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1 Department of Pharmacology and Toxicology and 2 Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912
It is commonly believed that
the activity of NO synthase (NOS) solely controls NO production from
its substrates, L-Arg and O2. The Michaelis-Menten constant
(Km) of NOS for
L-Arg is in the micromolar
range; cellular levels of L-Arg
are much higher. However, evidence strongly suggests that cellular
supply of L-Arg may become
limiting and lead to reduced NO and increased superoxide anion
(O
2·) formation, promoting
cardiovascular dysfunction. Uptake of
L-Arg into cells occurs
primarily (~85%) through the actions of a
Na+-independent, carrier-mediated
transporter (system y+). We have
examined the effects of NOS agonists (substance P, bradykinin, and ACh)
and NO donors
(S-nitroso-N-acetyl-penicillamine and dipropylenetriamine NONOate) on transport of
L-Arg into bovine aortic
endothelial cells (BAEC). Our results demonstrate that NOS agonists
increase y+ transporter activity.
A rapidly acting NO donor initially increases L-Arg uptake; however, after
longer exposure, L-Arg uptake is suppressed. Exposure of BAEC without
L-Arg to substance P and a
Ca2+ ionophore (A-23187) increased
O2· formation, which was blocked
with concurrent presence of
L-Arg or the NOS antagonist
N
-nitro-L-arginine methyl ester.
We conclude that factors including NO itself control
y+ transport function and the
production of NO and O2·.
nitric oxide; L-arginine uptake; vascular dysfunction; transporter regulation; endothelial cells
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