Shinkawa T, Yamasaki F, Notsu T, Nakakuki M, Nishijima K, Yoshitomi K, Imai M
Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan.
Eur J Pharmacol. 1993 Jul 20;238(2-3):317-25. doi: 10.1016/0014-2999(93)90863-d.
We investigated the mechanism of action of a novel 'high ceiling' diuretic, M17055, in in vivo clearance studies with anesthetized dogs during water diuresis and in vitro microperfusion studies of isolated rabbit renal tubules. In the clearance study, intravenous infusion of M17055 (1 mg/kg per h) decreased free water clearance and increased urinary excretion of Na+ and Cl- to a greater extent than did a maximum dose of furosemide (30 mg/kg per h). With the maximum dose of furosemide, an additional dose of M17055 or hydrochlorothiazide resulted in additional suppression of free water clearance. These results indicate that M17055 has some additional mechanisms of action in the distal nephron. In isolated rabbit cortical thick ascending limb of Henle's loop, M17055 applied to the lumen decreased the lumen positive transepithelial voltage at concentrations over 10(-6) M and suppressed the lumen-to-bath 36Cl- flux at 10(-5) M. In the connecting tubule, M17055 added to the lumen suppressed lumen negative transepithelial voltage in a concentration-dependent manner in a range from 10(-4) to 10(-3) M. The effect of M17055 on transepithelial voltage was also observed in the distal convoluted tubule and cortical collecting duct. Moreover, 10(-3) M of M17055 in the lumen significantly decreased the lumen-to-bath 22Na+ flux in the cortical collecting duct. From these observations, it appears that M17055 acts not only on the thick ascending limb of Henle's loop but also on the distal segments via inhibition of electrogenic Na+ transport.
我们在水利尿期间对麻醉犬进行的体内清除率研究以及对分离的兔肾小管进行的体外微灌注研究中，研究了新型“高效能”利尿剂M17055的作用机制。在清除率研究中，静脉输注M17055（1毫克/千克·小时）降低了自由水清除率，并使Na⁺和Cl⁻的尿排泄量增加，其程度比最大剂量的呋塞米（30毫克/千克·小时）更大。使用最大剂量的呋塞米时，额外给予一剂M17055或氢氯噻嗪会导致自由水清除率进一步受到抑制。这些结果表明，M17055在远端肾单位具有一些额外的作用机制。在分离的兔亨氏袢皮质厚升支中，管腔内应用M17055在浓度超过10⁻⁶M时降低了管腔正跨上皮电压，并在10⁻⁵M时抑制了管腔至浴液的³⁶Cl⁻通量。在连接小管中，管腔内添加M17055在10⁻⁴至10⁻³M范围内以浓度依赖方式抑制管腔负跨上皮电压。在远曲小管和皮质集合管中也观察到了M17055对跨上皮电压的影响。此外，管腔内10⁻³M的M17055显著降低了皮质集合管中管腔至浴液的²²Na⁺通量。从这些观察结果来看，M17055似乎不仅作用于亨氏袢皮质厚升支，还通过抑制电生性Na⁺转运作用于远端节段。
