Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice.
BACKGROUND
Dysfunctionally uncoupled endothelial nitric oxide synthase (eNOS) is involved in producing reactive oxygen species (ROS) in the diabetic endothelium. The present study investigated whether anti-diabetes drug Aminoguanidine (AG) has any effect on eNOS function and vascular oxidant stress.


RESULTS
Blood glucose levels were increased to 452.0 +/- 15.1 mg/dl in STZ-treated male C57BL/6J mice (148.4 +/- 3.2 mg/dl in untreated controls). Aortic productions of NO* and O(2)*- were measured specifically and sensitively using electron spin resonance. Diabetic mice had a marked increase in aortic O(2)*- production. Aortic hydrogen peroxide (H(2)O(2)) production was also increased in diabetic aortas and significantly attenuated by AG. AG however had only a marginal effect in reducing aortic O(2)*- production, which corresponded to a minimal effect in improving aortic nitric oxide (NO*) bioavailability. The endothelium-dependent vasodilatation however was modestly but significantly improved by AG, likely consequent to AG-induced reduction in hyper-contractility. NAD(P)H oxidase (NOX)-dependent O(2)*- production was completely attenuated by AG in endothelium-denuded diabetic aortas.


CONCLUSIONS
In summary, despite that AG is not an effective eNOS recoupling agent presumably consequent to its ineffectiveness in preventing endothelial NOX activation, it is inhibitory of aortic H(2)O(2) production, VSMC NOX activity, and hypercontractility in diabetes.
Oak
Jeong-Ho
JH
Department of Anesthesiology, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA. Oak_Jeong-ho@takeda.co.jp
Youn
Ji-Youn
JY
Cai
Hua
H
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004578:Electron Spin Resonance Spectroscopy; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D006146:Guanidines; D007004:Hypoglycemic Agents; D013481:Superoxides; D009569:Nitric Oxide; D006861:Hydrogen Peroxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; C004479:pimagedine