(Circulation. 1997;96:1586-1592.)
© 1997 American Heart Association, Inc.
Articles |
Inhibition of Nitric Oxide Synthesis Increases Adenosine Production via an Extracellular Pathway Through Activation of Protein Kinase C
From the First Department of Medicine, Osaka University School of Medicine, Osaka, Japan.
Correspondence to Masafumi Kitakaze, MD, The First Department of Medicine, Osaka University School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565, Japan. E-mail kitakaze{at}medone.med.osaka-u.ac.jp
Background NO is known to deactivate protein kinase C (PKC). Because we have reported that the activation of PKC activates ecto-5'-nucleotidase, we examined whether the inhibition of NO synthesis increases ecto-5'-nucleotidase activity through the activation of PKC.
Methods and Results The left anterior descending
coronary artery (LAD) was cannulated and perfused with blood
through a bypass tube from the left carotid artery in 65 open-chest
dogs. The intracoronary administration of
NG-nitro-L-arginine methyl ester
(L-NAME, 10 µg · kg-1 ·
min-1), an NO synthase inhibitor,
for 30 minutes increased (P<.05) adenosine levels
in coronary venous blood (123±10 versus 21±3 pmol/mL) and
ecto-5'-nucleotidase activity (64±6 versus 41±4 nmol ·
mg-1 · min-1)
in the LAD-perfused myocardium. The intracoronary
administration of 
,ß-methyleneadenosine 5'-diphosphate, an
inhibitor of ecto-5'-nucleotidase, or GF109203X or
calphostin C, both of which are PKC inhibitors, attenuated
the L-NAME–induced increases in adenosine levels and
ecto-5'-nucleotidase activity. Treatment of cultured human
coronary arterial endothelial cells
(HCAECs) with L-NAME for 30 minutes increased ecto-5'-nucleotidase
activity, which was inhibited by either GF109203X or calphostin C. NO
releasers decreased both ecto-5'-nucleotidase and PKC activities in
HCAECs. Treatment of HCAECs with zaprinast, a selective
inhibitor of cGMP-specific phosphodiesterase, with or
without atrial natriuretic peptide, increased intracellular
cGMP concentrations but did not change ecto-5'-nucleotidase
activity.
Conclusions These results indicate that the inhibition of NO synthesis increases both adenosine production and ecto-5'-nucleotidase activity through the activation of PKC and that NO modulates ecto-5'-nucleotidase via cGMP-independent mechanisms.
Key Words: adenosine • nitric oxide • proteins • cells
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