title: Afferent arteriolar dilation to 11, 12-EET analogs involves PP2A activity and Ca2+-activated K+ Channels.
abstract: The epoxygenase metabolite, 11, 12-epoxyeicosatrienoic acid (11, 12-EET), has renal vascular actions. 11, 12-EET analogs have been developed to determine the structure activity relationship for 11, 12-EET and as a tool to investigate signaling mechanisms responsible for afferent arteriolar dilation. We hypothesized that 11, 12-EET mediated afferent arteriolar dilation involves increased phosphoprotein phosphatase 2A (PP2A) and large-conductance calcium activated K+ (KCa) channels. We evaluated the chemically and/or metabolically table 11, 12-EET analogs: 11, 12-EET-N-methylsulfonimide (11, 12-EET-SI), 11-nonyloxy-undec-8(Z)-enoic acid (11, 12-ether-EET-8-ZE), and 11, 12-trans-oxidoeicosa-8(Z)-eonoic acid (11, 12-tetra-EET-8-ZE). Afferent arteriolar responses were assessed. Activation of KCa channels by 11, 12-EET analogs were established by single cell channel recordings in renal myocytes. Assessment of renal vascular responses revealed that 11, 12-EET analogs increased afferent arteriolar diameter. Vasodilator responses to 11, 12-EET analogs were abolished by K+ channel or PP2A inhibition. 11, 12-EET analogs activated renal myocyte large-conductance KCa channels. 11, 12-EET analogs increased cAMP by 2-fold and PP2A activity increased 3-8 fold in renal myocytes. PP2A inhibition did not significantly affect the 11, 12-EET analog mediated increase in cAMP and PP2A increased renal myocyte KCa channel activity to a much greater extent than PKA. These data support the concept that 11, 12-EET utilizes PP2A dependent pathways to activate large-conductance KCa channels and dilate the afferent arteriole.
authors.affiliation: Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA. jdimig@mcg.edu
authors.forename: John D
authors.initials: JD
authors.lastname: Imig
authors.forename: Christiana
authors.initials: C
authors.lastname: Dimitropoulou
authors.forename: D Sudarshan
authors.initials: DS
authors.lastname: Reddy
authors.forename: Richard E
authors.initials: RE
authors.lastname: White
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D007668:Kidney / Q000098:blood supply*; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D032342:Muscle Cells / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D014665:Vasodilator Agents; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D000242:Cyclic AMP; D010088:Oxidoreductases; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2; D015126:8,11,14-Eicosatrienoic Acid