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Vol. 55, Issue 2, 288-295, February 1999
Departments of
Cell and Molecular Physiology (J.C., R.L.R) and
Pharmacology (R.L.R), University of North Carolina, Chapel Hill, North
Carolina;
Department of Medicine, Vanderbilt University Medical School,
Nashville, Tennessee (J.H.C); and
Laboratory of Pulmonary Pathobiology,
National Institute of Environmental Health Science, Research Triangle
Park, North Carolina (D.C.Z.).
Epoxyeicosatrienoic acids (EETs), products of the cytochrome P-450
monooxygenase metabolism of arachidonic acid, can regulate the activity
of ion channels. We examined the effects of EETs on cardiac
L-type Ca2+ channels that play important roles
in regulating cardiac contractility, controlling heart rate, and
mediating slow conduction in normal nodal cells and ischemic
myocardium. Our experimental approach was to reconstitute porcine
L-type Ca2+ channels into planar lipid bilayers
where we could control the aqueous and lipid environments of the
channels and the regulatory pathways that change channel properties. We
found that 20 to 125 nM EETs inhibited the open probability of
reconstituted L-type Ca2+ channels, accelerated
the inactivation of the channels, and reduced the unitary current
amplitude of open channels. There was no selectivity among different
EET regioisomers or stereoisomers. When 11,12-EET was esterified to the
sn-2 position of phosphatidylcholine, restricting it to
the hydrophobic phase of the planar lipid bilayer, the reconstituted channels were similarly inhibited, suggesting that the EET interacts directly with Ca2+ channels through the lipid phase. The
inhibitory effects of EET persisted in the presence of microcystin, an
inhibitor of protein phosphatases 1 and 2A, suggesting that
dephosphorylation was not the mechanism through which these eicosanoids
down-regulate channel activity. This inhibition may be an important
protective mechanism in the setting of cardiac ischemia where
arachidonic acid levels are dramatically increased and EETs have been
shown to manifest preconditioning-like effects.
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