title: Involvement of inducible nitric oxide synthase in radiation-induced vascular endothelial damage.
abstract: 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-N(ω)-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-N(6)-(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.
authors.affiliation: Department of Chemical and Biological Warfare Research, The Armed Forces Medical Research Institute, P.O. Box 78-503, Chumok-dong, Yuseong-gu, Daejeon, 305-878, Republic of Korea.
authors.forename: Chang-Won
authors.initials: CW
authors.lastname: Hong
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Kim
authors.forename: Hongryull
authors.initials: H
authors.lastname: Pyo
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Lee
authors.forename: Suwan
authors.initials: S
authors.lastname: Kim
authors.forename: Sunyoung
authors.initials: S
authors.lastname: Lee
authors.forename: Jae Myoung
authors.initials: JM
authors.lastname: Noh
mesh_terms: D000818:Animals; D001783:Blood Flow Velocity / Q000502:physiology / Q000528:radiation effects; D002339:Carotid Arteries / Q000502:physiology* / Q000528:radiation effects*; D002478:Cells, Cultured; D004307:Dose-Response Relationship, Radiation; D042783:Endothelial Cells / Q000502:physiology* / Q000528:radiation effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D011817:Rabbits; D011829:Radiation Dosage; D014664:Vasodilation / Q000502:physiology* / Q000528:radiation effects*; D014965:X-Rays
chemical_list: D052247:Nitric Oxide Synthase Type II
keywords: inducible nitric oxide synthase; nitrotyrosine; radiation injuries; vascular endothelium