Afferent Arteriolar Dilation to 11, 12‐EET Analogs Involves PP2A Activity and Ca 2+ ‐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: 01-02-2008
• 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
+
(K
Ca
) 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 K
Ca
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 K
Ca
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 K
Ca
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 K
Ca
channels and dilate the afferent arteriole.