Eukaryotic elongation factor 2 kinase inhibitor A484954 potentiatesβ-adrenergic receptor agonist-induced acute decrease in diastolic blood pressure inrats

摘要

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) acts to inhibit protein translationthrough phosphorylating a specific substrate, eEF2. We previously found that the increasedeEF2K expression in mesenteric artery mediates hypertension development in spontaneouslyhypertensive rats. More recently, we have revealed that a selective eEF2K inhibitor,A484954 induced vasorelaxation via opening inward rectifier K channel andactivating β -adrenergic receptor in smooth muscle of rat isolated mesentericartery, which contributes to prevent noradrenaline-induced acute increase in bloodpressure (BP). In this study, we further explored acute effects of A484954 on BP in rats,especially focusing the action on β-adrenergic receptor. We also examined whether A484954affects contraction and heart rate (HR) of isolated heart. BP and HR were measured by acarotid cannulation method in rats. Isometric contraction and HR in rat isolated atriawere also measured pharmacologically. A484954 potentiated adrenaline-induced decrease indiastolic BP (DBP) but not increase in systolic BP (SBP). A484954 potentiatedisoproterenol-induced decrease in DBP but not SBP. Contrastingly, A484954 prevented anon-β-adrenergic receptor agonist, angiotensin II-induced increase in both SBP and DBP. Inisolated left atria, A484954 caused contraction, which was prevented by a β-adrenergicreceptor antagonist, propranolol. In isolated right atria, A484954 increased HR. Inconclusion, we for the first time demonstrated that A484954 potentiates β-adrenergicreceptor agonist-induced decrease in DBP possibly through vasorelaxation mediated viaactivating β -adrenergic receptor. It was also demonstrated that A484954 causescontraction of rat isolated heart via activating β -adrenergic receptor.