Role of Sodium Depletion in Acute Antidiuretic Effect of Bendroflumethiazide in Rats with Nephrogenic Diabetes Insipidus

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Title: Role of Sodium Depletion in Acute Antidiuretic Effect of Bendroflumethiazide in Rats with Nephrogenic Diabetes Insipidus
Authors: Janjua, Nadeem R.; Jonassen, Thomas E.; Langhoff, Susanna; Thomsen, Klaus; Christensen, Sten
Publisher: The Journal of Pharmacology and Experimental Therapeutics
Date Published: October 01, 2001
Reference Number: 560
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Abstract • Article • Translation
The mechanisms underlying the acute antidiuretic response to bendroflumethiazide (BFTZ; 0.25 mg/h for 3 h) in rats with nephrogenic diabetes insipidus (NDI) was investigated. NDI was induced in conscious chronically instrumented female Wistar rats either by chronic lithium administration (40-60 mmol Li/kg of diet for 4 weeks) or by acute infusion of V2 antagonist OPC-31260 (0.2 mg/h). Renal clearance experiments were performed in conscious rats instrumented with permanent catheters. During experiments total body water content was held constant by i.v. replacement of urine production (V) with 150 mM glucose. One group in addition received i.v. replacement of urinary sodium losses. In both models of NDI, BFTZ-induced antidiuresis was associated with a decrease in the delivery of tubular fluid to the distal nephron, as measured by lithium clearance (C(Li)). Both the antidiuresis and the decrease in C(Li) could be prevented by sodium replacement. BFTZ did not affect distal water handling as measured by V/C(Li). BFTZ did not induce antidiuresis in normal rats with water diuresis. It is concluded that in rats with NDI, thiazide-induced antidiuresis can be entirely explained by a fall in distal delivery of tubular fluid related to sodium depletion. This contrasts the response in rats with central diabetes insipidus, where thiazides in addition increase distal water reabsorption.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Members of the thiazide (TZ) family are known as diuretics, i.e., agents that cause an increase in urinary excretion. However, in patients with NDI, they induce an antidiuretic response. That is, TZs induce a reduction in urinary excretions. Though TZs are routinely used to help NDI patients reduce the urine output, the exact mechanisms of how they do this have not been verified. Researchers have hypothesized that TZs cause a contraction in the volume of fluid outside the kidney cells, and that this leads to a reduction in the amount of fluid that flows from one part of the tiny kidney tubes (called tubules) to the part of the tubules that dilute the fluid. This flow is called distal delivery, i.e., the distribution of fluid to the distal (distant) part of the tubule. Since the amount of urine that flows to the distal tubule is reduced, the urine remains more concentrated and the person does not urinate as much.

Janjua, et al., devised a research model to more closely examine the mechanics of TZ induced urine reduction in NDI patients. They induced NDI in two groups of rats by loading one group with lithium and the other group with an agent that prevented arginine vasopressin (AVP), the hormone that initiates the urine concentrating process, from uniting with its receptor. A third rat group was used as a control. The rats in this group were provided a constant influx of water so they would urinate excessively, but not because they had NDI.

The researchers then created three separate subgroups for both NDI rat groups:

  1. a time control subgroup of rats which received different methods of fluid replacement to balance urine loss;
  2. a group that received the thiazide, bendroflumethiazide (BFTZ) infusion;
  3. a group that received sodium replacement to replace the sodium the rats lost through their urine.

The last subgroup of rats was especially important, for the main dynamic the researchers investigated regarding the antidiuretic effect of TZs was the role sodium depletion played in TZs' ability to reduce urine flow in NDI patients.

The data showed that BFTZ reduced distal delivery in both NDI rat models, and that this was associated with a reduction in urine rate. However, in the rat NDI subgroups that received sodium replacement during the experiment, BFTZ exerted no reduction in urine output. That is, the ability for BFTZ to reduce urine in NDI rats was completely prevented if sodium replacement occurred concurrently. The researchers concluded that the sodium depletion that occurs with BFTZ causes a redistribution of body fluid that causes a reduction in distal delivery leading to a reduction in urine output.