(Hypertension. 1999;33:689-693.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Role of Nitric Oxide–cGMP Pathway in Adrenomedullin-Induced Vasodilation in the Rat
Correspondence to Yasunobu Hirata, MD, The Second Department of Internal Medicine, Faculty of Medicine, University of Tokyo 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail hirata-2im{at}h.u-tokyo.ac.jp
Abstract—We previously reported
that adrenomedullin (AM), a potent vasodilator peptide discovered in
pheochromocytoma cells, stimulates nitric oxide (NO) release in the rat
kidney. To further investigate whether the NO-cGMP pathway is involved
in the mechanisms of AM-induced vasodilation, we examined the effects
of E-4021, a cGMP-specific phosphodiesterase inhibitor, on
AM-induced vasorelaxation in aortic rings and perfused kidneys isolated
from Wistar rats. We also measured NO release from the kidneys using a
chemiluminescence assay. AM (10-10 to 10-7
mol/L) relaxed the aorta precontracted with phenylephrine
in a dose-dependent manner. Denudation of endothelium
(E) attenuated the vasodilatory action of AM (10-7 mol/L
AM: intact (E+) -25.7±5.2% versus denuded (E-) -7.8±0.6%,
P<0.05). On the other hand, pretreatment with
10-8 mol/L E-4021 augmented AM-induced vasorelaxation in
the intact aorta (-49.0±7.9%, P<0.05) but not in the
denuded one. E-4021 also enhanced acetylcholine (ACh)-induced
vasorelaxation in the rat intact aorta (10-7 mol/L ACh
-36.6±8.4% versus 10-8 mol/L E-4021+10-7
mol/L ACh -62.7±3.1%, P<0.05). In perfused kidneys,
AM-induced vasorelaxation was also augmented by preincubation with
E-4021 (10-9 mol/L AM -15.4±0.6% versus
10-8 mol/L E-4021+10-9 mol/L AM
-23.6±1.2%, P<0.01). AM significantly increased NO
release from rat kidneys (
NO: +11.3±0.8 fmol ·
min–1 · g–1 kidney at
10-9 mol/L AM), which was not affected by E-4021. E-4021
enhanced ACh-induced vasorelaxation (10-9 mol/L ACh
-9.7±1.7% versus 10-8 mol/L E-4021+10-9
mol/L ACh -18.8±2.9%, P<0.01) but did not affect
ACh-induced NO release from the kidneys. In the aorta and the kidney,
10-4 mol/L of
NG-nitro-L-arginine methyl
ester, an NO synthase inhibitor, and 10-5
mol/L of methylene blue, a guanylate cyclase
inhibitor, reduced the vasodilatory effect of AM. These
results suggest that the NO-cGMP pathway is involved in the mechanism
of AM-induced vasorelaxation, at least in the rat aorta and
kidney.
Key Words: adrenomedullin • nitric oxide • cyclic GMP • endothelium • phosphodiesterase inhibitors • rats
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