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(Circulation. 2003;107:271.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Divergent Nitric Oxide Bioavailability in Men and Women With Sickle Cell Disease

Mark T. Gladwin, MD; Alan N. Schechter, MD; Frederick P. Ognibene, MD; Wynona A. Coles, RT; Christopher D. Reiter, PhD; William H. Schenke, BA; Gyorgy Csako, MD; Myron A. Waclawiw, PhD; Julio A. Panza, MD; Richard O. Cannon, III, MD

From the Critical Care Medicine Department (M.T.G., F.P.O., W.A.C., C.D.R.) and Department of Laboratory Medicine (G.C.), Warren G. Magnuson Clinical Center; Laboratory of Chemical Biology (M.T.G., A.N.S., C.D.R.), National Institute of Diabetes, Digestive and Kidney Diseases; Office of Biostatistics Research (M.A.W.), National Heart, Lung and Blood Institute; and Cardiovascular Branch (W.H.S., J.A.P., R.O.C.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md.

Correspondence to Dr Mark T. Gladwin, National Institutes of Health, Bldg 10, Room 7D-43, 10 Center Dr, Bethesda, MD 20892-1662. E-mail mgladwin{at}nih.gov

Background— Although reduced endothelial nitric oxide (NO) bioavailability has been demonstrated in arteriosclerotic vascular disease, the integrity of this system in sickle cell disease remains uncertain.

Methods and Results— We measured forearm blood flow in 21 patients with sickle cell disease (hemoglobin SS genotype) and 18 black control subjects before and after intra-arterial infusions of acetylcholine, nitroprusside, and the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA). Endothelium-dependent vasodilation, measured by the percent increase in flow induced by acetylcholine infusion, was significantly greater than in controls (252±37% for patients versus 134±24% for controls; P<0.0001). However, there was a large sex difference in blood flow responses between female and male patients (340±46% versus 173±41%; P=0.035). Similarly, basal NO bioactivity, as measured by the percent decrease in flow induced by L-NMMA, was depressed in male compared with female patients (-17±5% versus -34±4%; P=0.01), as was the response to nitroprusside (86±21% versus 171±22%; P=0.008). L-NMMA reduced the blood flow response to acetylcholine in women, but not in men. Sex differences in vascular cell adhesion molecule-1 were appreciated, with significant correlations between levels of soluble vascular cell adhesion molecule-1 and blood flow responses to L-NMMA and nitroprusside (r=0.53, P=0.004 and r=-0.66, P<0.001, respectively).

Conclusions— NO bioavailability and NO responsiveness are greater in women than in men with sickle cell disease and determines adhesion molecule expression. Endothelium-dependent blood flows are largely non-NO mediated in male patients. These results provide a possible mechanism for reported sex differences in sickle cell disease morbidity and mortality and provide a basis for novel pharmacological interventions.

Key Words: nitric oxide • endothelium • anemia, sickle cell • acetylcholine • cell adhesion molecules

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