The eukaryotic elongation factor 2 kinase inhibitor, A484954, induces hypoglycaemic and hypotensive effects

Background and purpose: Eukaryotic elongation factor 2 kinase (eEF2K) belongs to the Ca²⁺/calmodulin-dependent protein kinase family. We previously revealed that A484954, a selective eEF2K inhibitor, caused hypotensive and diuretic effects via the production of nitric oxide (NO) in spontaneously hypertensive rats. Otsuka Long-Evans Tokushima Fatty (OLETF) rats are hypertensive because of obesity and type 2 diabetes. Because an NO synthase inhibitor was reported to increase the expression of sodium glucose co-transporter 2 (SGLT2), we hypothesised that A484954 causes not only hypotensive but also hypoglycaemic effects via NO production in OLETF rats.

Experimental approach: To test the hypothesis, we examined the effects of A484954 administration on hyperglycaemia and hypertension in OLETF rats. OLETF rats were given an intraperitoneal injection of A484954 (2.5 mg kg^-1 day^-1) for 7 days. Then, we measured blood and urinary glucose level, urine output, systolic blood pressure and ventricular contractility. We also conducted Western blotting and isometric tension measurements.

Key results: A484954 induced a decrease in blood glucose, an increase in urinary glucose excretion, and a decrease in protein expression of kidney SGLT2. In addition, A484954 induced a decrease in systolic blood pressure, an NO-dependent vasorelaxation, and a diuretic effect. Further, A484954 enhanced left ventricular contractility.

Conclusion and implications: We, for the first time, revealed that (1) A484954 caused hypoglycaemic effects through increasing urinary glucose excretion via decreasing SGLT2, (2) A484954 improved diabetic complication, including hypertension, through vasorelaxation and diuresis via NO production, and (3) A484954 had a positive inotropic effect.