Decreased sensitivity to nitric oxide in the aorta of severely hypercholesterolemic apolipoprotein E-deficient mice

A normal response to nitric oxide donors has been cited as evidence that im paired endothelium-dependent vasodilation during hypercholesterolemia is du e to decreased synthesis of nitric oxide. This tenet was examined by determ ining responses to nitric oxide gas as well as to acetylcholine and sodium nitroprusside in the isolated aorta of apolipoprotein E-deficient mice fed normal or Western-type cholesterol-rich diet until 21 or 35 weeks of age. I n mice fed normal chow, relaxation to all agents remained comparable to tha t obtained in wild-type mice. In mice fed Western diet, the relaxation to a cetylcholine as well as to nitric oxide was decreased at 35 weeks of age. A t 21 weeks of age, decreased sensitivity to nitric oxide was observed despi te a normal response to acetylcholine. The response to sodium nitroprusside was normal in all groups. A decrease in aortic superoxide dismutase activi ty as well as an increase in aortic superoxide anion generated in the prese nce of NADH as measured by lucigenin chemiluminescence was observed in the group fed Western diet at 35 weeks. This provides evidence that altered sup eroxide anion could contribute to the deterioration in nitric oxide sensiti vity that underlies the impaired endothelium-dependent relaxation. These da ta indicate that decreased sensitivity to nitric oxide may contribute to th e development of impaired endothelium-dependent relaxation in hypercholeste rolemia. The response to sodium nitroprusside appears not to reflect the de creased sensitivity of vascular smooth muscle to authentic nitric oxide.