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Vol. 26, Issue 5, 497-501, May 1998
Laboratory of Molecular Immunology (M.N., K.N.),
NHLBI, National
Institutes of Health, and the Department of Pharmacology (Y.O.),
University of Michigan Medical School
Guanabenz (Wytensin) was shown to inactivate nitric oxide synthase
(NOS) activity in vitro and in vivo. In
in vitro studies with the use of a cytosolic fraction from
penile tissue, the inactivation was found to depend on NADPH, time, and
the concentration of guanabenz. The L-, but not the D-, isomer of
arginine could protect from the inactivation, suggesting an active
site-directed event. The kinetics of inactivation could be described by
an apparent dissociation constant for the initial reversible complex
(Ki) and a pseudo first-order
inactivation constant (kinact) of 38.5 µM and 0.179 min-1, respectively. In in
vivo studies, guanabenz was shown to inhibit penile cytosolic NOS
activity in a dose- and time-dependent manner. Treatment of rats with
guanabenz (5 mg/kg/day) for 4 days caused a decrease of approximately
one-half in the NOS activity of the penile cytosolic fraction with a
concomitant loss in the amount of immunodetectable NOS protein.
Treatment for 4 days at a dose of 0.5 mg/kg/day showed a similar
decrease in activity, whereas a dose of 0.05 mg/kg/day showed no
effects. Due to the multitude of processes that are regulated by NO,
the inactivation of NOS is a potential mechanism to be considered in a
variety of biological effects associated with drugs.
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