(Circulation. 1995;92:2636-2644.)
© 1995 American Heart Association, Inc.
Articles |
Chronic Inhibition of Endothelium-Derived Nitric Oxide Synthesis Causes Coronary Microvascular Structural Changes and Hyperreactivity to Serotonin in Pigs
From the Research Institute of Angiocardiology and Cardiovascular Clinic and the First Department of Pathology (K.S.), Kyushu University School of Medicine, Fukuoka, Japan.
Correspondence to Kensuke Egashira, MD, PhD, The Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812, Japan.
Background Endothelium-derived nitric oxide (NO) is believed to regulate myocardial perfusion and structural changes in the vascular wall. Our objective was to determine whether chronic inhibition of NO synthesis causes structural and functional changes in coronary arteries.
Methods and Results Coronary vasomotor response was
studied in pigs before and after chronic oral administration of the NO
synthesis antagonist
N
-nitro-L-arginine methyl ester
(L-NAME) 30 mg · kg-1 · d-1
for 2
weeks. Chronic L-NAME treatment increased (P<.01)
arterial pressure but did not alter baseline
coronary blood flow (CBF), epicardial coronary
diameter, or heart rate. Chronic L-NAME treatment augmented
(P<.01) the decrease in CBF in response to
intracoronary serotonin (30 µg/kg) from
5±14% to 40±5% but did not alter the CBF response to
prostaglandin F2
. The
serotonin-induced decrease in CBF after acute L-NAME
administration was still less before (1.3±0.4%) than after chronic
L-NAME treatment (51±6%). Chronic L-NAME treatment attenuated the
increase in CBF with bradykinin (100 ng/kg) but did not alter the CBF
response to nitroglycerin (10 µg/kg). Compared with
intact pigs without L-NAME treatment, L-NAME–treated pigs had
significant thickening of the media in the microvessels (diameter,
<300 µm) but not in the large epicardial vessels. Chronic
intracoronary infusion of L-NAME at 3
mg · kg-1 · d-1 for 2 weeks,
which
did not produce arterial hypertension, caused similar
microvascular medial thickening.
Conclusions These results indicate that chronic administration of L-NAME caused coronary microvascular structural changes and hyperreactivity to serotonin in pigs in vivo, suggesting an important role of defective NO synthesis in coronary microvascular disorders.
Key Words: microcirculation • endothelium-derived factors • nitric oxide • coronary disease • remodeling
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