DrugRes/2016-03-1153/10.9.

2016/MPS Original Article

Effect of Antihypertensive Drugs on Uric Acid

Metabolism in Patients with Hypertension: Cross-
Sectional Cohort Study

Authors S. Ueno1, T. Hamada2, S. Taniguchi2, N. Ohtani3, S. Miyazaki4, E. Mizuta5, A. Ohtahara5, K. Ogino6,

A. Yoshida1, M. Kuwabara7, K. Yoshida8, H. Ninomiya9, H. Kotake10, F. Taufiq11, K. Yamamoto12,
I. Hisatome1

Affiliations Affiliation addresses are listed at the end of the article

Key words Abstract Results:  In patients treated with diuretics,

●
▶ hypertension
▼ beta-blockers and/or alpha-1 blockers SUA lev-
●
▶ antihypertensive agents
Background:  Hypertension is a common com- els were significantly higher than in patients
●
▶ hyperuricemia
plication in patients with gout and/or hyper- who were not taking these drugs. Besides, the
●
▶ gout
uricemia. Besides, hyperuricemia is a risk estimated glomerular filtration rate (eGFR) in

Downloaded by: Cornell. Copyrighted material.

●
▶ serum uric acid

●
▶ glomerular filtration factor of gout as well as ischemic heart disease in
●
▶ gender difference hypertensive patients. Moreover, the risk of gout
is modified by antihypertensive drugs. However,
it remains unclear how antihypertensive agents
affect uric acid metabolism.
Purpose:  In the present study, we investigated
the uric acid metabolism in treated hypertensive
patients to find out whether any of them would
influence serum levels of uric acid.
Patients and methods:  751 hypertensive
patients (313 men and 438 women) under anti-
hypertensive treatment were selected. Blood
pressure (BP), serum uric acid (SUA) and serum
creatinine (Scr) were measured and evaluated
statistically.
patients treated with diuretics, beta-blockers
and/or alpha-1 blockers was negatively corre-
lated with SUA level. There were gender differ-
ences in the effects of beta-blockers and alpha-1
blockers. Multiple regression analysis indicated
that both diuretics and beta-blockers signifi-
cantly contributed to hyperuricemia in patients
with medication for hypertension.
Conclusion:  Diuretics, beta-blockers and alpha-1
blockers reduced glomerular filtration rate and
raised SUA levels. Calcium channel blockers, ACE
inhibitors and angiotensin receptor blockers,
including losartan, did not increase SUA levels.

received 22.03.2016
accepted 06.07.2016
Bibliography
DOI http://dx.doi.org/
10.1055/s-0042-113183
Published online: 2016
Drug Res
© Georg Thieme Verlag KG
Stuttgart · New York
ISSN 2194-9379
Correspondence
Dr. T. Hamada
Department of Regional
Medicine
Tottori university Faculty of
Medicine
Nishimachi 36-1
683-8503, Yonago
Japan
Tel.:  + 81/859/38 6661
thammer@chukai.ne.jp
Introduction
▼ hypertension indicated the possibility that anti-
It has been reported that approximately 25 % of
hypertensive patients have hyperuricemia [1].
Beside of a risk for gout, hyperuricemia is a risk
factor for cardiovascular diseases. Hyperuricemia
was found to correlate with hypertension exclud-
ing the influence of other factors such as age and
renal function [2, 3]. Furthermore, many studies
found that hyperuricemia was independently
associated with cardiovascular events in patients
treated with antihypertensive drugs [4–6].
Choi et al. reported that the risk for developing
gout was modified by antihypertensive drugs [7].
Thiazide-type diuretics, angiotensin-converting
enzyme (ACE) inhibitors and some of angioten-
sin-II receptor blockers (ARB) were reported to
reduce renal excretion of urate and increased
serum uric acid levels [7, 8]. Beta-blockers also
elevate serum uric acid levels [9]. A sub-analysis
of data from a recent intervention study on
hypertensive drugs increased serum uric acid
levels as well as the incidence of cerebro/cardio-
vascular events [10]. On the other hand, it has
been reported that the angiotensin-II receptor
antagonist losartan and long-acting Ca channel
blockers (CCB) decreased serum uric acid levels
in patients with hypertension or coronary artery
disease, resulting in protection from gout and
cardiovascular events [5,  11]. In the Japanese
population, losartan has been reported to
decrease serum uric acid levels in hypertensive
patients with serum uric acid levels higher than
7.0 mg/dL [12].
It is important to control serum uric acid levels in
hypertensive patients treated with antihyperten-
sive drugs in order to reduce the risk of gout and
cardiovascular events. However, it remains
unclear how antihypertensive agents affect uric

