Nagashima K, Kusaka H, Sato K, Karasawa A
Department of Pharmacology, Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka, Japan.
Jpn J Pharmacol. 1994 Jan;64(1):9-17. doi: 10.1254/jjp.64.9.
We investigated the possible renal protective effects of KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), a selective and potent adenosine A1-receptor antagonist, against cephaloridine (CER)-induced acute renal failure (ARF) in rats. ARF was induced by intravenous injection of CER at a dose of 600 mg/kg body weight. KW-3902 at doses higher than 0.01 mg/kg (p.o.) dose-dependently attenuated the decrease of creatinine clearance and the increase of proteinuria in rats with CER-induced ARF. In contrast, furosemide and trichlormethiazide (TCM) increased urinary protein and aggravated the serum parameters. These results suggest that KW-3902 has some advantages over furosemide and TCM when used in combination with CER. In the diuretic study in the rats with established ARF induced by CER, KW-3902, furosemide and TCM caused a significant increase in sodium excretion, whereas acetazolamide was ineffective. These results suggest that the proximal tubule is functionally damaged in rats with CER-induced ARF, in accord with the histological observation demonstrating the degeneration of the proximal tubule. From the fact that KW-3902 induces diuretic action even in CER-induced ARF, it is suggested that KW-3902 acts, directly or indirectly, on the proximal tubule or other tubular sites in the kidney, resulting in the diuretic effect.
我们研究了选择性强效腺苷A1受体拮抗剂KW-3902（8-（去甲金刚烷-3-基）-1,3-二丙基黄嘌呤）对头孢菌素（CER）诱导的大鼠急性肾衰竭（ARF）可能的肾脏保护作用。通过静脉注射600mg/kg体重的CER诱导ARF。剂量高于0.01mg/kg（口服）的KW-3902剂量依赖性地减轻了CER诱导的ARF大鼠的肌酐清除率下降和蛋白尿增加。相比之下，呋塞米和三氯噻嗪（TCM）增加了尿蛋白并加重了血清参数。这些结果表明，KW-3902与CER联合使用时比呋塞米和TCM具有一些优势。在对CER诱导的已建立ARF的大鼠进行的利尿研究中，KW-3902、呋塞米和TCM导致钠排泄显著增加，而乙酰唑胺无效。这些结果表明，CER诱导的ARF大鼠近端小管功能受损，这与显示近端小管变性的组织学观察结果一致。从KW-3902即使在CER诱导的ARF中也能诱导利尿作用这一事实来看，提示KW-3902直接或间接作用于肾脏的近端小管或其他肾小管部位，从而产生利尿作用。
