The theory of the "four-component model" of urate excretion in humans is reevaluated, considering that a decrease in urate excretion induced by drugs like pyrazinamide or by endogenous compounds like lactate and ketone bodies might be a result of stimulation of urate reabsorption and not, as previously considered, of inhibition of urate secretion.

Several new non-peptide, orally active, angiotensin II receptor antagonists have recently been developed which enable to block the renin-angiotensin system at the AT1 receptor site. In contrast to angiotensin converting enzyme (ACE) inhibitors, these antagonists do not interfere with the metabolism of kinins. The effect of these agents on renal function may thus potentially differ from those of ACE inhibitors. Therefore, the renal pharmacology of various angiotensin II receptor antagonists has been examined in normotensive subjects. In normotensive subjects, losartan and irbesartan have been shown to have no effect on glomerular filtration rate and to induce either no change or a modest increase in renal blood flow. These results were confirmed thereafter in hypertensive patients where losartan produced a renal vasodilation with no change in glomerular filtration. In healthy subjects, both losartan and irbesartan induce an acute increase in urinary sodium excretion. The natriuretic response to losartan is proportionally more important during salt-depletion. In contrast to other angiotensin II receptor antagonists, losartan has a unique property to increase uric acid excretion. In this paper we show that this property is due to the potent inhibitory effect of the parent compound of losartan on the urate/anion transport in the human renal proximal tubule.

Mechanisms of urate transport were investigated in human renal brush-border membrane vesicles. The imposition of an outwardly directed Cl- gradient, in voltage-clamp and pH-clamp conditions, stimulated [14C]urate uptake. Organic anions, including pyrazinoate (PZA), probenecid, lactate, ketone bodies, succinate, and alpha-ketoglutarate in their monovalent forms, cis-inhibited [14C]urate uptake. The affinity order was PZA > urate > probenecid > other anions. Vesicle preloading with these anions trans-stimulated urate uptake. These observations demonstrate the presence of a urate/anion exchanger. p-Aminohippurate and OH- were not substrates for this exchanger. In the presence of an inwardly directed K+ gradient and valinomycin (intravesicular positive potential) [14C]urate uptake was stimulated. Voltage-sensitive [14C]urate uptake was cis-inhibited by organic anions in the following affinity order: urate > probenecid > PZA. The differences in affinity orders for the urate exchanger and the urate voltage-sensitive transport suggest different pathways for apical transport. The anion exchanger might be the main mechanism involved in urate tubular reabsorption in humans.

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The mechanisms involved in urate and p-aminohippurate (PAH) transport in the rabbit renal brush-border membrane were investigated through study of membrane vesicles. Transport of [14C]urate and [3H]PAH was measured by a rapid filtration method. As previously reported by others, no OH(-)-PAH exchanger could be demonstrated by imposing an outwardly directed OH- gradient (pHin 7.4, pHout 6). In contrast, an OH(-)-lactate exchanger (or H(+)-lactate cotransport) was demonstrated. In the presence of valinomycin and an inwardly directed K+ gradient, both [14C]urate and [3H]PAH vesicle uptake were stimulated, demonstrating a potential-driven transport of these two anions. Probenecid, PAH, or cold urate decreased potential-driven urate uptake, suggesting that this transport was facilitated by a specific transport mechanism. The potential-driven urate transport described here may play a role in the second step of urate secretion in rabbits, because rate (or PAH) is transported across the brush-border membrane from the negative interior of the cell to the more positive omen.