Krause S M, Walsh T F, Greenlee W J, Ranaei R, Williams D L, Kivlighn S D
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
J Am Soc Nephrol. 1997 Jul;8(7):1061-71. doi: 10.1681/ASN.V871061.
Renal insufficiency is a significant complication that occurs after surgical procedures, requiring cross-clamping of the aorta. The mechanism for this renal dysfunction is currently not known, but studies suggest a potential role of endothelin in mediating the insufficiency. Accordingly, the role of endothelin was assessed using the nonpeptidyl, dual ETA/ETB endothelin antagonist L-754,142 in a model of renal insufficiency in the anesthetized dog induced by cross-clamping the suprarenal aorta for 60 min, followed by 2 h of reperfusion. In vehicle-treated animals (saline, n = 8) after 2 h of reperfusion, plasma [ET-1] increased 66% and renal blood flow (RBF) was reduced by 38% compared with baseline. This decline was associated with an 84% increase in renal vascular resistance and a 54% reduction in GFR (baseline, 46 +/- 5 ml/min; 21 +/- 3 ml/min at 2 h; P < 0.01) and sodium reabsorption (baseline, 6.7 +/- 0.7 microEq/min; 3.0 +/- 0.5 microEq/min at 2 h, P < 0.01). After baseline measurements, pretreatment with L-754,142 at 0.3 mg/kg bolus + 0.1 mg/kg per h continuous infusion (low dose; n = 8) or 3.0 mg/kg bolus + 1 mg/kg per h infusion (high dose; n = 8) initiated 45 min before aortic cross-clamp led to a dose-dependent normalization of RBF and renal vascular resistance within 2 h of cross-clamp removal. GFR was also improved and returned to within 75% of baseline (P < 0.01 versus vehicle) by 2 h of reperfusion with L-754,142 (baseline, 55 +/- 5 ml/min; 42 +/- 5 ml/min at 2 h with the high dose). The improvement of GFR with L-754,142 treatment was associated with a preservation of sodium reabsorption compared with vehicle-treated animals. This study supports a role of endothelin in the pathogenesis of renal insufficiency after aortic cross-clamping and demonstrates that pretreatment with the dual ETA/ETB endothelin antagonist L-754,142 preserves RBF and sodium reabsorption, leading to a significant improvement in GFR.
肾功能不全是主动脉交叉钳夹手术后出现的一种严重并发症。目前尚不清楚这种肾功能障碍的机制，但研究表明内皮素在介导肾功能不全中可能起作用。因此，在麻醉犬的肾功能不全模型中，使用非肽类、双重ETA/ETB内皮素拮抗剂L-754,142评估内皮素的作用。该模型通过将肾上主动脉交叉钳夹60分钟，然后再灌注2小时诱导而成。在给予赋形剂处理的动物（生理盐水，n = 8）中，再灌注2小时后，血浆[ET-1]增加66%，肾血流量（RBF）较基线降低38%。这种下降与肾血管阻力增加84%以及肾小球滤过率（GFR）降低54%（基线为46±5 ml/分钟；2小时时为21±3 ml/分钟；P < 0.01）和钠重吸收降低（基线为6.7±0.7微当量/分钟；2小时时为3.0±0.5微当量/分钟，P < 0.01）相关。在进行基线测量后，在主动脉交叉钳夹前45分钟开始用0.3 mg/kg静脉推注+ 0.1 mg/kg每小时持续输注的L-754,142（低剂量；n = 8）或3.0 mg/kg静脉推注+ 1 mg/kg每小时输注（高剂量；n = 8）进行预处理，导致在去除交叉钳夹后2小时内RBF和肾血管阻力呈剂量依赖性恢复正常。用L-754,142再灌注2小时后，GFR也得到改善并恢复到基线的75%以内（与赋形剂处理的动物相比，P < 0.01）（基线为55±5 ml/分钟；高剂量时2小时为42±5 ml/分钟）。与赋形剂处理的动物相比，L-754,142治疗使GFR得到改善，同时钠重吸收得以保留。本研究支持内皮素在主动脉交叉钳夹后肾功能不全发病机制中的作用，并证明用双重ETA/ETB内皮素拮抗剂L-754,142预处理可保留RBF和钠重吸收，从而使GFR显著改善。
