Effects of the specific angiotensin II receptor antagonist losartan on urate homeostasis and intestinal urate transport.
Possible mechanisms for the hypouricemic effects of the angiotensin II receptor antagonist losartan were examined using rats with experimental chronic renal failure (CRF) and control animals. The results show that losartan has a uricosuric effect in rats with normal or decreased renal function. Renal clearance of urate was increased 3-fold in CRF rats and 2-fold in control rats after 7 days of intraperitoneal losartan administration. Although the results show that losartan and its metabolite EXP-3174 alter urate and Cl- transport across isolated short-circuited intestine, these agents do not promote urate secretion into the intestinal lumen. Unidirectional urate and Cl- fluxes were reduced across normal rat colon and unaltered in the small intestine in the presence of losartan. In CRF rat colon, net secretion of urate and Cl- was abolished after losartan addition at 10(-5) M. Transport across the small intestine of CRF rats did not change in the presence of a similar concentration of drug. Losartan treatment of CRF rats before the removal of colonic tissues reversed the basal net secretion of urate to net absorption. These results suggest that the changes in intestinal transport observed in the presence of losartan appear to be mediated via the angiotensin II receptor antagonistic action of this drug. Direct determination of the effects of angiotensin II on urate and Cl- transport across colonic tissues from control animals revealed a significant angiotensin II stimulation of urate secretion. These angiotensin II-induced alterations in transport were inhibitable by losartan.