Afferent arteriolar dilation to 11, 12-EET analogs involves PP2A activity and Ca2+-activated K+ Channels. Microcirculation 2008 Feb;15(2):137-50
Date
02/09/2008Pubmed ID
18260004Pubmed Central ID
PMC2654618DOI
10.1080/10739680701456960Scopus ID
2-s2.0-38949115541 (requires institutional sign-in at Scopus site) 63 CitationsAbstract
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.
Author List
Imig JD, Dimitropoulou C, Reddy DS, White RE, Falck JRMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAnimals
Arterioles
Cyclic AMP
Kidney
Large-Conductance Calcium-Activated Potassium Channels
Male
Muscle Cells
Oxidoreductases
Protein Phosphatase 2
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Vasodilation
Vasodilator Agents
