(Hypertension. 2000;36:97.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Mechanisms of Reduced Nitric Oxide/cGMP–Mediated Vasorelaxation in Transgenic Mice Overexpressing Endothelial Nitric Oxide Synthase
From the First Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan.
Abstract—NO, constitutively
produced by endothelial NO synthase (eNOS), plays a key
regulatory role in vascular wall homeostasis. We generated transgenic
(Tg) mice overexpressing eNOS in the endothelium and
reported the presence of reduced NO-elicited relaxation. The purpose of
this study was to clarify mechanisms of the reduced response to
NO-mediated vasodilators in eNOS-Tg mice. Thoracic aortas of Tg and
control mice were surgically isolated for vasomotor studies.
Relaxations to acetylcholine and sodium nitroprusside were
significantly reduced in Tg vessels compared with control vessels.
Relaxations to atrial natriuretic peptide and 8-bromo-cGMP
were also significantly reduced in Tg vessels. Reduced relaxations to
these agents were restored by chronic
NG-nitro-L-arginine methyl ester
treatment. Basal cGMP levels of aortas were higher in Tg mice than in
control mice, whereas soluble guanylate cyclase (sGC)
activity in Tg vessels was 
50% of the activity in control vessels.
Moreover, cGMP-dependent protein kinase (PKG) protein levels and PKG
enzyme activity were decreased in Tg vessels. These observations
indicate that chronic overexpression of eNOS in the
endothelium resulted in resistance to the
NO/cGMP-mediated vasodilators and that at least 2 distinct mechanisms
might be involved: one is reduced sGC activity, and the other is a
decrease in PKG protein levels. We reported for the first time that
increased NO release from the endothelium reduces sGC
and PKG activity in mice. These data may provide a new insight into the
mechanisms of nitrate tolerance and cross tolerance to
nitrovasodilators.
Key Words: nitric oxide synthase • mice, transgenic • guanylyl cyclase • protein kinases
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