Eukaryotic elongation factor 2 kinase inhibitor, A484954 potentiates β-adrenergic receptor agonist-induced acute decrease in diastolic blood pressure in rats

Eukaryotic elongation factor 2 (eEF2) kinase (eEF2K) acts to inhibit protein translation through phosphorylating a specific substrate, eEF2. We previously found that the increased eEF2K expression in mesenteric artery mediates hypertension development in spontaneously hypertensive rats. More recently, we have revealed that a selective eEF2K inhibitor, A484954 induced vasorelaxation via opening inward rectifier K(+) channel and activating β(2)-adrenergic receptor in smooth muscle of rat isolated mesenteric artery, which contributes to prevent noradrenaline-induced acute increase in blood pressure (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 A484954 affects contraction and heart rate (HR) of isolated heart. BP and HR were measured by a carotid cannulation method in rats. Isometric contraction and HR in rat isolated atria were also measured pharmacologically. A484954 potentiated adrenaline-induced decrease in diastolic BP (DBP) but not increase in systolic BP (SBP). A484954 potentiated isoproterenol-induced decrease in DBP but not SBP. Contrastingly, A484954 prevented a non-β-adrenergic receptor agonist, angiotensin II-induced increase in both SBP and DBP. In isolated left atria, A484954 caused contraction, which was prevented by a β-adrenergic receptor antagonist, propranolol. In isolated right atria, A484954 increased HR. In conclusion, we for the first time demonstrated that A484954 potentiates β-adrenergic receptor agonist-induced decrease in DBP possibly through vasorelaxation mediated via activating β(2)-adrenergic receptor. It was also demonstrated that A484954 causes contraction of rat isolated heart via activating β(1)-adrenergic receptor.