Epoetin beta pegol ameliorates flow‐mediated dilation with improving endothelial nitric oxide synthase coupling state in nonobese diabetic rats

BACKGROUND/AIMS: Patients with diabetic nephropathy have a high cardiovascular mortality. Epoetin beta pegol (continuous erythropoietin receptor activator, C.E.R.A.) is a drug for the treatment of renal anemia. In this study, we investigated the effect of C.E.R.A. on vascular endothelial function as evaluated by flow‐mediated dilation (FMD) and the relationship between hematopoiesis and FMD in diabetic nephropathy rats. METHODS: Male Spontaneously Diabetic Torii rats (SDT, 22 weeks old) were used. C.E.R.A. (0.6, 1.2 μg/kg) was administered subcutaneously once every 2 weeks for 8 weeks. At 1 week after last administration (31 weeks old), we assessed FMD in the femoral arteries of anesthetized rats using a high‐resolution ultrasound system. FMD was also measured 1 week after single C.E.R.A. treatment (5.0 μg/kg) to examine the influence of hematopoiesis. RESULTS: Flow‐mediated dilation was significantly decreased in SDT rats before the start of C.E.R.A. treatment (22 weeks old). Repeated administration of C.E.R.A. dose‐dependently improved FMD in SDT rats (31 weeks old) without changing blood glucose, nitroglycerin‐induced vasodilation, or kidney function. Long‐term administration of C.E.R.A. improved the state of endothelial nitric oxide synthase uncoupling in the femoral arteries of SDT rats, which showed a positive correlation with FMD. On the other hand, there was no correlation between FMD and Hb or Hct in SDT rats. Furthermore, at 1 week after single administration of C.E.R.A., FMD was not significantly improved although hemoglobin levels were comparable with levels following long‐term C.E.R.A. treatment. CONCLUSION: Long‐term treatment with C.E.R.A. improved FMD in SDT rats even after onset of endothelial dysfunction.