Ueno S et al. Uric Acid and Antihypertensive Drugs …  Drug Res

 Original Article DrugRes/2016-03-1153/10.9.2016/MPS

acid metabolism. In the present study, we investigated the rela-

tionship between antihypertensive drugs and uric acid metabo- a
8

Serum uric acid (mg/dl)

lism in hypertensive patients to find out whether any of the 7
antihypertensive agents lower serum uric acid levels.
6
5
4
Methods
3
▼
Patients 2
The subjects were 751 hypertensive patients (313 men and 438 1
women) living in Tottori and Shimane Prefectures who were 0
(–) (+) (–) (+) (–) (+)
treated with antihypertensive agents from November 1st in 2012
n = 597 n = 154 n = 665 n = 86 n = 716 n = 35
to October 30th in 2013. None of them had a history of treatment
with uric acid lowering agents or other dugs affecting serum Diuretics β-blockers α1-blockers
uric acid level. The ethics committee of each institution approved b
9

Serum uric acid (mg/dl)

this study (approved No. 2020) and informed consent was
8
obtained from every patient. The privacy of patients was pro-
7
tected in accordance to the Ethical Guidelines for Clinical Studies 6
established by the Ministry of Health, Labor and Welfare and the 5
Declaration of Helsinki. The following antihypertensive drugs 4
were administered to these patients: diuretics (157 patients), 3
2
CCBs (470), ACE inhibitors (59), losartan (43), other ARBs (442),
1
beta-blockers (85) and alpha-1 blockers (35). 0
As for clinical and laboratory data, heart rate, systolic/diastolic (–) (+) (–) (+) (+) (–)

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blood pressure (SBP/DBP), serum uric acid (SUA) and serum cre- n = 251 n = 62 n = 284 n = 29 n = 296 n = 17
atinine (Scr) were measured. Diuretics β-blockers α1-blockers
c
Statistical analysis 7
Serum uric acid (mg/dl)

