SB-203220

Mutational analysis based on pharmacological differences between mammalian and amphibian angiotensin II receptors (AT receptors) previously led to construction of a mutant receptor that gained >25000‐fold affinity for the biphenylimidazole, Losartan. This variant frog receptor also bound with high affinity other nonpeptides in the biphenylimidazole chemical class according to the following rank order of potency (expressed in Fmut values = mutant IC50/rAT1b IC50): Losartan, 0.91; L‐162,389, 1.0; L‐163,491, 1.9; L‐158,809, 3.5; L‐163,017, 3.9; SC‐51,316, 3.9. In contrast, the imidazoleacrylic acids, SKF‐108,566 (Fmut = 160) and SB‐203,220 (Fmut = 170), bound with markedly less affinity. Thus, nonconserved residues determining the molecular requirements for biphenylimidazole recognition are conserved in general, but are not identical to nonconserved residues necessary for high affinity binding of imidazoleacrylic acids.

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.