bis(maltolato)oxovanadium(iv) and Vascular-Diseases

The study has been designed to investigate the effect of BMOV, a protein tyrosine phosphatase (PTPase) inhibitor in uric acid and sodium arsenite-induced vascular endothelial dysfunction (VED). Uric acid (150 mg kg(-)(1) day(-)(1), i.p., 3 weeks) and sodium arsenite (1.5 mg kg(-)(1) day(-)(1), i.p., 2 weeks) were administered to produce VED in rats. VED was assessed by employing isolated aortic ring preparation, electron microscopy of thoracic aorta and estimating serum concentration of nitrite/nitrate. Further, serum thiobarbituric acid reactive substances (TBARS) and aortic production of superoxide anion were estimated to assess oxidative stress. Uric acid and sodium arsenite were noted to produce VED by attenuating acetylcholine-induced endothelium dependent relaxation, impairing the integrity of vascular endothelial lining, decreasing serum nitrite/nitrate concentration and increasing serum TBARS and aortic superoxide anion generation which were significantly attenuated by BMOV (0.2 mg ml(-)(1) day(-)(1) in drinking water) or atorvastatin (30 mg kg(-)(1) day(-)(1)p.o., a standard agent). However, these ameliorative effects of BMOV have been prevented by N-omega-nitro-L-arginine methyl ester (L-NAME) (25 mg kg(-)(1) day(-)(1), i.p.), an inhibitor of NOS and glibenclamide (5 mg kg(-)(1) day(-)(1), i.p.), a blocker of ATP-sensitive K(+) channel. It may be concluded that BMOV-induced inhibition of PTPase may activate eNOS by opening of ATP-sensitive K(+) channels and consequently decrease oxidative stress to prevent uric acid and sodium arsenite-induced vascular endothelial dysfunction.

Topics: Animals; Arsenites; Endothelium, Vascular; Male; Pyrones; Rats; Rats, Wistar; Sodium Compounds; Thiobarbituric Acid Reactive Substances; Uric Acid; Vanadates; Vascular Diseases

The study has been designed to investigate the effect of bis(maltolato) oxovanadium (BMOV), a protein tyrosine phosphatase inhibitor, on hypercholesterolemia and hypertension-induced vascular endothelial dysfunction. High fat diet (8 weeks) and deoxycorticosterone acetate (DOCA; 40 mg kg(-1), s.c.) were administered to rats to produce hypercholesterolemia and hypertension (mean arterial blood pressure >120 mmHg) 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. BMOV (0.2 mg/ml in drinking water) or atorvastatin (30 mg kg(-1), p.o.) markedly improved acetylcholine-evoked endothelium-dependent relaxation, lining of vascular endothelium, serum nitrite/nitrate concentration, and serum TBARS in hypercholesterolemic and hypertensive 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. It may be concluded that BMOV-induced inhibition of PTPase may improve vascular endothelial dysfunction.

Topics: Animals; Blood Pressure; Endothelins; Lipid Metabolism; Male; Microscopy, Electron, Scanning; Nitrates; Nitrites; Pyrones; Rats; Rats, Sprague-Dawley; Thiobarbituric Acid Reactive Substances; Vanadates; Vascular Diseases; Vasodilation

During embryonic development, the growth of blood vessels requires the coordinated activation of endothelial receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie-2. Similarly, in adulthood, activation of endothelial RTKs has been shown to enhance development of the collateral circulation and improve blood flow to ischemic tissues. Recent evidence suggests that RTK activation is negatively regulated by protein tyrosine phosphatases (PTPs). In this study, we used the nonselective PTP inhibitor bis(maltolato)oxovanadium IV (BMOV) to test the potential efficacy of PTP inhibition as a means to enhance endothelial RTK activation and improve collateral blood flow. In cultured endothelial cells, pretreatment with BMOV augmented VEGFR-2 and Tie-2 tyrosine phosphorylation and enhanced VEGF- and angiopoietin-1-mediated cell survival. In rat aortic ring explants, BMOV enhanced vessel sprouting, a process that can be influenced by both VEGFR-2 and Tie-2 activation. Moreover, 2 wk of BMOV treatment in a rat model of peripheral vascular disease enhanced collateral blood flow similarly to VEGF, and after 4 wk, BMOV was superior to VEGF. Taken together, these studies provide evidence that PTPs are important regulators of endothelial RTK activation and for the first time demonstrate the potential utility of phosphatase inhibition as a means to promote collateral development and enhance collateral blood flow to ischemic tissue.

Topics: Animals; Cell Survival; Cells, Cultured; Collateral Circulation; Endothelium, Vascular; Humans; In Vitro Techniques; Male; Neovascularization, Physiologic; Phosphoric Monoester Hydrolases; Protein Tyrosine Phosphatases; Pyrones; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases; Receptor, TIE-2; Vanadates; Vascular Diseases