Department of Experimental and Clinical Pharmacology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland.
Department of Nephrology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland.
Naunyn Schmiedebergs Arch Pharmacol. 2019 Feb;392(2):209-217. doi: 10.1007/s00210-018-1572-7. Epub 2018 Oct 29.
Glutamate (GLU) mainly through N-methyl-D-aspartate (NMDA) receptors plays pivotal role in kidney function regulation. Kynurenic acid (KYNA), a GLU receptors antagonist, is synthesized from kynurenine by kynurenine aminotransferases (KATs). Previously, it was shown that angiotensin II type 1 receptor blockers (ARBs) decrease KYNA production in rat brain in vitro. The aim of this study was to examine the influence of six ARBs: candesartan, irbesartan, losartan, olmesartan, telmisartan, and valsartan on KYNA production on rat kidney in vitro. The effect of ARBs was determined in kidney homogenates and on isolated KAT II enzyme. Among tested ARBs, irbesartan was the most effective KYNA synthesis inhibitor with IC of 14.4 μM. Similar effects were observed after losartan (IC 45.9 μM) and olmesartan administration (IC 108.1 μM), whereas candesartan (IC 475.3 μM), valsartan (IC 513.9 μM), and telmisartan (IC 669.5 μM) displayed lower activity in KYNA synthesis inhibition in rat kidney homogenates in vitro. On the other hand, valsartan (IC 27.5 μM) was identified to be the strongest KAT II inhibitor in rat kidney in vitro. Candesartan, losartan, and telmisartan suppressed KAT II activity with IC equal to 83.2, 83.3, and 108.3 μM, respectively. Olmesartan and irbesartan were the weakest KAT II inhibitors with IC values of 237.4 and 809.9 μM, respectively. Moreover, molecular docking suggested that studied ARBs directly bind to an active site of KAT II. In conclusion, our results indicate that ARBs decrease KYNA synthesis in rat kidney through enzymatic inhibition of KAT II, which may have impact on kidney function.
谷氨酸（GLU）主要通过 N-甲基-D-天冬氨酸（NMDA）受体在肾功能调节中发挥关键作用。犬尿氨酸酸（KYNA）是一种 GLU 受体拮抗剂，由犬尿氨酸通过犬尿氨酸氨基转移酶（KATs）合成。先前的研究表明，血管紧张素 II 型 1 型受体阻滞剂（ARBs）在体外可降低大鼠大脑中的 KYNA 产生。本研究旨在研究六种 ARBs（坎地沙坦、厄贝沙坦、氯沙坦、奥美沙坦、替米沙坦和缬沙坦）对大鼠肾脏中 KYNA 产生的体外影响。在肾匀浆和分离的 KAT II 酶上测定 ARBs 的作用。在所测试的 ARBs 中，厄贝沙坦是最有效的 KYNA 合成抑制剂，IC 为 14.4μM。洛沙坦（IC 45.9μM）和奥美沙坦给药后观察到类似的效果（IC 108.1μM），而坎地沙坦（IC 475.3μM）、缬沙坦（IC 513.9μM）和替米沙坦（IC 669.5μM）在大鼠肾匀浆体外 KYNA 合成抑制中表现出较低的活性。另一方面，缬沙坦（IC 27.5μM）被鉴定为大鼠肾脏中最强的 KAT II 抑制剂。坎地沙坦、洛沙坦和替米沙坦分别以 IC 等于 83.2、83.3 和 108.3μM 抑制 KAT II 活性。奥美沙坦和厄贝沙坦是最弱的 KAT II 抑制剂，IC 值分别为 237.4 和 809.9μM。此外，分子对接表明研究的 ARBs 直接与 KAT II 的活性位点结合。总之，我们的结果表明，ARBs 通过对 KAT II 的酶抑制作用降低大鼠肾脏中的 KYNA 合成，这可能对肾功能产生影响。
