Abstract：
: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.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Chen J,Capdevila JH,Zeldin DC,Rosenberg RLdoi
10.1124/mol.55.2.288subject
Has Abstractpub_date
1999-02-01 00:00:00pages
288-95issue
2eissn
0026-895Xissn
1521-0111journal_volume
55pub_type
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