Mechanisms underlying the relaxation by A484954, a eukaryotic elongation factor 2 kinase inhibitor, in rat isolated mesenteric artery

Eukaryotic elongation factor 2 kinase (eEF2K) is a calmodulin-related protein kinase which regulates protein translation. A484954 is an inhibitor of eEF2K. In the present study, we investigated the acute effects of A484954 on contractility of isolated blood vessels. Isometric contraction of rat isolated aorta and main branch of superior mesenteric artery (MA) was measured. Expression of an inward rectifier K⁺ (K_ir) channel subtype mRNA and protein was examined. A484954 caused relaxation in endothelium-intact [E (+)] and -denuded [E (-)] aorta or MA precontracted with noradrenaline (NA). The relaxation was higher in MA than aorta. The relaxation was partially inhibited by a nitric oxide (NO) synthase inhibitor, N^G-nitro-l-arginine methyl ester (300 μM) in E (+) MA. The relaxation was significantly smaller in MA precontracted with high K⁺ than NA. The A484954-induced relaxation was significantly inhibited by a K_ir channel blocker, BaCl₂ (1 mM) compared with vehicle control in E (-) MA. Expression of K_ir2.2 mRNA and protein was significantly higher in MA than aorta. We for the first time revealed that A484954 induces relaxation through opening smooth muscle K_ir (K_ir2.2) channel and through endothelium-derived NO in MA.