Vallon V, Richter K, Osswald H, Schömig E, Mühlbauer B
Department of Pharmacology, University of Tübingen, Germany.
Naunyn Schmiedebergs Arch Pharmacol. 1998 Aug;358(2):238-44. doi: 10.1007/pl00005248.
We previously described that 1,1'-diisopropyl-2,4'-cyanine (disprocynium24, DP24) exerts an eukaliuric diuresis and natriuresis in the anesthetized rat. The purpose of the present study was to localize the tubular site of action of DP24. Employing micropuncture experiments in anesthetized rats, we first tested the effect of systemic application of DP24 (300 microg/kg + 300 microg/kg h, i.v.) on whole kidney excretion rates as well as on fluid, sodium and potassium ion delivery to the early distal tubule (V(ED), Na+(ED), K+(ED)). It was found that the eukaliuric diuresis and natriuresis in response to DP24 was accompanied by a substantial increase in V(ED) and Na+(ED), suggesting a predominant tubular site of action upstream to the early distal tubule, most likely in the proximal tubule. DP24 caused a comparable fractional, although minor absolute increase in K+(ED) as compared to Na+(ED). Second, application of DP24 into the first surface loop of the proximal tubule significantly increased V(ED) and Na+(ED) at a concentration of about 10(-7) M, indicating that DP24 may act from the intratubular site. Third, microperfusion of tubular segments revealed that effects of DP24 on the proximal convoluted tubule and the loop of Henle accounted for about 70 and 30%, respectively, of its diuretic and natriuretic action upstream to the early distal tubule. With regard to the loop of Henle, the quantitative effect of DP24 on fluid and Na+ reabsorption proposed a predominant effect on the straight part of the proximal tubule rather than the thick ascending limb. Intratubular DP24 did not affect reabsorption in the distal tubule. In summary, the present findings indicate that: (1) the diuretic and natriuretic effect of DP24 resides predominantly in the proximal tubule, and (2) DP24 may act from the intratubular site. Since DP24 increased V(ED) and Na+(ED) without apparently affecting sodium or potassium ion transport in the distal tubule, the mechanism of the eukaliuric response remains unclear.
我们之前曾描述过，1,1'-二异丙基-2,4'-花青（双丙氰花青24，DP24）可使麻醉大鼠产生碱利尿和利钠作用。本研究的目的是确定DP24的肾小管作用部位。在麻醉大鼠中进行微穿刺实验，我们首先测试了静脉全身应用DP24（300μg/kg + 300μg/kg·h）对全肾排泄率以及对早期远端小管的液体、钠和钾离子输送量（V(ED)、Na+(ED)、K+(ED)）的影响。结果发现，DP24引起的碱利尿和利钠作用伴随着V(ED)和Na+(ED)的显著增加，提示其主要作用部位在早期远端小管上游，很可能在近端小管。与Na+(ED)相比，DP24使K+(ED)的相对增加幅度相当，但绝对增加幅度较小。其次，在近端小管的第一表面袢应用DP24，浓度约为10(-7) M时可显著增加V(ED)和Na+(ED)，表明DP24可能从肾小管内位点起作用。第三，肾小管节段微灌注显示，DP24对近端曲管和髓袢的作用分别约占其在早期远端小管上游利尿和利钠作用的70%和30%。关于髓袢，DP24对液体和钠重吸收的定量作用提示其主要作用于近端小管直部而非髓袢升支粗段。肾小管内的DP24不影响远端小管的重吸收。总之，目前的研究结果表明：（1）DP24的利尿和利钠作用主要位于近端小管；（2）DP24可能从肾小管内位点起作用。由于DP24增加了V(ED)和Na+(ED)，但未明显影响远端小管中钠或钾离子的转运，碱利尿反应的机制仍不清楚。
