© 1997 American Heart Association, Inc.
Articles |
Nitric Oxide–Independent Dilation of Conductance Coronary Arteries to Acetylcholine in Conscious Dogs
From the Department of Physiology, Faculty of Medicine, Université de Montréal and Institut de Cardiologie de Montréal (Canada). Correspondence to Michel Lavallée, Institut de Cardiologie de Montréal, 5000, Bélanger St East, Montréal, Québec, Canada H1T 1C8.
Abstract NO and prostacyclin formation cannot entirely
account for receptor-operated endothelium-dependent
dilation of coronary vessels, since vasodilator responses are
not completely suppressed by inhibitors of these agents.
Therefore, we considered that another factor, such as an
endothelium-derived hyperpolarizing factor described in
vitro, may participate in NO- and prostacyclin-independent
coronary dilator responses. In conscious instrumented dogs,
intracoronary acetylcholine (ACh, 30.0 ng ·
kg-1 · min-1) increased the external
epicardial coronary diameter (CD) by 0.18±0.03 mm (from
3.44±0.11 mm) when increases in coronary blood flow (CBF)
were prevented and increased the CD by 0.20±0.05 when CBF was allowed
to increase. After the administration of intracoronary
N
-nitro-L-arginine methyl
ester (L-NAME), CBF responses to ACh were abolished, but CD responses
(0.23±0.05 from 3.22±0.09 mm) were maintained. Blockade of NO
formation was confirmed by reduced CD baselines and blunted
flow-dependent CD responses caused by adenosine and transient
coronary artery occlusions after L-NAME administration.
ACh-induced CD increases resistant to L-NAME and
indomethacin were reduced after the administration of
intracoronary quinacrine, an inhibitor of
phospholipase A2, or proadifen, an inhibitor of
cytochrome P-450. Quinacrine or proadifen alone (without L-NAME) did
not alter CD responses to ACh, but L-NAME given after proadifen blunted
ACh-induced increases in CD. The increases in CD caused by
arachidonic acid given after
L-NAME+indomethacin were antagonized by proadifen but
not altered by quinacrine. Thus, a cytochrome P-450 metabolite of
arachidonic acid accounts for L-NAME–resistant
and indomethacin-resistant dilation of large
epicardial coronary arteries to ACh. Conversely, NO formation
is the dominant mechanism of ACh-induced dilation after blockade of the
cytochrome P-450 pathway.
Key Words: acetylcholine • nitric oxide • coronary artery • phospholipase A2 • cytochrome P-450
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