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Summary   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.

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