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Departments of Internal Medicine and Surgery and the Cardiovascular Center, University of Iowa College of Medicine and Veterans Affairs Medical Center, Iowa City, Iowa 52246
In the canine coronary microcirculation,
acetylcholine (ACh)-induced vasodilation of large (
100 µm)
epicardial arterioles (LgA), but not small (<100 µm) epicardial
arterioles (SmA), is blocked by nitric oxide (NO) synthase inhibitors
in vivo. We hypothesized that the ACh-induced vasodilation of SmA is
mediated by a cytochrome P-450
metabolite of arachidonic acid (AA). Epicardial coronary microvascular
diameters in dogs were measured at baseline and after treatment with
topically applied ACh (1, 10, and 100 µM), AA (1, 5, and 10 µM), or
sodium nitroprusside (SNP; 10-100 µM). Coronary microvascular
diameters were compared among control dogs (group
OO); dogs pretreated with
N
-nitro-L-arginine
(L-NNA; 70 µM
topically) (group NO); dogs pretreated with
L-NNA plus clotrimazole (Clo;
1.6 µM topically) or 17-octadecynoic acid (ODYA; 2 µM topically),
cytochrome P-450 monooxygenase
inhibitors (groups NC and
NY, respectively); dogs pretreated
with Clo alone (group OC); and dogs
pretreated with L-NNA plus Clo
with AA as the agonist (group AA).
ACh-induced vasodilation of LgA was abolished by
L-NNA alone, whereas in SmA,
L-NNA was without effect. Clo alone did not inhibit ACh-induced dilation in either SmA or LgA. However, the combinations of
L-NNA plus either Clo or ODYA
abolished ACh- and AA-induced dilation of SmA (100 µM ACh: NC, 3 ± 5%; NY, 8 ± 2%; 10 µM AA: 6 ± 3%) but did not affect
responses to SNP. These results suggest that the ACh-induced
vasodilation of SmA is mediated in part by cytochrome
P-450 metabolites of AA and provide
the first evidence that the cytochrome
P-450 pathway contributes to the
regulation of coronary resistance vessels in vivo.
arachidonic acid; arginine analog; endothelium-derived hyperpolarizing factor; clotrimazole; intravital microscopy
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