Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients.
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.
Hamada
Toshihiro
T
Department of Cardiovascular Medicine, Faculty of Medicine, Tottori University, Yonago, Japan. thammer@chukai.ne.jp
Ichida
Kimiyoshi
K
Hosoyamada
Makoto
M
Mizuta
Einosuke
E
Yanagihara
Kiyotaka
K
Sonoyama
Kazuhiko
K
Sugihara
Shinobu
S
Igawa
Osamu
O
Hosoya
Tatsuo
T
Ohtahara
Akira
A
Shigamasa
Chiaki
C
Yamamoto
Yasutaka
Y
Ninomiya
Haruaki
H
Hisatome
Ichiro
I
D000284:Administration, Oral; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000502:physiology; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D033461:Hyperuricemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D009154:Mutation; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D013777:Tetrazoles / Q000008:administration & dosage; D016896:Treatment Outcome; D014527:Uric Acid / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D027361:Organic Anion Transporters; D027701:Organic Cation Transport Proteins; C491241:SLC22A12 protein, human; D013777:Tetrazoles; D014527:Uric Acid; D004247:DNA; D019808:Losartan; C081643:candesartan