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Vol. 59, Issue 1, 24-29, January 2001
Department of Pharmacology, The University of Michigan Medical
School, Ann Arbor, Michigan
It is established that agmatine, an endogenously formed decarboxylated
arginine, is a weak competitive inhibitor of neuronal nitric-oxide
synthase (nNOS) with an apparent Ki value of
660 µM [Biochem J 316:247-249, 1996].
Although agmatine is known to bind to 
-adrenergic and imidazoline
receptors, it has been suggested that some of the pharmacological
actions of agmatine, such as the prevention of morphine tolerance, may
be due to the inhibition of nNOS. In the current study, we have
discovered that agmatine, at concentrations much lower than the
reported Ki value, leads to a time-,
concentration-, NADPH-, and calmodulin-dependent irreversible
inactivation of nNOS. 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 29 µM and 0.01 min
1, respectively. As determined by
high-performance liquid chromatography analysis, the mechanism of
inactivation involves alteration of the prosthetic heme moiety of nNOS,
in part to protein-bound products. Moreover, we discovered that
agmatine causes a 3-fold increase in the NADPH oxidase activity of nNOS
leading to the production of
H2O2 and is a likely cause
for the inactivation of the enzyme. Both the inactivation of nNOS and
the oxidative stress produced should now be considered in the
pharmacological actions of agmatine as well as provide insight into the
potential biological effects of endogenously formed agmatine.
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