Data are expressed as mean ± standard deviation (SD), and analy- 6

sis of variance was applied. Using Pearson’s function, we esti- 5
mated the product-moment correlation coefficients and 95 % 4
confidence intervals. We also estimated the odds ratios and 95 % 3
confidence intervals applying Fisher’s exact test. We set the level
2
of statistical significance at p < 0.05 [13].
1
In order to identify the factors contributing to hyperuricemia,
0
we used the multiple regression analysis.
(–) (+) (–) (+) (–) (+)
n = 346 n = 92 n = 381 n = 57 n = 420 n = 18
Diuretics β-blockers α1-blockers
Results
▼ Fig. 1  Antihypertensive agents and serum uric acid. a SUA in patients
Antihypertensive agents and serum uric acid treated with diuretic, beta-blocker or alpha-1 blocker. Open column:
There was not any significant correlation of SBP and DBP with patients with the individual drug. Closed column: in patients without the
SUA, respectively (data not shown). To investigate the associa- individual drug.  * p < 0.05. b SUA in male patients treated with diuretic,
tion between antihypertensive agents and serum uric acid beta-blocker or alpha-1 blocker.  * p < 0.05. c SUA in female patients
(SUA), we compared serum uric acid levels between patients treated with diuretic, beta-blocker or alpha-1 blocker.  * p < 0.05.
treated with each of these drugs and those treated without
them. As shown in ●  ▶  Fig. 1a, SUA level was significantly higher in
patients who were treated with diuretics, beta-blockers or with more than 2 antihypertensive agents, (SUA = 5.1 ± 1.4 mg/dl
alpha-1 blockers than in patients treated without these drugs. in patients treated with single drug, SUA = 5.4 ± 1.5 mg/dl in
There was no significant difference in SUA levels between patients treated with more than 2 agents).
patients treated with and without losartan, ACE, ARBs, exclud- To exclude the effects of diuretics on SUA in patients treated
ing losartan, or CCBs (data not shown). As shown in ●  ▶  Fig. 1b, c, with alpha-blockers or β-blockers, we compared SUA in patients
there was a gender difference in the effect of antihypertensive between with and without diuretics. After excluding the patients
agents on SUA. SUA was significantly higher in men treated with treated with diuretics, there was not any significant difference of
alpha-1 blockers than those without them, while SUA was sig- SUA in patients between with beta-blockers (5.25 ± 1.35 mg/dl)
nificantly higher in women treated with β-blockers than those or alpha-1 blockers (5.67 ± 1.71 mg/dl) and without those agents
without them. However, SUA was significantly higher in male (5.13 ± 1.38 and 5.13 ± 1.36 mg/dl, respectively).
and female patients treated with diuretics than those without
them. Relationship between antihypertensive agents and
Since many patients received antihypertensive combination occurrence of hyperuricemia
treatment, the level of SUA might be dependent on the number As shown in ●
 ▶  Table 1, patients were classified into 2 groups;
of agents. As expected, the level of SUA was elevated in patients hyperuricemia group (SUA ≥ 7.1 mg/dL for men and SUA ≥ 6.0 mg/

Ueno S et al. Uric Acid and Antihypertensive Drugs …  Drug Res

DrugRes/2016-03-1153/10.9.2016/MPS Original Article

dL for women) and normouricemia group (SUA < 7.1 mg/dL for
men and SUA < 6.0 mg/dL for women). The occurrence of hyper-
uricemia was significantly higher in patients treated with diu-
retics, β-blockers and/or alpha1-blockers than in patients
treated without these agents. On the other hand, the difference
between patients treated with Ca blockers, ACE inhibitors, ARB
including losartan, and those treated without these agents was
not statistically significant. While there was not a gender differ-
ence regarding prevalence of hyperuricemia treated with diuret-
ics, there was a gender difference regarding prevalence of
hyperuricemia in patients treated with β-blockers and alpha-1
blockers. To clarify the contributing factor for hyperuricemia
among the various factors such as age, gender, diuretics, β
-blockers and alpha1-blockers, we used the multiple regression
analysis and found that both diuretics and beta-blockers signifi-
cantly contributed to hyperuricemia in patients with medica-
tion for hypertension as shown in ●  ▶  Table 2.
Relationship between antihypertensive agents and
glomerular filtration rate
As shown in ●
 ▶  Table 3, there were significantly negative correla-
tions between eGFR and SUA levels in patients treated with diu-
retics (R =  − 0.34, p < 0.001), beta-blockers (R =  − 0.51, p < 0.001),
alpha-1 blockers (R =  − 0.46, p = 0.006), CCBs (R =  − 0.31, p < 0.001),
and ARBs (R =  − 0.24, p < 0.001). Conversely, there were no sig-
nificant correlations between eGFR and SUA levels in patients
with ACE inhibitor, and losartan. After accounting for gender dif-
ferences, there were significantly negative correlations between
eGFR and SUA levels in male patients with alpha-1 blockers
(R =  − 0.55, p = 0.012) and in women treated with ACE inhibitors
(R =  − 0.41, p = 0.035) and losartan (R =  − 0.64, p = 0.003).
Discussion
▼
SUA-increasing agents
It was reported that diuretics and beta-blockers increased the
incidence of gout in hypertensive patients in the UK [7]. In the
present study, we found that these drugs elevated serum uric
acid levels in Japanese hypertensive patients.
Diuretics are known to reduce renal blood flow and GFR while
elevating the level of SUA. These drugs were also reported to
increase SUA levels via an increase of renal tubular reabsorption
of uric acid via activation of the renin angiotensin system (RAS)
and sympathetic nerve system [14]. In present study, we found
that both SUA levels and the prevalence of hyperuricemia were
significantly higher in patients with diuretics. There was a nega-

