Epoxyeicosatrienoic acid activates BK channels in the cortical collecting duct.
The cortical collecting duct (CCD), which is involved in renal potassium (K) excretion, expresses cytochrome P450 (CYP)-epoxygenase. Here, we examined the effect of high dietary K on renal expression of CYP2C23 and CYP2J2 in the rat, as well as the role of CYP-epoxygenase-dependent metabolism of arachidonic acid in the regulation of Ca(2+)-activated big-conductance K (BK) channels. By Western blot analysis, high dietary K stimulated the expression of CYP2C23 but not CYP2J2 and increased 11,12-epoxyeicosatrienoic acid (11,12-EET) levels in isolated rat CCD tubules. Application of arachidonic acid increased BK channel activity, and this occurred to a greater extent in rats on a high-K diet compared with a normal-K diet. This effect was unlikely due to arachidonic acid-induced changes in membrane fluidity, because 11,14,17-eicosatrienoic acid did not alter BK channel activity. Inhibiting CYP-epoxygenase but not cyclooxygenase- or CYP-omega-hydroxylase-dependent pathways completely abolished the stimulatory effect of arachidonic acid on BK channel activity. In addition, application of 11,12-EET mimicked the effect of arachidonic acid on BK channel activity, even in the presence of CYP-epoxygenase inhibition. This effect seemed specific to 11,12-EET, because both 8,9- and 14,15-EET failed to stimulate BK channels. Finally, inhibition of CYP-epoxygenase abolished iberiotoxin-sensitive and flow-stimulated but not basal net K secretion in isolated microperfused CCD. In conclusion, high dietary K stimulates the renal CYP-epoxygenase pathway, which plays an important role in activating BK channels and flow-stimulated K secretion in the CCD.
Sun
Peng
P
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Liu
Wen
W
Lin
Dao-Hong
DH
Yue
Peng
P
Kemp
Rowena
R
Satlin
Lisa M
LM
Wang
Wen-Hui
WH
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000187:drug effects* / Q000378:metabolism*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D017419:Potassium, Dietary / Q000008:administration & dosage; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley
D000577:Amides; C000717351:Cyp2c23 protein, rat; D065607:Cytochrome P-450 Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; C121756:N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide; D010455:Peptides; D017419:Potassium, Dietary; D016718:Arachidonic Acid; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; C064719:iberiotoxin; D003577:Cytochrome P-450 Enzyme System; D000090762:Cytochrome P-450 CYP2J2; D015126:8,11,14-Eicosatrienoic Acid