Miyanoshita A, Terada M, Endou H
Department of Pharmacology, Faculty of Medicine, University of Tokyo, Japan.
J Pharmacol Exp Ther. 1989 Dec;251(3):1155-9.
Studies were conducted to investigate direct effects of loop diuretics on prostaglandin E2 (PGE2) production using microdissected nephron segments. At first, the effect of indomethacin on the diuretic response to furosemide was re-evaluated in anesthetized rats. Indomethacin significantly attenuated the diuretic, natriuretic and chloruretic effects of furosemide without significantly affecting inulin and p-aminohippurate clearance or filtration fraction. But, in nondiuretic states, indomethacin had no significant effects on these parameters. Furosemide, ethacrynic acid and bumetanide significantly increased PGE2 production in cortical and medullary thick ascending limbs of Henle's loop (P less than .001), but not PGE2 production in the cortical and outer medullary collecting tubules. The effect of furosemide on PGE2 production in CTAL was dose-dependent, and higher concentrations of of furosemide than 10(-6) M significantly increased PGE2 production. On the other hand, chlorothiazide showed no PGE2 productive stimulation in these four nephron segments. This study demonstrates that the enhanced PGE2 production in the thick ascending limb of Henle's loop by furosemide and other loop diuretics is one possible mechanism of these drugs.
本研究旨在利用显微解剖的肾单位节段，探讨袢利尿剂对前列腺素E2（PGE2）生成的直接影响。首先，在麻醉大鼠中重新评估了吲哚美辛对呋塞米利尿反应的影响。吲哚美辛显著减弱了呋塞米的利尿、利钠和利氯作用，但对菊粉和对氨基马尿酸清除率或滤过分数无显著影响。但是，在非利尿状态下，吲哚美辛对这些参数无显著影响。呋塞米、依他尼酸和布美他尼显著增加了亨氏袢皮质和髓质厚升支中的PGE2生成（P<0.001），但未增加皮质和外髓集合管中的PGE2生成。呋塞米对CTAL中PGE2生成的影响呈剂量依赖性，呋塞米浓度高于10(-6) M时显著增加PGE2生成。另一方面，氯噻嗪在这四个肾单位节段中未显示出对PGE2生成的刺激作用。本研究表明，呋塞米和其他袢利尿剂使亨氏袢厚升支中PGE2生成增加是这些药物作用的一种可能机制。
