Hydrochlorothiazide, amiloride and tolmetin in the treatment of diabetes insipidus of Brattleboro rats

Abstract

To test the effects of hydrochlorothiazide (HCTZ) alone and in combination with amiloride or tolmetin in the treatment of nephrogenic diabetes insipidus, metabolic studies of 12 days each were carried out in 36 male, Brattleboro rats. They were divided into five groups as follows: (A) controls; (B) high dose HCTZ at 6 mg/rat/day; (C) low dose HCTZ at 3 mg/rat/day; (D) HCTZ identical to (C) but with addition of amiloride at 0.6 mg/rat/day; (E) HCTZ identical to (C) but with addition of tolmetin at 40 mg/rat/day. The immediate response to treatment was a significant increase in urinary sodium excretion from mean values (mEq/kg/day) of less than 11 to values higher than 13, except group E with mean value of 12. There was marked increase in urinary potassium excretion (mEq/kg/day), from mean control value of 15.5 to 21.5, 20.8, 18.5 and 17.7 in groups B, C, D and E, respectively. During the last three days of the study, mean urine osmolality (Uosm) and free water reabsorption (T(C)H2O) increased significantly. These indices were higher in groups B, D and E than in group C. Serum osmolality decreased only in groups B, C and D but not in the HCTZ-tolmetin groups. Similarly, serum sodium concentration was significantly lower in groups B, C and D compared to the control and the HCTZ-tolmetin groups. Serum potassium concentration was reduced in all the treated groups, but in both the groups treated with HCTZ-amiloride and HCTZ-tolmetin, the reduction was smaller than the one observed in the high-HCTZ treated group. We conclude that both amiloride and tolmetin provide additive antidiuretic effects, when used in conjunction with thiazides, and serve to abbreviate the thiazide-induced hyperkaliuria and hypokalemia. Amiloride and/or tolmetin when used in combination with HCTZ is, therefore, superior to treatment with HCTZ alone. Finally, in view of the fact that they operate via different mechanisms, these agents may eventually prove to be equally satisfactory alternative therapies in the treatment of nephrogenic diabetes insipidus.