Concentration-Dependent Inhibitory Effect of Irbesartan on Renal Uric Acid Transporters

Abstract

Hyperuricemia has been associated with hypertension. Approximately 25% of patients with hypertension have hyperuricemia (1), and approximately 30% of patients with hyperuricemia or gout have hypertension (2). Therefore the effects of antihypertensive drugs on serum uric acid (SUA) level, especially angiotensin II-receptor blockers (ARBs), have been scrutinized in recent years. Losartan has been shown to increase urinary uric acid (UA) excretion and decrease SUA level (3). In contrast, other ARBs such as candesartan and valsartan do not have uricosuric activity (4, 5). Thus, it seems that the ability of each ARB to decrease SUA cannot be predicted until the uricosuric activities of all ARBs are examined. In the present study, we focused on another widely-used ARB, irbesartan. One report showed a tendency for irbesartan to decrease SUA level in hypertensive patients with hyperuricemia (6). Therefore we examined the effect of irbesartan on UA transporters involved in regulating SUA level. The UA transporter URAT1 is involved in lumen-to-cytosol reabsorption of UA along the proximal tubule (7). A sugar transport facilitator family member protein GLUT9 (URATv1) functions as an efflux transporter of UA from tubular cells (8) at the basolateral membrane. Mutation of URAT1 or URATv1 is associated with idiopathic renal hypouricemia (7, 9), indicating URAT1 and URATv1 play a dominant role in UA reabsorption and controlling SUA levels. We used Xenopus oocytes expressing URAT1 or URATv1 to examine the cis-inhibitory effects of irbesartan at various concentrations.Cloned human URAT1 and URATv1 were expressed in Xenopus oocytes as described previously (7,8). In brief, defolliculated oocytes were injected with 50 ng of cRNA that was transcribed in vitro using T7 RNA polymerase in the presence of cap analog. After incubation of oocytes in Barth's buffer at 18°C for 2 -3 days, uptake studies were performed in ND 96 buffer (96 mM NaCl, 2 mM KCl, 1.8 mM CaCl 2 , 1 mM MgCl 2 , 5 mM HEPES, pH 7.4) containing 20 μM [ 14 C]UA and ARBs at the indicated concentrations; after 1 h incubation, oocytes were lysed and dried at room temperature. Then the amount of the [ 14 C]UA uptake was measured in a scintillation counter and the uptake rate was determined. For determination of the kinetic parameters, the concentrations of urate were varied from 10 to 1500 μM. Kinetic parameters were obtained by using the Eadie-Hofstee equation. The experiments were performed using 8 -10 oocytes per experiment and repeated three times. All the data are given as the mean ± S.E.M. Student's t-test was used to determine significant differences. A value of P < 0.05 was considered to be significant. Concentration-Dependent Inhibitory Effect of Irbesartan on Renal Uric Acid TransportersMakiko Nakamura Medicine, Tokyo 181-8611, Japan Received March 3, 2010; Accepted July 14, 2010 Abstract. Hyperuricemia is currently recognized as a risk factor for cardiovascular diseases. It has been reported that the angiotensin II-receptor blocker (ARB) losartan decreases...

Novel allelic variants and evidence for a prevalent mutation in URAT1 causing renal hypouricemia: biochemical, genetics and functional analysis

“…10,18,24 Oocyte solubilization was done in 500 ml of 0.0625 N NaOH and final suspension was mixed with 3 ml of ULTIMA GOLD (PerkinElmer, Inc., Waltham, MA, USA) for radioactivity determination using a scintillation counter (LSC-5100; ALOKA, Tokyo, Japan). Eight oocytes were used per experiment with tests repeated three times.…”

Functional Analysis of Human Sodium-Phosphate Transporter 4 (NPT4/SLC17A3) Polymorphisms

“…cRNA synthesis and uptake measurements were performed as previously described (9,10). Briefly, the cDNA was linearized with Xba I, and the cDNA insert transcribed in vitro with the T7 mMESSAGE mMACHINE cRNA synthesis kit (Ambion, Austin, TX, USA).…”

Effects of Irbesartan on Uric Acid Metabolism in Patients with Treated Essential Hypertension

“…Irbesartan has been reported to reduce Sur by inhibiting the uptake of uric acid by both URAT1 and GLUT9 8,12) . The inhibition of URAT1 by irbesartan exceeded those of losartan in vitro.…”

“…CCBs, ACEIs, and α-blockers have been reported to suppress the production of the uric acid precursor hypoxanthine in skeletal muscles 7) . Losartan, specifically, has been reported to decrease Sur by enhancing urinary excretion of uric acid via inhibition of urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) 8) . As uric acid is reabsorbed into the tubular cells via URAT1 and subsequently transported into the blood by GLUT9, loss-offunction mutations of URAT1 or GLUT9 can induce renal hypouricemia 9,10) .…”

“…Experimental studies have shown that irbesartan inhibits both URAT1 and GLUT 9 8) . However, the effect of irbesartan on uric acid metabolism in hypertensive patients with varying levels of urinary uric acid excretion remains unknown.…”