb) was measured in anaesthetized animals. In the other study, heparin was given for 6 weeks, followed by tissue albumin clearance measurements in awake rats. Normal and diabetic rats receiving saline served as controls. 3. Blood glucose did not differ among the diabetic groups and ranged from 22 to 26 mmol/L. The mean (+/- SD) TERalb was increased by diabetes compared with values in normal rats (17.5 +/- 3 vs 14.1 +/- 3.3%/h, respectively). Neither unfractionated nor low molecular weight heparin significantly affected this increase. [131I]-Albumin clearance was significantly increased in diabetic rats in the eye, skin and skeletal muscle tissues compared with normal rats (0.17-0.40 vs 0.1-0.23 microL plasma/g per min). Low molecular weight heparin treatment did not affect the increased organ albumin clearance. 4. In conclusion, heparin treatment does not affect diabetes-induced vascular dysfunction as expressed by increased TERalb and clearance of albumin in rats.     

ANGIOTENSIN CONVERTING ENZYME IN THE BRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS

1. Angiotensin converting enzyme (ACE) was measured in homogenates of regions of rat brain using the substrate Hip-His-Leu. 2. The enzyme resembled classical ACE in its marked CI” dependence and inhibition by both SQ 20,881 (25 μmol/1) and EDTA (1 mmol/1). 3. Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (NT-WK) were killed at 20-22 weeks of age and their brains dissected into eight regions. 4. There were marked region variations of ACE with highest levels in striatum, hippocampus, cerebellum and pituitary and lower levels in hypothalamus and cerebral cortex. 5. In three brain regions ACE was significantly lower in SHR compared to NT-WK: medulla oblongata (P<0.05), hypothalamus (P<0-02) and cerebral cortex (P < 005). In the other sites the levels were not different. 6. These region-specific differences of ACE in the SHR could lead to altered production or metabolism of central neuropeptides postulated to be involved in the control of blood pressure.     

EFFECTS OF LOW DOSE INFUSION OF ATRIAL NATRIURETIC FACTOR ON ACUTE INHIBITION OF ANGIOTENSIN CONVERTING ENZYME IN NORMAL MAN

1. We have studied the effects of low dose infusions of atrial natriuretic factor (human ANF (99-126), 1.95 pmol/min per kg) on angiotensin converting enzyme (ACE) inhibitor-induced haemodynamic and hormonal changes in healthy subjects. 2. ACE inhibitor (captopril 25 mg, administered orally) was given against a background infusion of physiological saline (placebo day) or ANF (experimental day). 3. Compared with the placebo observations, ANF enhanced the fall in plasma aldosterone concentrations induced by captopril (P less than 0.05). 4. The rise of plasma renin activity following administration of ACE inhibitor which was observed during placebo infusion was abolished by ANF (P less than 0.05). 5. The responses of systemic blood pressure and heart rate to the converting enzyme inhibition were not affected by the infusion of ANF. 6. These results suggest that variations in endogenous circulating ANF may influence, in part, the response of these hormonal levels during ACE inhibition.     

ABNORMALITY OF THE GLOMERULAR ANGIOTENSIN II RECEPTOR IN EXPERIMENTAL DIABETIC NEPHROPATHY

1. The combined effect of diabetes and hypertension on the plasma angiotensin II (AII)/glomerular AII receptor (AII-R) relationship in streptozotocin-induced diabetes was investigated as well as the effect of glycaemic control on this relationship. 2. Diabetes was induced in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with streptozotocin 60 mg/kg and blood sugars maintained between 18–21 mmol/L (uncontrolled diabetes) and 4–8 mmol/L (controlled diabetes). Rats were killed on days 1 and 7. Angiotensin II receptor was estimated by saturation analysis and plasma AII by radio-immunoassay. 3. Angiotensin II receptors were significantly higher in non-diabetic SHR than WKY rats (708 ± 62 and 388 ± 36 fmol/mg protein, respectively, P = 0.0008). Plasma AII were comparable in both groups (47 ± 2.7, 38 ± 3.5 pg/mL, respectively) and a significant inverse relationship between AII/AII-R was observed (WKY P = 0.02 and SHR P = 0.004). 4. On day 7, plasma AII and AII-R levels in diabetic groups were comparable with those of their non-diabetic controls. Diabetic WKY rats maintained an inverse correlation between AII and AII-R (controlled P= 0.04 and uncontrolled P= 0.015), but this did not occur in the SHR. 5. Absence of receptor response to varying ligand concentrations in the diabetic SHR may contribute to the development of nephropathy. Glycaemic control does not appear to reverse this abnormality in the SHR, so that co-existent hypertension may have a more direct influence on renal function.     

EFFECT OF ENALAPRIL TREATMENT ON PROGRESSION OF THE NEPHROTOXIC SERUM NEPHRITIS MODEL OF RENAL FAILURE IN THE RAT

1. Nephrotoxic serum nephritis was induced immunologically in uninephrectomized Sprague-Dawley rats (n = 24). One-half were assigned randomly to treatment with enalapril (5 mg/kg per 24 h). 2. Untreated rats (n = 12) developed a progressive fall in creatinine clearance, a progressive rise in systolic blood pressure and marked proteinuria over a 6 week period. The mortality rate was 42% at 5 weeks and 66% at 6 weeks. 3. Enalapril-treated rats (n = 12) had no significant reduction in systolic blood pressure, and a similar reduction in creatinine clearance to that in untreated rats. Mortality was 50% at 5 weeks, and 92% at 6 weeks. 4. Proteinuria but not the blood pressure rise was significantly reduced by enalapril treatment. 5. Converting enzyme inhibitors may have a specific role in the treatment of nephritic diseases.