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tive correlation between eGFR and SUA level in patients treated
Table 1  Antihypertensive agents and frequency of hyperuricemia. with diuretics, suggesting that diuretics could decrease the uric
acid filtration rate.
Frequency of hyperuricemia (number p-value In patients treated with beta-blockers, both SUA levels and prev-
of hyperuricemia/total) alence of hyperuricemia were significantly higher, particularly
( + ) ( − ) in women. We found negative correlations between eGFR and
Diuretics 29.9 % (46/154) 15.2 % (91/597)  < 0.001 SUA levels in patients treated with beta-blockers, suggesting
  male 35.5 % (22/62) 16.3 % (41/251) 0.001 that beta-blockers might elevate SUA levels by reducing GFR.
  female 26.1 % (24/92) 15.5 % (50/346) 0.012 Beta-blockers are reported to activate alpha-receptors in periph-
β-blockers 31.4 % (27/86) 16.5 % (110/665) 0.002 eral vessels causing vasoconstriction [15]. It is possible that
  male 31.0 % (9/29) 19.0 % (54/284) 0.144
beta-blockers induce vasoconstriction in the nephrons decreas-
  female 31.6 % (18/57) 14.7 % (56/381) 0.004
ing thereby the filtration rate.
α-1 blockers 34.2 % (12/35) 17.5 % (125/716) 0.022
  male 47.1 % (8/17) 18.6 % (55/296) 0.010
  female 22.2 % (4/18) 16.7 % (70/420) 0.522
ACE inhibitors 20.0 % (12/60) 18.1 % (125/691) 0.728
Table 3  Antihypertensive agents and glomerular filtration rate.
  male 17.2 % (5/29) 20.4 % (58/284) 0.811
  female 22.6 % (7/31) 16.5 % (67/407) 0.453 Correlation coefficient (95 % CI) p-value
Ca blockers 17.3 % (82/474) 19.9 % (55/277) 0.674
Diuretics  − 0.341 ( − 0.472 to  − 0.194)  < 0.001
  male 19.4 % (39/201) 21.4 % (24/112) 0.507
  male  − 0.301 ( − 0.498 to  − 0.075) 0.010
  female 15.8 % (43/273) 18.8 % (31/165) 0.546
  female  − 0.440 ( − 0.597 to  − 0.250)  < 0.001
losartan 14.9 % (7/47) 18.5 % (130/704) 0.697
β-blockers  − 0.507 ( − 0.65 to  − 0.33)  < 0.001
  male 14.2 % (3/21) 20.5 % (60/292) 0.778
  male  − 0.654 ( − 0.809 to  − 0.414)  < 0.001
  female 15.4 % (4/26) 17.0 % (70/412) 0.999
  female  − 0.492 ( − 0.680 to  − 0.245)  < 0.001
other ARBs 20.0 % (89/446) 15.7 % (48/305) 0.150
α-1 blockers  − 0.456 ( − 0.685 to  − 0.144) 0.006
  male 23.3 % (44/189) 15.3 % (19/124) 0.112
  male  − 0.549 ( − 0.798 to  − 0.141) 0.012
  female 17.5 % (45/257) 16.0 % (29/181) 0.700
  female  − 0.417 ( − 0.766 to 0.121) 0.122
Upper low: whole patients, Middle low: male patients, Bottom low: female patients
ACE inhibitors  − 0.202 ( − 0.435 to 0.0571) 0.125
  male  − 0.169 ( − 0.489 to 0.191) 0.356
  female  − 0.407 ( − 0.682 to  − 0.033) 0.035
Table 2  Factors associated with hyperuricemia in multiple logistic regres- Ca blockers  − 0.309 ( − 0.388 to  − 0.244)  < 0.001
sion analysis.   male  − 0.341 ( − 0.452 to  − 0.220)  < 0.001
  female  − 0.393 ( − 0.494 to  − 0.282)  < 0.001
Variables OR 95 % CI P-value losartan  − 0.260 ( − 0.520 to 0.0432) 0.092
Age (year) 1.008 0.991–1.025 0.369   male 0.078 ( − 0.336 to 0.467) 0.716
Men/women 1.326 0.902–1.953 0.151   female  − 0.640 ( − 0.848 to  − 0.263) 0.003
Diuretics use 2.163 1.262–3.752 0.005 other ARBs  − 0.237 ( − 0.323 to  − 0.147)  < 0.001
Beta–blockers use 2.138 1.222–3.740 0.008   male  − 0.195 ( − 0.320 to  − 0.063) 0.004
Alpha1–blockers use 1.871 0.835–4.194 0.128   female  − 0.363 ( − 0.471 to  − 0.244)  < 0.001
OR: odd ratio, CI: confidence interval Upper low: whole patients, Middle low: male patients, Bottom low: female patients

