Department of Physiology, The Medical School, Shiraz University of Medical Sciences, Shiraz 71365-1689, Iran.
Can J Physiol Pharmacol. 2010 Dec;88(12):1191-201. doi: 10.1139/Y10-098.
The exact mechanism underlying thiazides-induced paradoxical antidiuresis in diabetes insipidus is still elusive, but it has been hypothesized that it is exerted either via Na+-depletion activating volume-homeostatic reflexes to decrease distal delivery, or direct stimulation of distal water reabsorption. This study examined how these two proposed mechanisms actually cooperate to induce an acute bendroflumethiazide (BFTZ)-antidiuretic effect in nephrogenic diabetes insipidus (NDI). Anaesthetized rats with lithium (Li)-induced NDI were prepared in order to measure their renal functional parameters, and in some of them, bilateral renal denervation (DNX) was induced. After a 30 min control clearance period, we infused either BFTZ into 2 groups, NDI+BFTZ and NDI/DNX+BFTZ, or its vehicle into a NDI+V group, and six 30 min experimental clearance periods were taken. During BFTZ infusion in the NDI+BFTZ group, transiently elevated Na+ excretion was associated with rapidly increased urinary osmolality and decreased free water clearance, but Li clearance and urine flow declined in the later periods. However, in the NDI/DNX+BFTZ group, there was persistently elevated Na+ excretion with unchanged Li clearance and urine flow during the experimental period, while alterations in free water clearance and urinary osmolality resembled those in the NDI+BFTZ group. In conclusion, BFTZ initially exerted two direct effects of natriuresis-diuresis and stimulating free water reabsorption at the distal nephron in NDI, which together elevated Na+ excretion and urinary osmolality but kept the urine volume unchanged in the first hour. Thereafter, the resultant sodium depletion led to the activation of neural reflexes that reduced distal fluid delivery to compensate for BFTZ-induced natriuresis-diuresis which, in cooperation with the direct distal BFTZ-antidiuretic effect, resulted in excretion of urine with a low volume, high osmolality, and normal sodium.
噻嗪类药物在尿崩症中引起的反常利尿的确切机制仍不清楚，但据推测，它是通过钠耗竭激活体积调节反射来减少远端输送，或者直接刺激远端水重吸收来发挥作用。本研究检查了这两种拟议的机制如何在肾性尿崩症（NDI）中实际合作诱导急性苯氟噻嗪（BFTZ）抗利尿作用。用锂（Li）诱导的 NDI 麻醉大鼠，以测量其肾功能参数，并在其中一些大鼠中诱导双侧肾去神经（DNX）。在 30 分钟的对照清除期后，我们将 BFTZ 或其载体分别输注到 2 组，即 NDI+BFTZ 和 NDI/DNX+BFTZ 组，以及 NDI+V 组，然后进行 6 个 30 分钟的实验清除期。在 NDI+BFTZ 组中输注 BFTZ 时，短暂的钠排泄增加伴随着尿渗透压的迅速升高和自由水清除率的降低，但在后期 Li 清除率和尿量下降。然而，在 NDI/DNX+BFTZ 组中，在实验期间持续升高的钠排泄伴随着不变的 Li 清除率和尿量，而自由水清除率和尿渗透压的变化与 NDI+BFTZ 组相似。总之，BFTZ 最初在 NDI 中对远端肾单位具有两种直接的排钠利尿和刺激自由水重吸收的作用，这两种作用一起升高了钠排泄和尿渗透压，但在第一个小时内保持尿量不变。此后，钠耗竭导致神经反射的激活，减少远端液体输送以补偿 BFTZ 诱导的排钠利尿，这与直接的远端 BFTZ 抗利尿作用合作，导致排出的尿液具有低体积、高渗透压和正常钠。
