Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure.
Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure.
复制标题
血管紧张素抑制对慢性肾衰竭血管病变的血压独立作用。
DOI：
10.1038/ki.1992.259
复制
发表时间：
1992
影响因子：
19.6
通讯作者：
Fogo,A
中科院分区：
文献类型：
--
作者：
Kakinuma,Y;Kawamura,T;Bills,T;Yoshioka,T;Ichikawa,I;Fogo,A
血管紧张素抑制剂对慢性肾功能衰竭血管病变的血压非依赖性作用。先前在进行性肾衰竭实验模型中的研究表明，抗高血压药物保护肾小球免受硬化的能力通常无法从其对全身血压的影响中预测。本研究旨在确定抗高血压药物，特别是血管紧张素II转换酶抑制剂（ACEI）的这种不依赖于全身血压的结构保护作用是否仅限于肾小球，以及这种作用是否通过血管紧张素II（Ang II）介导。在肾大部切除术（sNPX）的大鼠模型中使用以下实验药物方案：所谓的三联疗法[TRX;利血平5 mg/L饮用水（DW）、肼苯哒嗪80 mg/L DW和氢氯噻嗪25 mg/L DW的组合]，或ACEI（captopril，CPL，600 mg/L DW，enalapril，ENL，400 mg/L DW或lisinopril，LSL，200 mg/L DW），或新的Ang II受体拮抗剂（Ang IIR，L-158，809，20 mg/L DW）。这些剂量在初步研究中被确定为在长达12周的早期阶段控制全身血压所需的最低剂量。此外，另一组用较高剂量的L-158，809（80 mg/L DW）治疗，具有等效的全身升压作用。在肾活检后肾次全切除术后8周开始治疗，并在16周时处死动物。在ACEI治疗的大鼠中，颈动脉壁增厚（WT），定义为中膜增厚与外血管壁半径的比值，与正常年龄匹配的对照组相似（所有ACEI治疗的大鼠中为0.073，正常对照组为0.074），显著低于TRX（比值0.118）或未治疗的sNPX（0.130）。更值得注意的是，ACEI治疗大鼠的冠状小动脉WT平均为0.139，分别小于TRX（0.298）和未治疗sNPX对照（0.388）的一半和三分之一。肠系膜动脉WT获得了相似的结果。这些结果与肾小球硬化改变密切相关。在未经治疗的sNPX对照大鼠中，肾小球硬化从活检到尸检标本平均增加了458%。尽管TRX将硬化的增加程度抑制到平均212%，但这种保护作用远低于ACEI。在后者中，从活检到尸检，硬化平均仅增加65%。虽然所有ACEI都比TRX更有效，但在这些剂量下，卡托普利和赖诺普利组的获益最大。血管紧张素Ⅱ受体对肾和肾外结构也有保护作用，低剂量组颈动脉、肠系膜动脉和冠状动脉的硬化指数分别增加34%，WT分别为0.088、0.117和0.112。高剂量具有更大的保护作用，尽管全身压力与低剂量相当。研究结果表明，在控制全身血压所需的最低剂量下，ACEI和Ang IIR在保护肾小球结构方面比其他血管扩张剂更有效。ACEI和Ang IIR的这种更大的结构保护效力不仅限于肾小球，而且延伸到其他全身血管床，在慢性肾功能衰竭中也会发生各种病变。Ang Ⅱ受体和ACEI类似的结果进一步表明，慢性肾功能衰竭时肾小球和肾小球外血管的进行性形态学损害涉及血管紧张素Ⅱ的局部作用。
Blood pressure-independent effect of angiotensin inhibition on vascular lesions of chronic renal failure. Previous studies in experimental models of progressive renal failure have shown that the capacity of antihypertensive drugs to protect glomeruli from sclerosis is often unpredictable from their effect on systemic blood pressure. The present study was undertaken to ascertain whether this systemic blood pressure-independent structure-preserving effect of antihypertensives, particularly angiotensin II converting enzyme inhibitors (ACEI), is confined to the glomerulus or not, as well as whether this effect is mediated via angiotensin II (Ang II). The following experimental drug regimens were used in the rat model of subtotal nephrectomy (sNPX): so-called triple therapy [TRX; a combination of reserpine 5 mg/liter drinking water (DW), hydralazine 80 mg/liter DW and hydrochlorothiazide 25 mg/liter DW], or ACEI (either captopril, CPL, 600 mg/liter DW, enalapril, ENL, 400 mg/liter DW or lisinopril, LSL, 200 mg/liter DW), or a novel Ang II receptor antagonist (Ang IIR, L-158,809, 20 mg/liter DW). These dosages were identified in pilot studies to be the minimum required to control systemic blood pressure in the early phase up to 12 weeks. In addition, a separate group was treated with a higher dose of L-158,809 (80 mg/liter DW) with equipotent systemic pressor effect. Treatment was initiated eight weeks after subtotal nephrectomy following renal biopsy, and animals were sacrificed at 16 weeks. In ACEI treated rats, carotid arterial wall thickening (WT), defined as ratio of media thickening to radius of outer vessel wall, was similar to normal age-matched control (0.073 in all ACEI treated rats, vs. 0.074 in normal control) and significantly less than with TRX (ratio 0.118) or untreated sNPX (0.130). Even more remarkably, coronary arteriole WT in ACEI-treated rats averaged 0.139, a value less than one half and one third of TRX (0.298) and untreated sNPX control (0.388), respectively. Similar results were obtained for mesenteric artery WT. These findings were closely paralleled by changes of glomerular sclerosis. In untreated sNPX control rats, glomerular sclerosis increased from biopsy to autopsy specimens by an average of 458%. Although TRX dampened the degree of increase in sclerosis to on average 212%, this protective effect was far less than that achieved by ACEI. In the latter, sclerosis increased on average only 65% from biopsy to autopsy. Although all ACEIs were more effective than TRX, captopril and lisinopril groups showed greatest benefit at these doses. Ang IIR also protected renal and extrarenal structures with 34% increase of sclerosis index in low dose and WT 0.088, 0.117 and 0.112, respectively in carotid, mesenteric and coronary arteries. Higher dose had greater protective effects, although systemic pressures were comparable to the low dose. The findings indicate that in minimum dosages required for controlling systemic blood pressures ACEI and Ang IIR are more potent than other vasodilators in protecting glomerular structure. This greater structure-preserving potency of ACEI and Ang IIR is not limited to the glomerulus, but extends to other systemic vascular beds, where variable lesions also develop in chronic renal failure. The similar results with Ang IIR and ACEI further indicate that the progressive morphological damage of glomerular and extraglomerular vasculatures in chronic renal failure involves local action of angiotensin II.