Involvement of inducible nitric oxide synthase in radiation-Induced vascular endothelial damage

The use of radiation therapy has been linked to an increased risk of cardiovascular disease. to understand the mechanisms underlying radiation-induced vascular dysfunction,we employed two models. first,we examined the effect of x-ray irradiation on vasodilation in rabbit carotid arteries. carotid arterial rings were irradiated with 8 or 16 gy using in vivo and ex vivo methods. we measured the effect of acetylcholine-induced relaxation after phenylephrine-induced contraction on the rings. in irradiated carotid arteries,vasodilation was significantly attenuated by both irradiation methods. the relaxation response was completely blocked by 1h-[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one,a potent inhibitor of soluble guanylate cyclase. residual relaxation persisted after treatment with l-nω-nitroarginine (l-na),a non-specific inhibitor of nitric oxide synthase (nos),but disappeared following the addition of aminoguanidine (ag),a selective inhibitor of inducible nos (inos). the relaxation response was also affected by tetraethylammonium,an inhibitor of endothelium-derived hyperpolarizing factor activity. in the second model,we investigated the biochemical events of nitrosative stress in human umbilical-vein endothelial cells (huvecs). we measured inos and nitrotyrosine expression in huvecs exposed to a dose of 4 gy. the expression of inos and nitrotyrosine was greater in irradiated huvecs than in untreated controls. pretreatment with ag,l-n6-(1-iminoethyl) lysine hydrochloride (a selective inhibitor of inos),and l-na attenuated nitrosative stress. while a selective target of radiation-induced vascular endothelial damage was not definitely determined,these results suggest that no generated from inos could contribute to vasorelaxation. these studies highlight a potential role of inos inhibitors in ameliorating radiation-induced vascular endothelial damage. © the author 2013. published by oxford university press on behalf of the japan radiation research society and japanese society for therapeutic radiology and oncology.