Pollock D M, Polakowski J S
Pharmaceutical Discovery, Abbott Laboratories, Abbott Park, Illinois, USA.
J Am Soc Nephrol. 1997 Jul;8(7):1054-60. doi: 10.1681/ASN.V871054.
The purpose of this study was to determine the effect of chronic ETA receptor blockade, using the orally active antagonist A-127722 in rats with reduced renal mass. The initial series of experiments was designed to characterize the effects of the ETA-selective antagonist A-127722 on arterial pressure and renal function when administered via drinking water over a 4-wk period. Male Sprague-Dawley rats were acclimated to metabolism cages, and baseline 24-h urine collections were obtained. A-127722 was placed in the drinking water at concentrations that delivered doses of 1 to 10 mg/kg per d. The compound had no effect on any of the variables measured, including arterial pressure, food and water intake, urine volume, and sodium and potassium excretion. In a separate group of rats, ETA receptor blockade was verified after 3 d of drinking water containing A-127722. Rats were anesthetized, a jugular vein catheter was inserted for infusions, and a femoral artery catheter was used for monitoring arterial pressure. The pressor response to intravenous injection of Big endothelin-1 (1 nmol/kg, intravenously) was inhibited by > 50% in rats given A-127722 at 10 mg/kg per d, which confirms the efficacy of A-127722 in blocking ETA-mediated responses when placed in drinking water. In an additional series of experiments, rats were anesthetized, the right kidney was removed, and two of three major branches of the left renal artery were ligated. After recovery, rats were returned to their cages and given A-127722 in the drinking water to deliver 1 or 10 mg/kg per d. Control rats underwent the same surgical procedures but were given tap water to drink. After 4 wk, rats that were treated with A-127722 developed similar increases in arterial pressure and urinary protein excretion as rats that received tap water. Therefore, although the ETA receptor antagonist A-127722 can inhibit ETA-mediated hypertension, it has no effect on hypertension produced by a reduction in renal mass. It is concluded that ETA receptor activation does not play a significant role in the functional derangements associated with renal mass reduction in the rat.
本研究的目的是确定使用口服活性拮抗剂A-127722对肾质量降低的大鼠进行慢性ETA受体阻断的效果。最初的一系列实验旨在表征ETA选择性拮抗剂A-127722在通过饮用水给药4周期间对动脉血压和肾功能的影响。雄性Sprague-Dawley大鼠适应代谢笼，并收集24小时基线尿液。将A-127722以每天提供1至10mg/kg剂量的浓度置于饮用水中。该化合物对所测量的任何变量均无影响，包括动脉血压、食物和水摄入量、尿量以及钠和钾排泄。在另一组大鼠中，饮用含A-127722的水3天后验证了ETA受体阻断情况。将大鼠麻醉，插入颈静脉导管用于输注，并使用股动脉导管监测动脉血压。在每天给予10mg/kg A-127722的大鼠中，对静脉注射大内皮素-1（1nmol/kg，静脉内）的升压反应被抑制>50%，这证实了A-127722置于饮用水中时阻断ETA介导反应的功效。在另一系列实验中，将大鼠麻醉，切除右肾，并结扎左肾动脉三个主要分支中的两个。恢复后，将大鼠放回笼中，并给予饮用水中的A-127722以每天提供1或10mg/kg。对照大鼠接受相同的外科手术，但给予自来水饮用。4周后，用A-127722治疗的大鼠与接受自来水的大鼠相比，动脉血压和尿蛋白排泄出现了类似的升高。因此，尽管ETA受体拮抗剂A-127722可以抑制ETA介导的高血压，但它对肾质量降低所产生的高血压没有影响。得出的结论是，ETA受体激活在与大鼠肾质量降低相关的功能紊乱中不发挥重要作用。
