Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

Abstract

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 ^unol/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 /tmol/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 II 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 /imol/min (P<.01) in salt-depleted subjects and from 3.1 ±0.2 to 9.66±0.6 /tmol/min (/ > <.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.

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

“…Participants were instructed not to smoke or to drink alcohol or any caffeine-containing beverages during that day. On the following day, the participants were investigated in the research unit, after an overnight fast, to undergo clearance studies as reported previously [12]. In brief, two intravenous catheters were inserted into antecubital veins, one for the infusion of sinistrin (an analogue of inulin) and para-aminohippurate (PAH) and a second into the contralateral forearm for drawing blood.…”

Comparative effects of chronic ACE inhibition and AT1 receptor blocked losartan on cardiac hypertrophy and renal function in hypertensive patients

“…In parallel to these changes in urinary uric acid elimination, plasma uric acid has been shown to decrease significantly after an acute or repeated administration of losartan. 24 Indeed, in salt-loaded volunteers, losartan has been shown to induce an increase in urinary potassium excretion instead of an expected decrease, due to inhibition of aldosterone secretion. 24 …”

“…24 Indeed, in salt-loaded volunteers, losartan has been shown to induce an increase in urinary potassium excretion instead of an expected decrease, due to inhibition of aldosterone secretion. 24 …”

Effects on Uric Acid Metabolism of the Drugs except the Antihyperuricemics

“…Captopril and enalapril increased uric acid excretion, and captopril significantly reduced serum uric acid in hypertensive patients with hyperuricemia [47], while it has been reported that ACEinhibitors have not been associated with lower serum uric levels [48,49]. Angiotensin II receptor blocker (ARB), losartan increased excretion of uric acid and decreased the serum uric acid level in both healthy and hypertensive subjects [50][51][52]. After 100 mg administration of losartan, plasma concentrations of uric acid decreased by 8% and 16%, at 1.5 and 2.5 hour, respectively.…”