Cao Z, Cooper M E, Wu L L, Cox A J, Jandeleit-Dahm K, Kelly D J, Gilbert R E
Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg West, Victoria, Australia.
Hypertension. 2000 Oct;36(4):561-8. doi: 10.1161/01.hyp.36.4.561.
The renin-angiotensin system (RAS) and endothelin system may both play a role in the pathogenesis of progressive renal injury. The aims of the present study were 3-fold: first, to explore the possible benefits of dual blockade of the RAS with an ACE inhibitor and an angiotensin type 1(AT1) receptor antagonist; second, to examine the relative efficacy of endothelin A receptor antagonism (ETA-RA) compared with combined endothelin A/B receptor antagonism (ETA/B-RA); and third, to assess whether interruption of both RAS and endothelin system had any advantages over single-system blockade. Subtotally nephrectomized rats were studied as a model of progressive renal injury and randomly assigned to one of the following treatments for 12 weeks: perindopril (ACE inhibitor), irbesartan (AT1 receptor antagonist), BMS193884 (ETA-RA), bosentan (ETA/B-RA), and a combination of irbesartan with either perindopril or BMS193884. Treatment with irbesartan or perindopril was associated with an improved glomerular filtration rate and reductions in blood pressure, urinary protein excretion, glomerulosclerosis, and tubular injury in association with reduced gene expression of transforming growth factor-beta(1) and matrix protein type IV collagen. The combination of irbesartan with perindopril was associated with further reductions in blood pressure and urinary protein excretion. No beneficial effects of either BMS193884 or bosentan were noted. Furthermore, the addition of BMS193884 to irbesartan did not confer any additional benefits. These findings suggest that the RAS but not the endothelin system is a major mediator of progressive renal injury after renal mass reduction and that the combination of an AT1 receptor antagonist with an ACE inhibitor may have advantages over the single agent of RAS blocker treatment.
肾素 - 血管紧张素系统（RAS）和内皮素系统可能在进行性肾损伤的发病机制中均起作用。本研究的目的有三个：第一，探讨用血管紧张素转换酶（ACE）抑制剂和1型血管紧张素（AT1）受体拮抗剂双重阻断RAS的潜在益处；第二，研究内皮素A受体拮抗（ETA - RA）与内皮素A/B受体联合拮抗（ETA/B - RA）相比的相对疗效；第三，评估同时阻断RAS和内皮素系统是否比单系统阻断具有任何优势。将次全肾切除大鼠作为进行性肾损伤模型进行研究，并随机分配至以下治疗组之一，为期12周：培哚普利（ACE抑制剂）、厄贝沙坦（AT1受体拮抗剂）、BMS193884（ETA - RA）、波生坦（ETA/B - RA），以及厄贝沙坦与培哚普利或BMS193884的联合用药。厄贝沙坦或培哚普利治疗与肾小球滤过率改善、血压降低、尿蛋白排泄减少、肾小球硬化和肾小管损伤减轻相关，同时转化生长因子 - β（1）和IV型胶原基质蛋白的基因表达降低。厄贝沙坦与培哚普利联合用药与血压和尿蛋白排泄的进一步降低相关。未观察到BMS193884或波生坦有任何有益作用。此外，在厄贝沙坦中添加BMS193884未带来任何额外益处。这些发现表明，RAS而非内皮素系统是肾质量减少后进行性肾损伤的主要介质，并且AT1受体拮抗剂与ACE抑制剂联合使用可能比单一的RAS阻滞剂治疗具有优势。
