Divergent nitric oxide bioavailability in men and women with sickle cell disease.
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.


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.
Gladwin
Mark T
MT
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Md 20892-1662, USA. mgladwin@nih.gov
Schechter
Alan N
AN
Ognibene
Frederick P
FP
Coles
Wynona A
WA
Reiter
Christopher D
CD
Schenke
William H
WH
Csako
Gyorgy
G
Waclawiw
Myron A
MA
Panza
Julio A
JA
Cannon
Richard O
RO
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy / Q000503:physiopathology*; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood; D044383:Black People; D001794:Blood Pressure; D003404:Creatinine / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000627:therapeutic use; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009599:Nitroprusside / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009952:Ornithine / Q000097:blood; D012039:Regional Blood Flow / Q000187:drug effects; D012737:Sex Factors; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D015415:Biomarkers; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D003404:Creatinine; D009952:Ornithine; D000109:Acetylcholine; D006918:Hydroxyurea