Guan Z, Miller S B, Greenwald J E
Department of Medicine, Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri, USA.
Kidney Int. 1995 Jun;47(6):1569-75. doi: 10.1038/ki.1995.220.
Atrial natriuretic factor (ANF) has been demonstrated to be effective in the treatment of acute renal failure (ARF) in both rat and humans. The biological effects of ANF are presumed to be mediated by the generation of intracellular 3',5'-cyclic guanosine monophosphate (cGMP). Therefore, the current investigation examined whether zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, would be effective in the treatment of established acute renal failure in the rat. Acute renal failure was induced by 60 minutes of bilateral renal artery clamping. Twenty-four hours after the ischemic insult, rats received either vehicle (5% Dextrose), zaprinast (0.03 or 0.3 mg/kg/min) or ANF24 (0.2 micrograms/kg/min) intravenously for four hours. Renal function, as measured by daily serum creatinine (days 1 to 7) and day 2 inulin clearances, was dramatically improved by zaprinast but not ANF treatment. Forty-eight hours post-renal ischemia, glomerular filtration rate (GFR) was 0.14 +/- 0.04 (ml/min/100 g body wt) in the vehicle and 0.94 +/- 0.29 in the zaprinast treated animals. To evaluate the mechanism by which zaprinast accelerated renal recovery, we measured regional blood flow in the postischemic rat kidneys during drug treatment with a laser doppler flowmeter. Both high and low dose zaprinast significantly increased cortical (17%) and outer medullary blood flow (40% and 60%), an effect not seen with ANF. In summary, zaprinast is effective in the treatment of established ischemic ARF. The mechanism by which zaprinast accelerates renal recovery is due to its unique ability to stimulate regional renal blood flow and increase intracellular cGMP in the setting of tissue ischemia.
心房利钠因子（ANF）已被证明在大鼠和人类急性肾衰竭（ARF）的治疗中有效。ANF的生物学效应被认为是由细胞内3',5'-环鸟苷单磷酸（cGMP）的生成介导的。因此，本研究检测了扎普司特（M&B 22948），一种鸟苷3',5'-环单磷酸（cGMP）特异性磷酸二酯酶抑制剂，是否对已建立的大鼠急性肾衰竭治疗有效。通过双侧肾动脉夹闭60分钟诱导急性肾衰竭。缺血损伤24小时后，大鼠静脉注射溶媒（5%葡萄糖）、扎普司特（0.03或0.3mg/kg/min）或ANF24（0.2μg/kg/min）4小时。通过每日血清肌酐（第1至7天）和第2天菊粉清除率测定的肾功能，扎普司特治疗后显著改善，而ANF治疗则无此效果。肾缺血48小时后，溶媒组的肾小球滤过率（GFR）为0.14±0.04（ml/min/100g体重），扎普司特治疗组为0.94±0.29。为了评估扎普司特加速肾脏恢复的机制，我们在用激光多普勒血流仪进行药物治疗期间测量了缺血后大鼠肾脏的局部血流。高剂量和低剂量扎普司特均显著增加皮质血流（17%）和外髓血流（40%和60%），ANF则无此作用。总之，扎普司特对已建立的缺血性ARF治疗有效。扎普司特加速肾脏恢复 的机制是其在组织缺血情况下刺激局部肾血流并增加细胞内cGMP的独特能力。
