Indirect coupling of urate and p-aminohippurate transport to sodium in human brush-border membrane vesicles

[C-14]urate and p-[C-14]aminohippurate (PAH) uptake by human brush-border membrane vesicles (BBMV) were measured in the presence of an inwardly oriented sodium gradient. No direct sodium cotransport was observed. Indirect [C-14]urate coupling to sodium transport was demonstrated by cis-stimulation of [C-14]urate with nicotinate or pyrazinoate (PZA) in the extravesicular medium but not by adding lactate, alpha-ketoglutarate, or beta-hydroxybutyrate. Indirect sodium coupling of [C-14]PAH uptake was observed only when alpha-ketoglutarate was added to the extravesicular medium, a mechanism similar to that of basolateral membranes. The ability for PZA (and nicotinate) to cis-stimulate urate uptake was correlated with a high apparent affinity for the urate/anion exchanger. In urate-loaded vesicles, for identical medium concentrations, [C-14]PZA uptake via the urate-anion exchanger was 10 times higher than [C-14]lactate uptake. Such high PZA affinity for the urate exchanger, working in parallel with PZA sodium cotransport can account for the stimulation of urate reabsorption by PZA in vivo.