Effects of aging and atherosclerosis on endothelial and vascular smooth muscle function in humans.

BACKGROUND: Nitric oxide is an endothelium dependent dilator, which may protect against atherosclerosis. Several studies have shown a decrease in nitric oxide activity with aging, however none have assessed aging and atherosclerosis separately. We tested the hypothesis that aging blunts both basal and receptor-mediated endothelial nitric oxide release in humans. METHODS: We examined whether forearm blood flow responses to intra-arterial acetylcholine, and nitroprusside, were altered with aging, with and without co-infusion of an inhibitor of nitric oxide synthase (N(G)-mono-methyl-L-arginine) in three groups of human subjects; a group with clinical atherosclerotic vascular disease (n = 31, 21 M), otherwise healthy elderly (n = 17, 13 M), and healthy young controls (n = 15, 8 M). RESULTS: There was no difference in basal flows between the three groups. There was also no difference in the dilatation to either acetylcholine or nitroprusside responses between the AVD and the healthy elderly group; however, aging significantly decreased acetylcholine or nitroprusside responses when compared to the young controls (p < 0.02). Furthermore, the ratio between acetylcholine and nitroprusside, a marker of endothelial NO synthase activity, was significantly greater in the young volunteers (0.816 +/- 0.094% vs. 0.892 +/- 0.146 % vs. 1.389 +/- 0.2%, in atherosclerotic vascular disease, healthy elderly group, and young controls respectively). CONCLUSIONS: Forearm blood flow responses to endothelium dependent and independent stimuli are blunted with aging, independent of the presence of atherosclerotic disease. Moreover, the normal aging process may induce significant global vascular dysfunction (involving the endothelium and the vascular smooth muscle); to as great a degree as clinically manifest atherosclerosis.

Xanthine oxidase inhibition reverses endothelial dysfunction in heavy smokers.

BACKGROUND: Cigarette smoking causes endothelial dysfunction, possibly through increased oxidant stress. The enzyme xanthine oxidase produces oxidative free radicals. We tested the hypothesis that xanthine oxidase contributes to endothelial dysfunction in cigarette smokers by administering the inhibitor allopurinol. METHODS AND RESULTS: Fourteen cigarette smokers (31+/-4 pack years) and 14 age- and sex-matched healthy non-smoking control subjects participated in a single-blinded, randomized, 2-phase crossover study. All subjects had no other risk factors for atherosclerosis. Inhibition of xanthine oxidase was achieved by a single oral dose of 600 mg of allopurinol on the day of the study. Stimulated nitric oxide endothelial responses were assessed by forearm blood flow responses to intraarterial administration of acetylcholine and bradykinin 4 to 7 hours later; basal nitric oxide was assessed using the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA); and nitroprusside was used to assess sensitivity to nitric oxide. Dilatation produced by acetylcholine was significantly less in smokers (254+/-57%) than healthy controls (390+/-55%) (P=0.009). Allopurinol reversed endothelial dysfunction in smokers (acetylcholine, 463+/-78%, P=0.001) without affecting responses in non-smokers (401+/-80%). Bradykinin responses were also impaired in smokers (P=0.003), and improved with allopurinol, though not significantly (P=0.06). Responses to nitroprusside and L-NMMA were not significantly different between smokers and controls and were not altered by allopurinol. CONCLUSIONS: Smoking-induced endothelial dysfunction of resistance vessels is rapidly reversed with oral allopurinol. These data suggest that xanthine oxidase contributes importantly to endothelial dysfunction caused by cigarette smoking.