Ueno S et al. Uric Acid and Antihypertensive Drugs …  Drug Res

 Original Article
Although alpha-1 blockers are expected to lower serum uric acid
by increasing excretion of uric acid in the proximal tubules [18],
they do not influence the level of serum uric acid. In the present
study, both SUA levels and prevalence of hyperuricemia were
significantly elevated in patients treated with alpha-1 blockers,
particularly in men. However, the underlying mechanisms by
which alpha-1 blockers elevate serum uric acid remain unknown.
It is possible that some alpha-1 blockers raise angiotensin II lev-
els [19], which could increase SUA via enhanced tubular reab-
sorption of uric acid.
In the present study, many patients received antihypertensive
combination treatment; the level of SUA might be dependent on
the number of agents. The level of SUA was elevated in patients
with more than 2 antihypertensive agents. We assumed that the
patients who need more than 2 drugs may be complicated with
the disorders to elevate SUA such as metabolic syndrome or
chronic kidney disease and thus show higher baseline SUA.
After excluding the patients treated with diuretics there was not
any significant difference of SUA in patients between with beta-
blocker or alpha-blockers and without those agents, indicating
the combination of diuretics influenced the SUA in patients
treated with beta-blockers or alpha-blockers. However, the mul-
tivariate regression analysis indicated the diuretic and beta-
blockers as contributing factors to hyperuricemia. We need the
further investigations whether beta-blockers independently
could contribute to hyperuricemia or not.
Agents that do not increase SUA
CCBs and losartan [8] are well known to lower SUA by increasing
renal excretion of uric acid, although ARBs have been reported
not to influence SUA [8, 20]. In the present study, we found that
in patients treated with CCBs and ARBs, including losartan, SUA
levels were similar to those in patients treated without these
agents, which was consistent with the finding that there was no
significant difference in the occurrence of hyperuricemia
between patients treated with Ca blockers and ARBs, including
losartan, and those treated without these agents. There were
negative correlations between SUA and eGFR in patients treated
with these agents. This might suggest that the uric acid lowering
action of both CCBs and ARBs, including losartan, could cancel
the decrease in its excretion through a decrease of renal blood
flow [8].
There were several controversial reports on the effects of ACE
inhibitors on uric acid metabolism. Some reports showed that
ACE inhibitors increased the risk for developing gout [7]. In con-
trast, others reports showed ACE inhibitors reduced reabsorp-
tion of uric acid in renal paroxysmal tubules to exert a uricosuric
action [16, 17]. In the present study, ACE inhibitor did not influ-
ence SUA, while there was a significant negative correlation
between eGFR and SUA. These results suggested that ACE inhibi-
tors might cancel the elevation of SUA by reducing eGFR by other
mechanisms.
