Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter
Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter
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DOI：
10.1124/jpet.106.112755
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Tamai, Ikumi
中科院分区：
文献类型：
--
作者：
Iwanaga, Takashi;Sato, Masanobu;Tamai, Ikumi
血尿酸（SUA）是目前公认的心血管疾病的危险因素。据报道，血管紧张素II受体阻滞剂（ARB），氯沙坦，降低SUA水平，而其他ARB，如坎地沙坦，没有降低作用。由于肾脏尿酸转运蛋白（URAT 1）是控制SUA水平的重要因素，我们研究了URAT 1在临床相关浓度下各种ARB对SUA水平的差异效应中的参与。这项研究是通过使用URAT 1表达非洲爪蟾卵母细胞。氯沙坦、普托沙坦和替米沙坦对URAT 1摄取尿酸表现出顺式抑制作用，而在较高浓度下，只有替米沙坦具有顺式抑制作用，这些ARB在竞争性抑制动力学中降低了摄取。另一方面，坎地沙坦、EXP3174 [2-正丁基-4-氯-1-[（2 '-（1H-四唑-5-基）联苯-4-基）甲基]咪唑-5-羧酸]（氯沙坦的主要代谢产物）、奥美沙坦和缬沙坦无抑制作用。在卵母细胞中预加载这些ARB增强了URAT 1介导的尿酸摄取，显示出反式刺激效应。本研究首次证明了ARB对URAT的差异效应1，某些ARB同时具有顺式抑制和反式刺激作用（取决于浓度），而其他ARB仅表现出反式刺激或顺式抑制作用，这可以解释临床观察到的ARB对SUA水平的差异效应。此外，研究发现，ARBs对URAT 1的这种差异效应可以从ARBs的部分化学结构中预测，这将是有用的信息，在不增加SUA的情况下，ARBs的适当使用和开发。
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-yl)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.