NO is an important regulator of vascular tone, blood flow,
and adhesion. In SCD patients, not only is the generation NO
dramatically decreased, but the amount available for use is limited
as well. Its bioavailability can be reduced in several ways:
1) via increases in the free radical superoxide, 2) through the
products of hemolysis (free heme and arginase), and 3) through
the ‘‘uncoupling’’ of endothelial NOS (eNOS; Fig. 2).
The interaction between superoxide and NO is more detrimental
than their individual actions. While in normal systems superoxide
can easily be dismutated by SOD, the overproduction of
O2
2 seen in SCD overwhelms the defenses of body and reacts
at diffusion-limited rates with NO. The reaction of NO and superoxide
results in the generation of peroxynitrite (ONOO2): a
powerful and highly reactant oxidant. The generation of ONOO2
is favored over spontaneous superoxide dismutation and NO
autoxidation; the interaction is faster than both NO’s reaction
with hemoglobin and superoxide’s reaction with SOD (11).
ONOO2 has the opportunity to form
OH and nitrogen dioxide
(NO2), two other potent oxidants (11). The reaction between NO
and O2
2 is double in that it not only further decreases the concentration
of NO, but also produces more reactive free radicals