Eukaryotic elongation factor 2 kinase inhibitor, A484954 lowered blood pressure in spontaneously hypertensive rats via inducing vasorelaxation
Eukaryotic elongation factor 2 kinase inhibitor, A484954 lowered blood pressure in spontaneously hypertensive rats via inducing vasorelaxation
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DOI：
10.1016/j.jphs.2020.07.007
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发表时间：
2020-11-01
影响因子：
3.5
通讯作者：
Yamawaki, Hideyuki
中科院分区：
文献类型：
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作者：
Kodama, Tomoko;Okada, Muneyoshi;Yamawaki, Hideyuki
真核延伸因子 2 (eEF2) 激酶 (eEF2K) 抑制蛋白质翻译。我们之前报道自发性高血压大鼠 (SHR) 的肠系膜动脉 (MA) 中 eEF2K 表达上调。我们最近发现 A484954 是一种 eEF2K 抑制剂，可在正常 Wistar 大鼠中急性抑制升压药激动剂诱导的血压 (BP) 升高。在这项研究中，我们检查了 A484954 对 SHR 中血压的急性影响并探讨了潜在机制。 SHR 中通过颈动脉插管法测量血压。测量 SHR 的 MA 等长收缩。通过低温十二烷基硫酸钠-聚丙烯酰胺凝胶电泳和蛋白质印迹法测量内皮一氧化氮合酶（eNOS）二聚化。 A484954 降低 15 周龄 SHR 的血压。 A484954 诱导 4 周龄和 7-9 周龄 SHR 的 MA 松弛。在 4 周龄 SHR 的 MA 中，A484954 诱导的松弛几乎被 NOS 抑制剂 N-G-硝基-L-精氨酸甲酯 (L-NAME) 完全抑制，β 受体阻滞剂普萘洛尔显着抑制。另一方面，在 7-9 周龄 SHR 的 MA 中，A484954 诱导的松弛部分被 L-NAME、吲哚美辛（环加氧酶抑制剂）或 L-NAME 刺吲哚美辛抑制。 A484954 促进人内皮细胞中 eNOS 的二聚化。总之，我们发现 A484954 可能通过产生内皮衍生舒张因子来舒张血管，从而降低 SHR 中的血压。 (C) 2020 作者。由 Elsevier B.V. 代表日本药理学会制作和主办。
Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) suppresses protein translation. We previously reported eEF2K expression was upregulated in mesenteric arteries (MA) from spontaneously hypertensive rats (SHR). We have recently revealed A484954, an eEF2K inhibitor, acutely suppressed vasopressor agonists-induced increase of blood pressure (BP) in normal Wistar rats. In this study, we examined the acute effects of A484954 on BP in SHR and explored underlying mechanisms. BP was measured by a carotid cannulation method in SHR. Isometric contraction in MA from SHR was measured. Endothelial nitric oxide synthase (eNOS) dimerization was measured by low-temperature sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting. A484954 lowered BP in 15-week-old SHR. A484954 induced relaxation in MA from both 4- and 7-9-week-old SHR. In MA from 4-week-old SHR, A484954-induced relaxation was inhibited almost completely by a NOS inhibitor, N-G-nitro-L-arginine methyl ester (L-NAME) and significantly by a beta blocker, propranolol. In MA from 7-9-week-old SHR, on the other hand, A484954-induced relaxation was inhibited partly either by L-NAME, indomethacin, a cyclooxygenase inhibitor, or L-NAME thorn indomethacin. A484954 promoted the dimerization of eNOS in human endothelial cells. In summary, we have revealed A484954 lowers BP in SHR perhaps through the vasorelaxation via the production of endothelium-derived relaxing factors. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society.