Adaptation to the natriuretic actions of hydrochlorothiazide, frusemide and amiloride, by rats

Rats treated thrice daily with maximally natriuretic doses of amiloride or of frusemide showed a markedly diminished natriuretic response (adapted) by the third day and complete adaptation to hydrochlorothiazide by the fifth day of treatment. Normal rats supplied with 0.7 % NaCI as drinking fluid and adrenalectomized rats maintained by either a high salt intake or by injections of doca could not adapt to the natriuretic effects of hydrochlorothiazide. There was no adaptation to the effects of these diuretics on K+ excretion. Treatment of rats for eight successive days with amiloride, frusemide or hydrochlorothiazide caused significant elevation of the juxtaglomerular index and hyperactivity in the zona glomerulosa of the adrenal. Treatment for eight days with spironolactone did not produce these changes. The in vitro production of aldosterone was significantly increased in glands taken from animals pretreated for eight days with hydrochlorothiazide: spironolactone did not influence this synthesis. Plasma concentrations of corticosterone were unaffected by eight days of exposure to hydrochlorothiazide, were raised by this exposure to frusemide and were lowered by amiloride. It is considered that the reninangiotensin-aldosterone system plays a rôle in adaptation, over days, to the natriuretic effects of sulphonamide and probably other natriuretic diuretics, in the rat.