Gender difference
It is well known that serum uric acid and blood pressure levels
are lower in women [21, 22]. Accordingly, the prevalence of both
hypertension and hyperuricemia was significantly lower in
females. So far, there has not been any study on gender differ-
ences regarding the relationship between serum uric acid and
antihypertensive agents. In this study, we found a gender differ-
ence regarding the relationship between use of β-blockers or
alpha-1 blockers and SUA; namely, in women treated with
Ueno S et al. Uric Acid and Antihypertensive Drugs …  Drug Res
DrugRes/2016-03-1153/10.9.2016/MPS
β-blockers SUA was elevated and there was a negative correla-
tion between SUA and eGFR. In male patients treated with alpha
1 receptor blockers SUA was elevated and negatively correlated
with eGFR. Further investigations about these differences and
their mechanisms are required.
Conclusion
▼
SUA in patients treated with diuretics, beta-blockers and/or
alpha-1 blockers is significantly higher compared to patients
without those medications. Those underlying mechanisms
remained unknown, and further studied are needed. Some anti-
hypertensive medications might be a risk of not only hyper-
uricemia but also gout.
Acknowledgement
▼
We deeply appreciated the contribution of members as follows:
Toshio Ishii, Yoshifusa Matsuura, Narimasa Hirata, You Tanaka,
Masuo Morimoto, Hiroshi Nasu, Saichi Goto, Isao Matsuoka,
Tomoko Urabe, Shinsuke Suzuki, Narifumi Norimoto, Tomomi
Kitamuro, Kenjiro Kitamura, Masanori Nishio, Nobuyuki Oyake,
Downloaded by: Cornell. Copyrighted material.
Tetsuya Sasaki, You Murakami, Hiroaki Tanaka, Yoshikazu Mori,
Takahiro Mawada, Hiromoto Kosaka, Jiro Uemasu, Yoshnori Mat-
suda, Yoshinori Noguchi, Maki Shio, Masahiko Sawaguchi, Akio
Yano, Masashi Watanabe, Hideo Shida, Shigeo Maruyama,
Takashi Nishio, Tomoyuki Furuse.
Conflict of Interest
▼
We did not have any COI on this study.
Affiliations
1
 Division of Regenerative Medicine and Therapeutics, Institute of Regenera-
tive Medicine and Biofunction, Graduate School of Medical Sciences, Tottori
University, Yonago, Japan
2
 Department of Community-based Family Medicine, Tottori University
Faculty of Medicine, Yonago, Japan
3
 Department of Pharmacology, Dokkyo Medical College, Tochigi, Japan
4
 Division of Cardiology, Fujii Masao Memorial Hospital, Kurayosi, Japan
5
 Department of Cardiology, San-in Rosai Hospital, Yonago, Japan
6
 Department of Clinical Laboratory, Tottori University Hospital, Yonago
Japan
7
 Department of Cardiology, Toranomon Hospital, Tokyo, Japan
8
 Center for Promoting Next-Generation Highly advanced Medicine, Tottori
University Hospital, Yonago, Japan
9
 Department of Biological Regulation, Tottori University Faculty of
Medicine, Yonago, Japan
10
 Kotake Cardiology Clinic, Yonago, Japan
11
 Division of Cardiology, Faculty of Medicine Diponegoro University,
Semarang, Indonesia
12
 Division of Cardiovascular Medicine, Department of Molecular Medicine
and Therapeutics, Faculty of Medicine, Tottori University
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