Abstract
Angiotensin II receptor blockers (ARBs) exhibit a range of effects on serum uric acid (SUA) level, and therefore it is important to clarify their influence on renal handling and production of uric acid to understand the mechanism of ARB-induced alteration of SUA level. In vitro studies using cultured cells expressing transporters, such as URAT1, OATs and MRP4, showed that losartan and pratosartan have concentration-dependent cis-inhibitory and trans-stimulatory effects, while other ARBs exhibited only cis-inhibitory or trans-stimulatory effects on uric acid transport via URAT1, which plays a major role in reabsorption of uric acid. ARBs also inhibited uric acid transport by OAT3, which may be involved in tubular secretion across the basolateral membrane of proximal tubular cells. An in vitro study using male Sprague-Dawley (SD) rat renal brush-border membrane vesicles (rBBMVs) showed that several ARBs modulate uric acid transport across the apical membrane of proximal tubular cells. An in vivo study in male SD rats was broadly consistent with the in vitro findings ; for example, pratosartan, which shows a uricosuric effect in humans, increased urinary excretion of uric acid and reduced SUA level. ARBs exhibited no effect on xanthine oxidoreductase (XO) activity at 10μM, demonstrating that they do not affect uric acid production. These results indicate that modulation of the activity of uric acid transporters accounts for the changes of renal handling of uric acid by ARBs, and this in turn results in alteration of SUA level. Different ARBs appear to have different effects on uric acid transporters such as URAT1 and OAT3, leading to differential effects on the disposition of uric acid in kidney.
