title: 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.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
authors.affiliation: Faculty of Pharmacy, China Pharmaceutical University, Nanjing, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Luo
authors.forename: De-Zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Yu-Si
authors.initials: YS
authors.lastname: Cheng
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Yuan
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003925:Diabetic Angiopathies / Q000517:prevention & control*; D065128:Endothelin Receptor Antagonists; D005786:Gene Expression Regulation / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use*; D010879:Piperazines / Q000627:therapeutic use*; D011687:Purines / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*
chemical_list: D015415:Biomarkers; C513821:CPU0213; D065128:Endothelin Receptor Antagonists; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019255:NADPH Oxidases; D020780:Matrix Metalloproteinase 9