SALT-DEPENDENT RENAL EFFECTS OF AN ANGIOTENSIN-II ANTAGONIST IN HEALTHY-SUBJECTS

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n=7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P<.05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P<.05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin 11 antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets. Urinary uric acid excretion increased from 3.5 +/- 0.2 to 11.1 +/- 0.5 mumol/min (P<.01) in salt-depleted subjects and from 3.1 +/- 0.2 to 9.66 +/- 0.6 mumol/min (P<.01) in salt-loaded volunteers. This marked uricosuric effect of losartan was associated with a decrease in plasma uric acid. The time course of these changes in uric acid excretion suggests that it is a property of the parent compound rather than of a metabolite. These results demonstrate that in healthy subjects the angiotensin II receptor antagonist losartan is a natriuretic and kaliuretic compound, in particular during salt depletion. Moreover, losartan promotes uric acid excretion, an effect that appears to be independent of angiotensin II blockade.