© 1996 American Heart Association, Inc.
Articles |
Identification of Epoxyeicosatrienoic Acids as Endothelium-Derived Hyperpolarizing Factors
From the Departments of Pharmacology and Toxicology and Physiology and the Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Correspondence to William B. Campbell, PhD, Department of Pharmacology and Toxicology, Medical College of Wisconsin, 8701 Watertown Plank Rd, Milwaukee, WI 53226.
Abstract Endothelial cells release several
compounds, including prostacyclin, NO, and
endothelium-derived hyperpolarizing factor (EDHF),
that mediate the vascular effects of vasoactive hormones. The identity
of EDHF remains unknown. Since arachidonic acid causes
endothelium-dependent relaxations of
coronary arteries through its metabolism to
epoxyeicosatrienoic acids (EETs) by cytochrome P450,
we wondered if the EETs represent EDHFs. Precontracted bovine
coronary arteries relaxed in an
endothelium-dependent manner to methacholine. The
cytochrome P450 inhibitors, SKF 525A and
miconazole, significantly attenuated these relaxations. They were also
inhibited by tetraethylammonium (TEA), an
inhibitor of Ca2+-activated
K+ channels, and by high
[K+]o
(20 mmol/L). Methacholine also caused
hyperpolarization of coronary smooth muscle
(-27±3.9 versus -40±5.1 mV), which was completely
blocked by SKF
525A and miconazole. In vessels prelabeled with
[3H]arachidonic acid, methacholine
stimulated the release of 6-ketoprostaglandin
F1
, 12-HETE, and the EETs.
Arachidonic acid relaxed precontracted coronary
arteries, which were also blocked by TEA, charybdotoxin, another
Ca2+-activated K+ channel
inhibitor, and high [K+]o.
14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET relaxed precontracted
coronary vessels (EC50, 1x10-6
mol/L). The four regioisomers were equally active. TEA, charybdotoxin,
and high [K+]o attenuated the EET
relaxations. 11,12-EET hyperpolarized coronary smooth muscle
cells from -37±0.2 to -59±0.3 mV. In the
cell-attached mode of
patch clamp, both 14,15-EET and 11,12-EET increased the open-state
probability of a Ca2+-activated K+
channel in coronary smooth muscle cells. This effect was
blocked by TEA and charybdotoxin. These data support the hypothesis
that the EETs are EDHFs.
Key Words: cytochrome P450 • arachidonic acid • K+ channels • smooth muscle • membrane potential
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