Inhibition of protein tyrosin phosphatase improves vascular endothelial dysfunction.
The study has been designed to investigate the effect of Bis-(maltolato) oxovanadium (BMOV), an inhibitor of protein tyrosin phosphatase (PTPase), in diabetes mellitus and hyperhomocysteinemia induced vascular endothelial dysfunction. Streptozotocin (55 mg kg(-1), i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce diabetes mellitus (serum glucose >140 mg dl(-1)) and hyperhomocysteinemia (serum homocysteine>10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta and serum concentration of nitrite/nitrate. Serum thiobarbituric acid reactive substances (TBARS) were estimated to assess oxidative stress. Atorvastatin has been employed in the present study as standard drug to improve vascular endothelial dysfunction. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg(-1), p.o.) in diabetic and hyperhomocysteinemic rats significantly reduced serum glucose and homocysteine concentration. BMOV or atorvastatin markedly improved acetylcholine induced endothelium dependent relaxation, vascular endothelial lining, serum nitrite/nitrate concentration and serum TBARS in diabetic and hyperhomocysteinemic rats. However, this ameliorative effect of BMOV has been prevented by l-NAME (25 mg kg(-1), i.p.), an inhibitor of NOS or by glibenclamide (5 mg kg(-1), i.p.), a blocker of ATP sensitive K(+) channels. Therefore, it may be concluded that BMOV induced inhibition of PTPase may activate eNOS due to opening of ATP sensitive K(+) channels and consequently reduce oxidative stress to improve vascular endothelial dysfunction.
Shah
Dhvanit I
DI
Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Patiala-147002 Punjab, India.
Singh
Manjeet
M
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008715:Methionine; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000494:pharmacology* / Q000627:therapeutic use; D011753:Pyrones / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology* / Q000627:therapeutic use; D014664:Vasodilation
D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D015221:Potassium Channels; D011753:Pyrones; D017392:Thiobarbituric Acid Reactive Substances; C074212:bis(maltolato)oxovanadium(IV); D014638:Vanadates; D013311:Streptozocin; D008715:Methionine; D019001:Nitric Oxide Synthase; D017027:Protein Tyrosine Phosphatases; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester