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

JD Imig, C Dimitropoulou, DS Reddy, RE White… - …, 2008 - Taylor & Francis
JD Imig, C Dimitropoulou, DS Reddy, RE White, JR Falck
Microcirculation, 2008Taylor & Francis
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 …
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.
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