Afferent Arteriolar Dilation to 11, 12-EET Analogs Involves PP2A Activity and Ca2 +-Activated K+ Channels

• Published in: Microcirculation (New York, N.Y. 1994) Vol. 15; no. 2; pp. 137 - 150
• Main Authors: Imig, John D., Dimitropoulou, Christiana, Reddy, D. Sudarshan, White, Richard E., Falck, John R.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Informa UK Ltd 01-02-2008; Blackwell Publishing Ltd
• Subjects: 8,11,14-Eicosatrienoic Acid - analogs & derivatives; 8,11,14-Eicosatrienoic Acid - pharmacology; Animals; Arterioles - metabolism; Cyclic AMP - metabolism; CYP450 metabolites; endothelium-derived hyperpolarizing factor; epoxyeicosatrienoic acids; Kidney - blood supply; Large-Conductance Calcium-Activated Potassium Channels - antagonists & inhibitors; Large-Conductance Calcium-Activated Potassium Channels - metabolism; Male; Muscle Cells - metabolism; Oxidoreductases - metabolism; Protein Phosphatase 2 - antagonists & inhibitors; Protein Phosphatase 2 - metabolism; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; vascular smooth muscle; Vasodilation - drug effects; Vasodilator Agents - pharmacology
• ISSN: 1073-9688; 1549-8719
• DOI: 10.1080/10739680701456960

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.