Nabokov A, Amann K, Wagner J, Gehlen F, Münter K, Ritz E
Department of Internal Medicine, University of Heidelberg, Germany.
Nephrol Dial Transplant. 1996 Mar;11(3):514-20.
Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists.
5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague-Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks.
Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR.
SNX caused a significant (P < 0.01) increase of systolic blood pressure (170 +/- 8.6 mmHg) compared to sham operated controls (131 +/- 5.3 mmHg). Blood pressure was significantly (P < 0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153 +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg). Compared to sham operated rats (0.03 +/- 0.01) glomerulosclerosis index (GSI) was significantly (P < 0.01) higher in the untreated SNX group (0.9 +/- 0.15). Significantly lower GSI was found in Trandolapril treated (0.29 +/- 0.04), BMS 182874 treated (0.36 +/- 0.05), and Ro 46-2005 treated animals (0.45 +/- 0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P < 0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P < 0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower.
Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists interfere with development of glomerulosclerosis by mechanisms which are, at least in part, independent of systemic blood pressure.
慢性肾衰竭实验模型研究表明，内皮素系统在肾瘢痕形成过程中起重要作用。内皮素受体（ETR）拮抗剂可干扰疾病进展，但尚未明确：（i）这是否适用于所有肾损伤模型；（ii）该效应在多大程度上受全身血压调节；（iii）ETAR拮抗剂与ETA/ETBR拮抗剂的效应是否相似。
对雄性Sprague-Dawley大鼠进行手术切除5/6肾组织（SNX）。通过灌胃比较血管紧张素转换酶抑制剂群多普利（0.1毫克/千克/天）、ETAR拮抗剂BMS 182874（30毫克/千克/天）和ETA/ETBR拮抗剂Ro 46-2005（30毫克/千克/天）。实验持续八周。
采用尾容积法测量收缩压。对肾脏进行灌注固定，并通过定量PCR对ET-1以及ETA/ETBR进行形态计量分析。
与假手术对照组（131±5.3毫米汞柱）相比，SNX导致收缩压显著升高（P<0.01）（170±8.6毫米汞柱）。群多普利治疗组血压显著降低（P<0.001）（128±5.3毫米汞柱），但BMS 182874治疗组（153±5.9毫米汞柱）和Ro 46-2005治疗组（167±7.6毫米汞柱）血压未显著降低。与假手术大鼠（0.03±0.01）相比，未治疗的SNX组肾小球硬化指数（GSI）显著升高（P<0.01）（0.9±0.15）。群多普利治疗组（0.29±0.04）、BMS 182874治疗组（0.36±0.
