Abstract

Background

The angiotensin receptor blocker losartan inhibited urate transporter 1 (URAT1) according to in vitro experiments. However, it is still unknown whether the inhibitory effect of losartan on URAT1 contributes to its uricosuric action in humans.

Methods

Thirty-two patients with hypertension and nine patients with idiopathic renal hypouricemia (five with and four without hypertension) were enrolled for this study. Hypertensive patients were prescribed oral losartan (50 mg/day, n = 16) or candesartan (8 mg/day, n = 16). Before and after 1-month treatment, the serum concentration of urate (Sur) and creatinine (Scr), and the clearance value of urate (Cur) and creatinine (Ccr) were determined. Clearance studies using the URAT1 inhibitor benzbromarone (100 mg/day) or losartan (50 mg/day) loading test were also performed in these patients.

Results

Blood pressure (BP) significantly decreased in the patients treated with either losartan or candesartan. Losartan significantly reduced Sur, which was associated with a concomitant increase in the Cur/Ccr ratio, whereas candesartan did not alter these parameters. In hypertensive patients with loss-of-function mutation of URAT1, losartan did not alter either Sur or Cur/Ccr, nor did benzbromarone. The lack of effect of URAT1 inhibitors on renal excretion of urate was independent of the renal function of hypouricemic patients. On the other hand, both losartan and benzbromarone increased Cur/Ccr ratio in hypertensive patients harboring the wild URAT1 gene, regardless of the presence of hypouricemia.

Conclusions

These findings suggested that losartan inhibited URAT1 and thereby it lowered Sur levels in hypertensive patients.

The angiotensin II receptor blocker losartan lowers serum concentration of urate (Sur) in hypertensive subjects through a significant uricosuric action.1,2,3,4 This effect has been reported to result from the inhibition of urate/anion transport in brush-border cells of the renal proximal tubules.5,6 Losartan inhibited urate transporter 1 (URAT1: SLC22A12) expressed in Xenopus oocytes, one of the apical urate/anion exchangers that reabsorb urate in the proximal tubules.7,8 However, it is still unknown whether the uricosuric action of losartan in humans depends on the inhibition of URAT1, because several other urate/anion exchangers have been identified in the human kidney.9,10

Loss-of-function mutations of URAT1 cause idiopathic renal hypouricemia due to high urinary urate excretion. Exercise-induced acute renal failure and nephrolithiasis have been reported as complications of hypouricemia.11,12 Neither probenecid nor benzbromarone alters Sur or urinary urate excretion in patients carrying URAT1 mutations, as it would be expected from their inhibitory action on URAT1.11

In this study, we first confirmed the uricosuric action of losartan in hypertensive patients in comparison with candesartan. Second, we examined the effect of losartan and benzbromarone on urinary urate excretion in hypertensive patients with idiopathic hypouricemia with homozygote and compound heterozygote of loss-of-function mutations of URAT1.

Methods

Patients and clearance study in hypertensive patients. Thirty-two untreated hypertensive outpatients (66 years old on average, 24 males) attending Tottori University Hospital, Shinsei Hospital, and Nosaka Clinic (Yonago, Japan) were enrolled for this study. All of them had a systolic blood pressure (BP) > 140 mm Hg and/or a diastolic BP > 90 mm Hg. None of them had gout or urinary calculi, or were they under treatment with oral antidiabetic agents, nonsteroidal anti-inflammatory drugs or fibrates. All the procedures carried out in this study were in accordance with the Helsinki Declaration of 1975 as revised in 1983. All patients provided written informed consent for their participation in the study whose protocol had been authorized by the ethical committee of Tottori University. Clinic BP was measured using a mercury sphygmomanometer and a cuff of appropriate size (in accordance with the 2005 American Heart Association Committee on Blood Pressure Determination). After the patient sat for 5 min, BP was measured three times at 1–2- min intervals, and the mean value was taken as the average BP for that visit.

The patients were randomly assigned to a losartan group (n = 16, 12 males, with an average age of 55) or to a candesartan group (n = 16, 12 males, with an average age of 56). The two treatment groups were comparable in terms of age, BMI, weight, height, baseline sitting BP, fasting plasma glucose levels, serum levels of total cholesterol, and triglycerides.

