Angiotensin-II stimulates nitric oxide release in isolated perfused renal resistance arteries

 Nitric oxide (NO) has been implicated as a modulator of the vascular effects of angiotensin II (ANG II) in the kidney. We used a NO-sensitive microelectrode to study the effect of ANG II on NO release, and to determine the effect of selective inhibition of the ANG II subtype I receptor (AT1) with losartan (LOS) and candesartan (CAN). NO release from isolated and perfused renal resistance arteries was measured with a porphyrin-electroplated, carbon fiber. The vessels were microdissected from isolated perfused rat kidneys and perfused at constant flow and pressure in vitro. The NO-electrode was placed inside the glass collection cannula to measure vessel effluent NO concentration. ANG II stimulated NO release in a dose-dependent fashion: 0.1 nM, 10 nM and 1000 nM ANG II increased NO-oxidation current by 85±18 pA (n = 11), 148±22 pA (n = 11), and 193±29 pA (n = 11), respectively. These currents correspond to changes in effluent NO concentration of 3.4±0.5 nM, 6.1±1.1 nM, and 8.2±1.3 nM, respectively. Neither LOS (1 μM) nor CAN (1 nM) significantly affected basal NO production, but both AT1-receptor blockers markedly blunted NO release in response to ANG II (10 nM): 77±6% inhibition with LOS (n = 8) and 63±9% with CAN (n = 8). These results are the first to demonstrate that ANG II stimulates NO release in isolated renal resistance arteries, and that ANG II-induced NO release is blunted by simultaneous AT1-receptor blockade. Our findings suggest that endothelium-dependent modulation of ANG II-induced vasoconstriction in renal resistance arteries is mediated, at least in part, by AT1-receptor-dependent NO release. Received: 24 September 1997 / Accepted: 20 October 1997     

Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function

Objective: We studied the pharmacokinetics and pharmacodynamics of single and multiple doses of candesartan cilexetil 8 mg per day in hypertensive patients with different degrees of renal function impairment. Candesartan is an angiotensin II subtype 1 (AT1) receptor antagonist that is administered orally as candesartan cilexetil which is converted in the active compound. Methods: Twenty-three patients were included, divided into groups according to creatinine clearance (cr cl. group A >60 nl · min⁻¹ · 1.73 m⁻², group B 30–60 ml · min⁻¹ · 1.73 m⁻² and group C 15–30 ml · min⁻¹ · 1.73 m⁻²). Results: Trough serum concentrations of candesartan were higher in group C compared with group A. The values did not increase after multiple dosing, indicating absence of accumulation. There was a significant negative correlation between the area under the concentration-time curve extrapolated to time infinity (AUC_inf) and the glomerular filtration rate (GFR) indicating a lower renal clearance of candesartan in patients with impaired renal function. The onset of haemodynamic and hormonal effects was gradual. During the single-dose study blood pressure as well as plasma renin activity (PRA) and angiotensin II were unchanged at peak. At day 5 of the multiple-dose study blood pressure was lower and both PRA and angiotensin II were higher compared with baseline. Conclusion: Although serum trough levels increased during repeated administration and half-life was higher in patients with impaired renal function, candesartan cilexetil at a dose of 8 mg per day does not lead to drug accumulation in these patients. This dose is effective in lowering blood pressure and appears to be suitable for patients with renal function impairment. Received: 3 August 1998 / Accepted in revised form: 19 October 1998     

迪之雅对糖尿病肾病治疗效果的临床研究

目的：探讨迪之雅对糖尿病肾病治疗效果。方法：将100例糖尿病肾病患者,分为糖尿病肾病组1和糖尿病肾病组2,再随机分为迪之雅组和对照组。结果：治疗16周,迪之雅组24h尿蛋白测定、尿β2微球蛋白水平均有明显下降,血清一氧化氮上升,血浆内皮素1水平明显下降。结论：提示迪之雅对糖尿病肾病的治疗能取得较好的效果,从远景上可延缓糖尿病肾病患者的肾功能损害。     

