© 1997 American Heart Association, Inc.
Articles |
Epoxyeicosatrienoic Acids Activate K+ Channels in Coronary Smooth Muscle Through a Guanine Nucleotide Binding Protein
From the Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee.
Abstract Epoxyeicosatrienoic acids (EETs) are
endothelium-derived arachidonic acid
metabolites of cytochrome P450. They dilate coronary arteries,
open K+ channels, and hyperpolarize vascular smooth
muscles. However, the mechanisms of these smooth muscle actions remain
unknown. This study examined the effects of EETs on the
large-conductance Ca2+-activated K+
channel (KCa) in smooth muscle cells of small bovine
coronary arteries. In cell-attached patch-clamp experiments,
11,12-EET produced a 0.5- to 10-fold increase in the activity of the
KCa channels when added in concentrations of 1, 10, and 100
nmol/L. In the inside-out excised membrane patch mode, 11,12-EET was
without effect on the activity of the KCa channel unless
GTP (0.5 mmol/L) or GTP and ATP (1 mmol/L) were added to the
bath solution. In the presence of GTP and ATP, the increase in the
KCa channel activity with 11,12-EET in inside-out patches
was comparable to that in cell-attached patches. This effect of
11,12-EET in inside-out patches was blocked by the addition of
GDP-ß-S (100 µmol/L). In outside-out patches, 11,12-EET also
increased the KCa channel activity when GTP and ATP were
added to the pipette solution. The addition of a specific
anti-GS
antibody (100 nmol/L) in the pipette solution
completely blocked the activation of the KCa channels
induced by 11,12-EET. An anti-Gß
or anti-Gi
antibody was without effect. We conclude that 11,12-EET
activates the KCa channels by a
GS-mediated mechanism. This mechanism contributes to the
effects of EETs as endothelium-derived hyperpolarizing
factors to hyperpolarize and relax arterial smooth muscle.
Key Words: endothelium-derived hyperpolarizing factor • patch clamp • K+ channel • eicosanoid • G protein
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