Everyday at 7:00 AM, one group of patients received oral losartan (50 mg/day), and the other group candesartan (8 mg/day). Urine samples were collected from 8:00 to 10:00 AM and venous blood sample was drawn halfway through each clearance period before and after 1-month treatment; Sur, urine levels of urate, as well as serum and urine levels of creatinine (Scr and Ucr, respectively) were promptly determined. Renal clearance for urate (Cur) and creatinine (Ccr) was determined as described elsewhere.12

Mutation analysis of URAT1 and clearance study of hypertensive patients with idiopathic renal hypouricemia. Five hypertensive outpatients with idiopathic renal hypouricemia (49 years old on average, three men) and four normotensive outpatients with idiopathic renal hypouricemia (all women whose average age was 56) were enrolled for this study. These patients were unrelated and provided written informed consent for the study. Genomic DNA was isolated from peripheral blood cells and the mutations in SLC22A12 encoding URAT1 were surveyed according to the method described by Ichida et al.11

Renal clearance study to determine Cur and Ccr was performed as described elsewhere.12 To reduce the inconvenience to the patients, the clearance study consisted of two single-clearance periods of 2 h each (before administration: from 10:00 to 12:00 AM; after the administration of 100 mg benzbromarone or 50 mg losartan at 12:00 AM; from 1:00 to 3:00 PM), and a venous blood sample was drawn halfway through each clearance period. A month after the benzbromarone test, the patients received 50 mg oral losartan and the same measurements were taken.

Eight hypertensive subjects carrying the wild URAT1 gene matched for age and gender with five hypertensive hypouricemia patients were subjected to the benzbromarone and losartan tests.

To estimate the validity of a single period for the clearance test, we conducted probenecid and losartan loading tests in hypertensive case no. 2 using the multiple-clearance method described by Steele and Rieselbach.13 Each test consisted of two phases: one before and one after the administration of 2 g oral probenecid or 50 mg oral losartan as a single dose. The phase before the administration of the drug consisted of a single-clearance period of 30 min. A venous blood sample was drawn halfway through each clearance phase.14 Oral hydration with 500 ml water before each study was promoted to obtain a sufficient volume of urine (>1 ml/min) and thereby avoid bladder catheterization, changes in glomerular filtration rate, and urate reabsorption into renal tubules throughout the clearance study. The various parameters related to the handling of urate such as Cur, Ccr, and the Cur/Ccr ratio were calculated as described previously.14

Statistical analysis. Data are expressed as the mean ± s.e. Differences with a P value of <0.05 were considered statistically significant. Two-way analysis of variance with repeated measures was performed to analyze the effects of losartan and candesartan. Wilcoxon's test was used to assess the effect of losartan on hypouricemic patients.

Results

Effects of losartan and candesartan on BP and renal excretion of urate in hypertensive patients

Systolic BP in the sitting position significantly decreased in the losartan group (158 ± 3/89 ± 3 mm Hg to 138 ± 4/77 ± 2 mm Hg, P < 0.01) and candesartan group (165 ± 5/90 ± 2 mm Hg to 143 ± 4/79 ± 3 mm Hg, P < 0.01). There were no statistical differences in the pre- and postadministration values between the two groups. All patients carried the wild-type SLC22A12 gene.

There were no statistical differences in the baseline values of Scr (0.93 ± 0.05 and 0.88 ± 0.04 mg/dl in the losartan- and candesartan-treatment groups), Sur (6.7 ± 0.3 and 6.6 ± 0.3 mg/dl, respectively), Cur (4.62 ± 0.61 and 5.23 ± 0.49 ml/min/ 1.73 cm2, respectively), or Ccr (70.1 ± 6.0 and 70.2 ± 6.3 ml/min/1.73 cm2, respectively between the two groups). Losartan induced a significant reduction in Sur (6.7 ± 0.3 to 6.1 ± 0.3 mg/dl, P < 0.01), whereas candesartan did not (6.6 ± 0.3 to 6.7 ± 0.4 mg/dl). Losartan induced a significant increase in Cur (4.62 ± 0.61 to 6.33 ± 0.74 ml/min/1.73 cm2, P < 0.01). Cur/Ccr was significantly elevated in the losartan group (7.0 ± 0.8 to 9.8 ± 1.1%, P < 0.01). However, candesartan did not influence Cur (5.23 ± 0.49 to 4.52 ± 0.54 ml/min/1.73 cm2) or Cur/Ccr (7.9 ± 0.8 to 6.8 ± 0.9%).

Because changes in renal excretion of urate induced by angiotensin receptor blockers might be influenced by renal adaptation during their administration, we reexamined the acute effects of candesartan (before and 2 h after its administration) on renal excretion of urate. Candesartan did not influence Sur (5.2 ± 0.6 to 5.2 ± 0.6 mg/dl), Scr (0.9 ± 0.1 to 0.9 ± 0.1 mg/dl), Cur (9.63 ± 1.43 to 8.71 ± 1.32 ml/min/1.73 cm2), or Cur/Ccr (7.2 ± 1.2 to 7.5 ± 1.3%) measured 2 h after its administration.

