1 Gamma radiation impairs vascular function, leading to the depression of endothelium-dependent vasodilatation. Loss of the nitric oxide (NO) pathway has been implicated, but little is known about radiation eects on other endothelial mediators. 2 This study investigated the mechanisms of endothelial dysfunction in rabbits subjected to wholebody irradiation from a cobalt 60 source. 3 The endothelium-dependent relaxation of rabbit aorta evoked by acetylcholine (ACh) or A23187 was impaired in a dose-dependent manner by irradiation at 2 Gy or above. Inhibition was evident 9 days post-irradiation and persisted over the 30 day experimental period. 4 Endothelium-independent responses to glyceryl trinitrate (GTN), sodium nitroprusside (SNP) and 3-morpholino-sydnonimine (SIN-1) were suppressed over a similar dose range at 7 ± 9 days postirradiation, but recovered fully by 30 days post-irradiation. 5 In healthy vessels, ACh-induced relaxation was inhibited by L-N o -nitroarginine (L-NA; 3610 74 M) and charybdotoxin (10 78 M) plus apamin (10 76 M) but resistant to indomethacin, indicating the involvement of NO and endothelium-derived hyperpolarizing factor (EDHF). Supporting this, ACh caused smooth muscle hyperpolarization that was reduced by L-NA and charybdotoxin plus apamin. 6 In irradiated vessels, responses to ACh were insensitive to L-NA but abolished by charybdotoxin plus apamin, indicating selective loss of NO-mediated relaxation. 7 In animals treated shortly after irradiation with the antioxidant, a-tocopherol acetate, the NOdependent relaxation was restored without eect on the EDHF-dependent component. 8 The results imply that radiation selectively impairs the NO pathway as a consequence of oxidative stress, while EDHF is able to maintain endothelium-dependent relaxation at a reduced level.