HPLC法测定坎地沙坦酯中有关物质和降解产物

目的　研究坎地沙坦酯原料药中有关物质和降解产物的测定方法。方法　采用高效液相色谱法。色谱系统为 :色谱柱KromasllC18柱 ,流动相 0 0 6mol/L醋酸钠 (冰醋酸调节pH4 5 ) 甲醇 (2 0∶80 ) ,检测波长 2 5 5nm。结论　本法可将原料药有关物质和破坏条件下的降解产物与主药有较好的分离度 ,并对合成中间体进行纯度检查 ,适用于原料的质量控制。     

培哚普利和坎地沙坦联合治疗原发性高血压左心室肥厚和颈动脉重塑疗效观察

目的探讨培哚普利和坎地沙坦联合治疗原发性高血压（EH）患者左心室肥厚（LVH）及颈动脉重塑的疗效。方法将142例伴LVH的EH患者随机分为培哚普利组（n=44）、坎地沙坦组（n=55）和联合治疗组（n=43）。设定目标血压值为收缩压（SBP）〈140mmHg和舒张压（DBP）〈90mmHg。3组患者分别口服起始剂量培哚普利4mg/d、坎地沙坦4mg/d和培哚普利4mg/d加坎地沙坦4mg/d。随访4周,若血压未能达标,则增加剂量,最大剂量为培哚普利8mg/d加坎地沙坦8mg/d。同时3组患者均口服氢氯噻嗪25mg/d,总疗程均为36周。检测治疗前后24h动态血压、心率（HR）、左室舒张末期内径（LVDd）、室间隔厚度（IVST）、左室舒张末期后壁厚度（LVPW）、左室质量指数（LVMI）和心胸比率（CTR）,检测颈动脉内膜-中膜厚度（IMT）、内径（ID）及IMT/ID。结果（1）3组治疗后24hSBP、24hDBP均分别较治疗前显著降低（P〈0.05）,而3组间比较差异无统计学意义（P〉0.05）;（2）3组治疗后LVDd、IVST、LVPW、LVMI、HR和CTR均分别较治疗前显著性降低（P〈0.05）,颈总动脉和颈内动脉IMT减小、ID增加、IMT/ID比值改善（P〈0.05或P〈0.01）,其中联合治疗组疗效最为显著（P〈0.05或P〈0.01）。结论培哚普利和坎地沙坦联合用药在逆转LVH、抑制心脏交感活性及改善颈动脉重塑方面较培哚普利或坎地沙坦单独用药具有更为显著的作用,且这些作用独立于降压疗效之外。     

坎地沙坦对不稳定型心绞痛患者相关炎性因子及预后的影响分析

目的探讨坎地沙坦对不稳定型心绞痛患者相关炎性因子及预后的影响。方法选择不稳定型心绞痛患者80例,随机分为观察组和对照组。对照组采用常规治疗,观察组在对照组基础上应用坎地沙坦。结果观察组治疗后干扰素γ、白细胞介素2水平与对照组治疗后比较,差异有统计学意义(P<0.05);观察组主要心脏不良事件发生率显著低于对照组,差异有统计学意义(P<0.05)。结论坎地沙坦能显著降低不稳定型心绞痛患者不良心脏事件发生率,改善预后,可能与其抑制炎性反应有关。     

坎地沙坦酯片的制备及初步稳定性研究

目的:制备坎地沙坦酯片并优化处方,并对其进行初步稳定性考察。方法:采用Box-Behnken试验设计,以填充剂配比(X1)、崩解剂(X2,%)和润滑剂(X3,%)用量为影响因素,以片重差异(Y1,%)、脆碎度(Y2,%)、崩解时限(Y3,min)、坎地沙坦酯溶出度(Y4,%)为片剂考察指标,得到最优处方;采用f2相似因子法评价自制制剂和参比制剂在溶出介质中的体外溶出行为。通过高温、高湿、光照试验初步考察制剂稳定性。结果:坎地沙坦酯片的最优处方组成为:填充剂一水乳糖与预交化淀粉比例为7∶1、崩解剂交联羧甲基纤维素钠占片重为5.5%,润滑剂硬脂酸镁占片重为0.5%。自制片剂和参比制剂在4种溶出介质中的累积溶出度相似因子f2分别为60.62,73.34,66.95,68.60。结论:制备的坎地沙坦酯片各项指标均符合规定,工艺稳定可靠。     

