cpu0213 and Diabetic-Angiopathies

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.. 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.. 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.. 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.

Topics: Animals; Aorta, Thoracic; Biomarkers; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelin Receptor Antagonists; Gene Expression Regulation; In Vitro Techniques; Male; Matrix Metalloproteinase 9; Muscle, Smooth, Vascular; NADPH Oxidases; Nitric Oxide; Nitric Oxide Synthase Type II; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; RNA, Messenger; Sildenafil Citrate; Sulfones