Clinical characteristics and URAT1 genes in hypertensive and normotensive patients with idiopathic renal hypouricemia

Table 1 summarizes the SLC22A12 genes and clinical characteristics of five hypertensive patients and four normotensive patients with idiopathic renal hypouricemia. In hypertensive patients, Sur values were ≤2.0 mg/dl (1.1 ± 0.3 mg/dl), and both Cur (38.9 ± 9.6 ml/min/1.73 cm2) and Cur/Ccr values (69.2 ± 4.7%) were significantly elevated. In normotensive patients, Sur values were also ≤2.0 mg/dl (1.5 ± 0.4 mg/dl), and both Cur (35.9 ± 10.1 ml/min/1.73 cm2) and Cur/Ccr values (52.9 ± 13.5%) were significantly elevated. These findings were compatible with the diagnosis of idiopathic renal hypouricemia. Except for C1429A, all other mutations were previously reported to be loss-of-function mutations.7,11 The urate transport activity of the C1429A mutant was significantly decreased as analyzed by expression studies in Xenopus oocytes (data not shown). Case no. 5 in the hypertensive group had hypouricemia associated with excess urate excretion, although she carried the wild-type SLC22A12 gene.

Table 1

Clinical data and SLC22A12 genes of renal hypouricemic patients with or without hypertension

Lack of uricosuric effect of URAT 1 inhibitors in hypouricemic hypertensive patients with URAT 1 mutations

Table 2 shows the effect of benzbromarone and losartan on the renal excretion of urate in four hypouricemic hypertensive patients harboring URAT1 mutations (hypertensive case nos. 1–4 in Table 1). In hypertensive subjects carrying the wild-type URAT1 gene, benzbromarone (100 mg) significantly increased Cur/Ccr from 7.9 ± 0.7 to 40.0 ± 6.0% (P < 0.01, n = 8) and losartan (50 mg) also significantly increased it from 7.0 ± 0.5% to 13.0 ± 3.0% (P < 0.01, n = 8). On the other hand, in hypouricemic hypertensive patients with URAT1 mutations (hypertensive case no. 5 in Table 1), benzbromarone (100 mg) did not cause any alterations in Sur, Scr, Ccr, or Cur. Losartan (50 mg) significantly decreased both systolic BP (from 162 ± 10 to 138 ± 8 mm Hg, P < 0.01) and diastolic BP (from 92 ± 7 to 78 ± 8 mm Hg, P < 0.01), but it did not influence Sur, Scr, Ccr, or Cur. In hypertensive case no. 2, we had previously evaluated the validity of single-clearance test by comparing it with a multiple-clearance test after probenecid administration.12 We reestimated the losartan test in hypertensive case no. 2 using a single- and a multiple-clearance test as shown in Table 3, and found that losartan did not change renal excretion of urate in hypertensive case no. 2, regardless of the clearance tests. In a hypertensive patient with idiopathic renal hypouricemia who harbored the wild-type URAT1 gene (hypertensive case no. 5), both benzbromarone and losartan increased renal excretion of urate, the same as in hypertensive subjects who harbored the wild-type URAT1 gene (Figure 1), excluding the possibility that low levels of serum urate might mask the uricosuric action of these agents.

Table 3

Effect of losartan on renal excretion of urate in a hypouricemic hypertensive patient (no. 2) who carried the mutant URAT1 gene as assessed by multiple- and single-clearance tests

Cur/Ccr ratio in hypertensive patients with homozygous, compound heterozygous SLC22A12 mutations and hypertensive patients carrying the wild-type URAT1 gene after loading tests. (a) Benzbromarone test: hypertensive hypouricemia with homozygote/compound heterozygote of mutant URAT1: n = 4; hypertensive hypouricemia with wild-type URAT1: n = 1; hypertensive subjects with wild-type URAT1: n = 8. (b) Losartan test: hypertensive hypouricemia with homozygote/compound heterozygote of mutant URAT1: n = 4; hypertensive hypouricemia with wild-type URAT1: n = 1; hypertensive subjects with wild-type URAT1: n = 8. **P < 0.01 vs. Cur/Ccr value before loading.

Table 2

Effect of losartan and benzbromarone on renal excretion of urate in hypouricemic hypertensive patients carrying the mutant URAT1 gene

To investigate the influence of impaired renal function on the pharmacological estimation of renal excretion of urate, we distributed eight URAT1-deficient patients (four with and four without hypertension) into those with normal Ccr (n = 4, Ccr = 86.1 ± 9.0 ml/min/1.73 cm2) and impaired Ccr (n = 4, Ccr = 45.1 ± 5.3 ml/min/1.73 cm2), and compared the effects of benzbromarone on renal excretion of urate. As shown in Table 4, benzbromarone did not change renal excretion of urate in these two groups.

