Fujimura A, Shiga T, Kajiyama H, Ohashi K, Ebihara A
Department of Clinical Pharmacology, Jichi Medical School, Tochigi, Japan.
Life Sci. 1991;49(13):931-7. doi: 10.1016/0024-3205(91)90075-m.
We have previously demonstrated a time-dependent variability in the diuretic effects of trichlormethiazide, a thiazide diuretic agent, in young rats. The study suggested that the time-dependent variations in urinary trichlormethiazide and susceptibility of renal tissues to the agent might be involved in this phenomenon. The present study was undertaken to test a hypothesis that such a daily variation in the effects of trichlormethiazide is blunted by age. Trichlormethiazide (0.5 and 2.0 mg/kg) was given orally at 1200 hrs (day trial) or at 2400 hrs (night trial) in young (10-11 week old) and aged (23-24 month old) Wistar rats. Urine was collected for 8 hours after the agent and urinary excretions of sodium, chloride and trichlormethiazide were determined. Urine volume and urinary excretions of sodium, chloride and trichlormethiazide following the agent were significantly greater at 1200 hrs than at 2400 hrs in the young rats. However these administration time-dependent changes in the effects of trichlormethiazide and its urinary amount diminished in the aged rats. In the day and night trials, there were significant correlations between urinary trichlormethiazide and its effects (urine volume, urinary sodium and chloride) in both groups of rats. The regression lines in each parameter of two trials differed in the young, but not in the aged group of rats. These data indicate that the mode of the time-dependent changes in the effects of trichlormethiazide is altered in aged Wistar rats. Dampening of the time-dependent variations in urinary trichlormethiazide and susceptibility to the agent might be involved in these chronopharmacological alterations in aged rats.
我们之前已经证明，噻嗪类利尿剂三氯噻嗪对幼龄大鼠的利尿作用存在时间依赖性变化。该研究表明，尿液中三氯噻嗪的时间依赖性变化以及肾组织对该药物的敏感性可能与这一现象有关。本研究旨在验证一个假设，即三氯噻嗪作用的这种每日变化会随着年龄增长而减弱。在12:00（日间试验）或24:00（夜间试验）给年轻（10 - 11周龄）和老年（23 - 24月龄）的Wistar大鼠口服三氯噻嗪（0.5和2.0 mg/kg）。给药后收集8小时尿液，测定钠、氯和三氯噻嗪的尿排泄量。年轻大鼠在12:00给药后，尿液量以及钠、氯和三氯噻嗪的尿排泄量显著高于24:00给药后。然而，在老年大鼠中，三氯噻嗪作用及其尿量的这些给药时间依赖性变化减弱。在日间和夜间试验中，两组大鼠尿液中三氯噻嗪及其作用（尿量、尿钠和尿氯）之间均存在显著相关性。年轻组大鼠两次试验各参数的回归线不同，但老年组大鼠则无差异。这些数据表明，老年Wistar大鼠中三氯噻嗪作用的时间依赖性变化模式发生了改变。老年大鼠中这些时辰药理学改变可能与尿液中三氯噻嗪时间依赖性变化的减弱以及对该药物敏感性的降低有关。