左旋氨氯地平对阵发性房颤并高血压患者房颤的影响

目的观察左旋氨氯地平对阵发性房颤并高血压患者P波离散度（Pd）、左房内径、高敏C反应蛋白（hs—CRP）水平、房颤发作情况的影响。方法将阵发性房颤并高血压患者100例随机分为治疗组（50例）和对照组（50例）。降压药物治疗组给予左旋氨氯地平,对照组给予坎地沙坦,随访1年,观察治疗前后Pd、左房内径、hs—CRP水平及房颤发作情况。结果至随访结束,在长期应用胺碘酮的患者中,对照组房颤复发17例,占81．0％,治疗组房颤复发22例,占95．7％,两组之间差异无统计学意义（x^2=1．122,P〉0．05）。未长期应用胺碘酮的患者,对照组、治疗组在7-12个月时房颤发作次数均较治疗前减少（t=2．823,P〈0．01;t=2．655,P〈0．05）,但两组之间差异无统计学意义（t=0．594,P〉0．05）。与治疗前比较,对照组、治疗组的Pd、左房内径、hs—CRP均降低（t=4．025-13．546,P〈0．01）,治疗后两组之间Pd、左房内径、hs—CRP比较,差异无统计学意义（t=1．234-1．514,P〉0．05）。结论左旋氨氯地平可减少阵发性房颤并高血压患者房颤的复发,降低Pd、左房内径和hs—CRP水平,其效果与坎地沙坦没有差异。     

银杏达莫注射液联合坎地沙坦酯治疗早期糖尿病肾病的疗效观察

目的探究银杏达莫注射液联合坎地沙坦酯治疗早期糖尿病肾病的临床疗效。方法选取2015年5月—2016年12月在厦门市第五医院进行治疗的236例早期糖尿病肾病,随机分为对照组和治疗组,每组各118例。对照组口服坎地沙坦酯片,1片/次,1次/d。治疗组在对照组治疗基础上静脉滴注银杏达莫注射液,20 m L银杏达莫注射液加入到250 m L生理盐水,1次/d。两组均连续治疗8周。观察两组的临床疗效,同时观察两组治疗前后血肌酐(Scr)、尿素氮(BUN)、24 h尿蛋白(TP/24 h)、总胆固醇(TC)、血流动力学指标的变化情况。结果治疗后,对照组和治疗组的总有效率分别为83.05%、91.53%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者TP/24 h、Scr、BUN、TC、血液黏度、纤维蛋白原均显著降低,同组治疗前后差异有统计学意义(P0.05);治疗后,治疗组TP/24 h、Scr、BUN、TC、血液黏度、红细胞压积、纤维蛋白原低于对照组,两组比较差异具有统计学意义(P0.05)。结论银杏达莫注射液联合坎地沙坦酯治疗糖尿病肾病具有较好的临床疗效,可降低患者尿微量蛋白水平,降低血液黏度,改善肾功能,具有一定的临床推广应用价值。     

HPLC测定坎地沙坦酯氨氯地平片有关物质及降解产物

目的 建立测定坎地沙坦酯氨氯地平片有关物质的高效液相色谱法。方法 采用Inertsil ODS-SP C18（150 mm× 4.6 mm,5 μm）色谱柱,以0.035 mol·L-1 KH2PO4（磷酸调pH 3.0）-甲醇-乙腈为流动相,梯度洗脱,检测波长238 nm,流速1.0 mL·min-1。结果 特异性杂质和破坏条件下产生的降解产物与主药分离较好,3批样品最大单个杂质为坎地沙坦酯杂质B,总杂质均〈0.5%。结论 本法专属性强,灵敏度高,重现性好,能够有效控制产品质量。