Arachidonic Acid Inhibits Epithelial Na Channel Via Cytochrome P450 (CYP) Epoxygenase-dependent Metabolic Pathways

Autor: Ganesh S.S. Yaddanapudi, John R. Falck, Alberto Nasjletti, Wen-Hui Wang, Dao-Hong Lin, Rowena Kemp, Yuan Wei
Jazyk: angličtina
Rok vydání: 2004
Předmět:
Epithelial sodium channel
Male
Physiology
Metabolite
030204 cardiovascular system & hematology
Cytochrome P-450 CYP2J2
Sodium Channels
Membrane Potentials
Rats
Sprague-Dawley
chemistry.chemical_compound
0302 clinical medicine
Cytochrome P-450 Enzyme System
epoxyeicosatrienoic acid
Cells
Cultured
0303 health sciences
Arachidonic Acid
biology
respiratory system
Na reabsorption
Oxygenases
Arachidonic acid
Female
Ion Channel Gating
hormones
hormone substitutes
and hormone antagonists
Signal Transduction
Epoxygenase
inorganic chemicals
medicine.medical_specialty
ENaC
Epoxyeicosatrienoic acid
cortical collecting duct
Article
03 medical and health sciences
Internal medicine
medicine
Animals
Patch clamp
Kidney Tubules
Collecting
Epithelial Sodium Channels
030304 developmental biology
Dose-Response Relationship
Drug
urogenital system
MS-PPOH
Sodium
Cytochrome P450
Rats
Endocrinology
chemistry
biology.protein
Cyclooxygenase
Zdroj: The Journal of General Physiology
ISSN: 1540-7748
0022-1295
Popis: We used the patch-clamp technique to study the effect of arachidonic acid (AA) on epithelial Na channels (ENaC) in the rat cortical collecting duct (CCD). Application of 10 μM AA decreased the ENaC activity defined by NPo from 1.0 to 0.1. The dose–response curve of the AA effect on ENaC shows that 2 μM AA inhibited the ENaC activity by 50%. The effect of AA on ENaC is specific because neither 5,8,11,14-eicosatetraynoic acid (ETYA), a nonmetabolized analogue of AA, nor 11,14,17-eicosatrienoic acid mimicked the inhibitory effect of AA on ENaC. Moreover, inhibition of either cyclooxygenase (COX) with indomethacin or cytochrome P450 (CYP) ω-hydroxylation with N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS) failed to abolish the effect of AA on ENaC. In contrast, the inhibitory effect of AA on ENaC was absent in the presence of N-methylsulfonyl-6-(propargyloxyphenyl)hexanamide (MS-PPOH), an agent that inhibits CYP-epoxygenase activity. The notion that the inhibitory effect of AA is mediated by CYP-epoxygenase–dependent metabolites is also supported by the observation that application of 200 nM 11,12-epoxyeicosatrienoic acid (EET) inhibited ENaC in the CCD. In contrast, addition of 5,6-, 8,9-, or 14,15-EET failed to decrease ENaC activity. Also, application of 11,12-EET can still reduce ENaC activity in the presence of MS-PPOH, suggesting that 11,12-EET is a mediator for the AA-induced inhibition of ENaC. Furthermore, gas chromatography mass spectrometry analysis detected the presence of 11,12-EET in the CCD and CYP2C23 is expressed in the principal cells of the CCD. We conclude that AA inhibits ENaC activity in the CCD and that the effect of AA is mediated by a CYP-epoxygenase–dependent metabolite, 11,12-EET.
Databáze: OpenAIRE
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