Aminoguanidine inhibits aortic hydrogen peroxide production, VSMC NOX activity and hypercontractility in diabetic mice

Abstract

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.Methods and 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 2O 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.Conclusion: 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 2O 2production, VSMC NOX activity, and hypercontractility in diabetes. © 2009 Oak et al; licensee BioMed Central Ltd.