Interaction of nonpeptide angiotensin II receptor antagonists with the urate transporter in rat renal brush-border membranes.
The angiotensin II (AII) antagonist, losartan, increases uric acid excretion when administered to humans. However, the active metabolite of losartan, EXP 3174, and other nonpeptide AII antagonists such as eprosartan and SB 203220 are devoid of uricosuric activity. To investigate the mechanism of losartan-induced uricosuria, we examined the effects of losartan, EXP 3174, eprosartan and SB 203220 on OH- -dependent [14C]urate uptake into rat proximal tubule brush-border membrane vesicles. Losartan (10 microM) inhibited [14C]urate uptake at all time points examined, except at equilibrium (2 hr). Losartan had no effect on urate uptake in the absence of an OH- gradient. The inhibitory effect of losartan on urate uptake was concentration dependent (IC50 = 9.5 +/- 1.4 microM) and competitive in nature. The other AII antagonists also inhibited urate uptake but were 6-8-fold less potent than losartan with IC50 values of EXP 3174 (65 +/- 13 microM), eprosartan (60 +/- 7.0 microM) and SB 203220 (74 +/- 12.5 microM). In contrast to the effects of the nonpeptide AII antagonists, the peptide antagonist, Sar1,Ile8-AII, as well as AII itself had no effect on urate uptake. These results suggest that the uricosuric activity of losartan is, at least in part, due to inhibition of urate reabsorption in the proximal tubule and is unrelated to AII receptor activity. Furthermore, losartan has a greater affinity for the urate/anion exchanger than the other AII antagonists tested. These results are in direct agreement with observations made after administration of these compounds to humans.
Edwards
R M
RM
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania, USA.
Trizna
W
W
Stack
E J
EJ
Weinstock
J
J
D000179:Acrylates / Q000494:pharmacology; D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000494:pharmacology; D002250:Carbon Radioisotopes; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D007700:Kinetics; D019808:Losartan; D008297:Male; D008871:Microvilli / Q000187:drug effects / Q000378:metabolism; D009281:Naphthalenes / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014527:Uric Acid / Q000493:pharmacokinetics*
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D007093:Imidazoles; D009281:Naphthalenes; D013777:Tetrazoles; D013876:Thiophenes; D000804:Angiotensin II; D014527:Uric Acid; C068373:eprosartan; C009210:sarleucin; C095799:SB 203220; C066026:losartan carboxylic acid; D019808:Losartan