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.
['Serizawa|Kenichi|K|http://orcid.org/0000-0001-5330-441X', 'Yogo|Kenji|K|', 'Tashiro|Yoshihito|Y|', 'Kawasaki|Ryohei|R|', 'Endo|Koichi|K|', 'Shimonaka|Yasushi|Y|', 'Hirata|Michinori|M|']
D000818:Animals D015415:Biomarkers D003920:Diabetes Mellitus D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004730:Endothelium, Vascular D004921:Erythropoietin D005263:Femoral Artery D006410:Hematopoiesis D006454:Hemoglobins D008297:Male D052250:Nitric Oxide Synthase Type III D011092:Polyethylene Glycols D011919:Rats, Inbred Strains D020127:Recovery of Function D015398:Signal Transduction D013997:Time Factors D014664:Vasodilation
Epoetin beta pegol Flow-mediated dilation Diabetic nephropathy Endothelial dysfunction Chronic kidney disease Erythropoietin-stimulating agents