The Mechanism of Antidiuresis Associated With the Administration of Hydrochlorothiazide to Patients With Vasopressin-Resistant Diabetes Insipidus*

Abstract

Laragh, Heinemann, and Demartini first reported that the administration of chlorothiazide during water diuresis results in an increased rate of solute excretion without significant changes in the rate of urine flow (1,2 repeatedly confirmed (6-13), and the thiazide derivatives have now attained a place of therapeutic usefulness in patients with vasopressinresistant diabetes insipidus (13).Inhibition of solute reabsorption in the distal nephron alone does not account for the antidiuretic effect of the thiazide derivatives. As indicated above, such inhibition of solute reabsorption would merely increase urinary osmolality without affecting urinary volume. Therefore, the mechanism whereby volume is reduced must reside in some other direct or indirect action of these agents. The results of the present studies are consistent with the view that the antidiuretic effect of hydrochlorothiazide is a consequence of the losses of sodium induced by the agent and is not due to any unique property of the thiazide derivatives. The antidiuresis is enhanced by a low sodium intake. is diminished by a high sodium intake, and may also be produced by mercurial diuretics, despite apparent differences in the site and mode of action of the latter agents. METHODSMultiple studies were performed on four hospitalized male subj ects with vasopressin-resistant diabetes insipidus, ranging in age from seven to, seventeen years. Two were brothers, a third had an affected brother, and all had a history of polyuria and polydipsia dating from infancy. Maximal urine osmolalities after a 17-to 20-hour thirst were less than 100 mOsm per kg in three subjects, and not greater than 130 mOsm per kg in one subject (S. Z.). None of the four subjects demonstrated any increase in urinary concentration when dehydration was followed by the administration of vasopressin. All were free of other renal functional abnormalities. The intakes of sodium were controlled by the addition of weighed amounts of sodium chloride to a standard diet containing 9 mEq of sodium. In all instances in which the effects of hydrochlorothiazide were studied, the drug was administered orally, 25 mg every 8 hours. A mini-1988

Lithium and the antidiuretic hormone.

“…Before lithium treatment in the four animals studied, the excretion of ADH ranged from 0. (Earley & Orloff, 1962).…”

“…The polyuria does not respond to exogenous ADH in the form of DDAVP but clorexolone does reduce urine volume, apparently acting as it would in diabetes insipidus (Earley & Orloff, 1962). Levy, Forrest & Heninger (1973) gave chlorothiazide to a patient with lithium-induced polyuria and found that this reduced the polyuria.…”

“…Hence, in the presence or absence of functioning ADH, less urine will be formed. A low sodium diet would therefore produce the same result or enhance the effect of the diuretics acting on sodium transport in the distal tubule (Earley & Orloff, 1962). In the treatment with diuretics of patients with lithium-induced polyuria, there are obvious dangers in either reducing sodium or water intake severely -both will cause an increase in the serum lithium concentration which could be dangerous (Macfie, 1975 Wied, 1965) and seem identical to those of lithium (Johnson & Barker, 1972).…”

Antidiuretic Effect of Hydrochlorothiazide in Lithium-Induced Nephrogenic Diabetes Insipidus Is Associated with Upregulation of Aquaporin-2, Na-Cl Co-transporter, and Epithelial Sodium Channel

“…However, the mechanism by which thiazide diuretics produce their paradoxic antidiuretic effect in patients or animals with diabetes insipidus is poorly understood. Inhibition of NaCl reabsorption in the distal convoluted tubule alone does not account for the antidiuretic effect of the thiazide diuretics (6).…”

“…Thiazide diuretics paradoxically decrease urine volume and increase urine osmolality presumably by producing a mild sodium depletion (6). The widely accepted hypothesis suggests that thiazide-induced sodium depletion causes a reduction in distal delivery associated with enhanced fractional water reabsorption in the collecting duct (6,7).…”