| Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter. | |
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MedLine Citation:
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PMID: 17043154 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Serum uric acid (SUA) is currently recognized as a risk factor for cardiovascular disease. It has been reported that an angiotensin II receptor blocker (ARB), losartan, decreases SUA level, whereas other ARBs, such as candesartan, have no lowering effect. Because the renal uric acid transporter (URAT1) is an important factor controlling the SUA level, we examined the involvement of URAT1 in those differential effects of various ARBs on SUA level at clinically relevant concentrations. This study was done by using URAT1-expressing Xenopus oocytes. Losartan, pratosartan, and telmisartan exhibited cis-inhibitory effects on the uptake of uric acid by URAT1, whereas at higher concentrations, only telmisartan did, and these ARBs reduced the uptake in competitive inhibition kinetics. On the other hand, candesartan, EXP3174 [2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yI)methyl]imidazole-5-carboxylic acid] (a major metabolite of losartan), olmesartan, and valsartan were not inhibitory. Preloading of those ARBs in the oocytes enhanced the URAT1-mediated uric acid uptake, showing a trans-stimulatory effect. The present study is a first demonstration of the differential effects of ARBs on URAT1 that some ARBs are both cis-inhibitory and trans-stimulatory, depending on concentration, whereas others exhibit either a trans-stimulatory or cis-inhibitory effect alone, which could explain the clinically observed differential effects of ARBs on SUA level. Furthermore, it was found that such differential effects of ARBs on URAT1 could be predicted from the partial chemical structures of ARBs, which will be useful information for the appropriate use and development of ARBs without an increase of SUA. |
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Authors:
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Takashi Iwanaga; Masanobu Sato; Tomoji Maeda; Toshio Ogihara; Ikumi Tamai |
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Publication Detail:
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Type: Journal Article Date: 2006-10-16 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 320 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2007 Jan |
Date Detail:
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Created Date: 2006-12-21 Completed Date: 2007-02-12 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 211-7 Citation Subset: IM |
Affiliation:
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Department of Molecular Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science, 2641 Yamasaki, Noda, Chiba 278-8510, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II Type 1 Receptor Blockers
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blood,
pharmacology* Animals Dose-Response Relationship, Drug Female Imidazoles / pharmacology Losartan / pharmacology Organic Anion Transporters / physiology* Organic Cation Transport Proteins / physiology* Pyrazinamide / analogs & derivatives, pharmacology Tetrazoles / pharmacology Uric Acid / metabolism Valine / analogs & derivatives, pharmacology Xenopus laevis |
| Chemical | |
Reg. No./Substance:
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0/Angiotensin II Type 1 Receptor Blockers; 0/Imidazoles; 0/Organic Anion Transporters; 0/Organic Cation Transport Proteins; 0/SLC22A12 protein, human; 0/Tetrazoles; 0/olmesartan; 114798-26-4/Losartan; 137862-53-4/valsartan; 69-93-2/Uric Acid; 7004-03-7/Valine; 98-96-4/Pyrazinamide; 98-97-5/pyrazinoic acid |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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