Table 4

Effect of benzbromarone on renal excretion of urate in URAT1-deficient hypouricemic patients distributed into those with normal Ccr and those with impaired Ccr

Discussion

In this study, we found that in hypertensive patients the effects of losartan on renal excretion of urate differed significantly from those of candesartan.15,16 Moreover, the lack of a uricosuric response to losartan in patients harboring the mutant URAT1 gene demonstrated the contribution of URAT1 to the uricosuric action of losartan in humans.

We demonstrated that candesartan did not increase urate excretion 2 h after its administration, or after 1 month of treatment. In this regard, we had previously reported that losartan significantly increased urate excretion 2 h after its administration,4 and that the increase was similar after 1 month of treatment. Taken together, these findings show that the effects of these angiotensin receptor blockers on urate excretion are not influenced by renal adaptation.

Urate transport in the kidney involves glomerular filtration, reabsorption, secretion, and postsecretory reabsorption.17 Experimental studies using the human brush-border membrane have shown that urate reabsorption is mediated by urate/anion exchangers, whereas secretion is mediated by voltage-sensitive transporters.11,18,19 URAT1 is involved in transporters for urate reabsorption across the apical luminal membrane of proximal tubules,7 whereas organic anion transporters MRP4 and NPT1 are involved in the secretion.9 Functional experiments using Xenopus oocytes showed that losartan blocked the uptake of urate through URAT1, like benzbromarone or probenecid.8 However, it is still unknown whether losartan induces uricosuria in hypertensive patients harboring the wild-type URAT1 gene. Moreover, renal excretion of urate has not been investigated in URAT1-deficient hypertensive patients given losartan.

Idiopathic renal hypouricemia is an inherited and heterogeneous disorder characterized by impaired tubular urate transport. We could enroll only four hypouricemic patients without hypertension and five hypouricemic patients with hypertension for this study, because renal hypouricemia itself is a rare disease with an incidence of 0.12–0.72%.11 Eight patients, three compound heterozygotes and five homozygotes, carried SLC22A12 mutations as previously identified in several reports,7,11,19,20 constituting a human model of functional knockout of URAT1. We demonstrated that losartan at a clinical dose level failed to induce uricosuria in URAT1-deficient hypouricemia patients. This is the first evidence that loss-of-function of URAT1 abolished the urate-lowering effect induced by losartan in humans. This effect of losartan was comparable with the effect of benzbromarone on the renal excretion of urate in hypertensive patients.

The results of the multiple-clearance test of urate were comparable to those of the single-clearance test, demonstrating the validity of the single-clearance test. The URAT1 inhibitor did not modify urate excretion in the URAT1-deficient patients with or without impaired renal function, indicating impaired renal function associated with idiopathic renal hypouricemia did not affect the results of the URAT1 inhibitor loading test. Various types of URAT1 inhibitors modified urate excretion in renal hypouricemia patients with intact URAT1, even if Sur was very low (≤2.0 mg/dl).11,12,13,20,21,22,23,24,25 In fact, both losartan and benzbromarone increased Cur/Ccr in a renal hypouricemia patient who harbored the wild-type URAT1 gene, excluding the possibility that a low level of urate might mask the uricosuric action of these agents.

Urate-induced hypertension has been investigated in both experimental and clinical studies.26,27 In this study, we demonstrated that without causing any changes in Sur value, losartan significantly lowered BP in URAT1-deficient hypertensives of which extent was comparable with that in hypertensives harboring the wild-type URAT1 gene. Thus, we postulate that losartan induces a particularly brisk response of BP regardless of Sur values.

Although serum urate levels are also controlled by the production of uric acid in the liver, losartan and its active metabolite E-3174 have been reported to exert no inhibitory effects on the xanthine oxidase activity in an in vitro experiment.9

According to the LIFE study,28 the contribution of Sur to the efficacy of losartan in preventing cardiovascular events and stroke was estimated to be 29%. It has been implied that uric acid would play a role in vascular smooth muscle cell proliferation, nitric oxide synthesis, inflammation, local activation of the renin–angiotensin system, and endothelial dysfunction.26,27,29,30 However, the potential contribution of the Sur-lowering effect of losartan to positive cardiovascular and renal outcomes remains to be demonstrated.

In conclusion, we demonstrated that the uricosuric action of losartan was abolished in hypertensive patients who carried loss-of-function mutations in the URAT1 gene, while in hypertensive patients harboring the wild-type URAT1 gene losartan induced uricosuria, indicating that URAT1 is responsible for the uricosuric action of losartan in humans.

Disclosure:

The authors declared no conflict of interest.

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