Sildenafil improves diabetic vascular activity through suppressing endothelin receptor A, iNOS and NADPH oxidase which is comparable with the endothelin receptor antagonist CPU0213 in STZ-injected rats

Objectives Abnormal vascular activity in diabetes is related not only to impaired nitric oxide bioavailability but also to inflammatory cytokines, endothelin A receptor (ET_A) activation and NADPH oxidase in the vasculature. The potential role of sildenafil in improving vascular function was investigated. Its action was likely blocking upregulated ET_A and NADPH oxidase, and was compared with the endothelin receptor antagonist CPU0213. Methods Diabetes was induced by single-dose administration of streptozotocin (65 mg/kg, i.p.) to rats and the vascular activity of the thoracic aorta was measured. Key findings An increase in contractile tone to phenylephrine and a decrease in relaxant tone to acetylcholine was found in the thoracic aorta. Oxidative stress was evident by increased malondialdehyde and reduced glutathione peroxidase levels in serum and upregulation of ET_A, MMP-9 (matrix metalloproteinase-9), inducible nitric oxide synthase and NADPH oxidase p67^phox were found in the vascular wall. The vascular abnormalities and abnormal biomarkers were attenuated significantly by either sildenafil or CPU0213 along with an improvement of nitric oxide bioavailability and vascular activity. Conclusions Improvement of diabetic vascular abnormal activity by sildenafil results from its suppression of activation of ET_A and NADPH oxidase in the vasculature, and these actions are comparable with those of the endothelin receptor antagonist CPU0213.