Imig John D, Dimitropoulou Christiana, Reddy D Sudarshan, White Richard E, Falck John R
Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912, USA.
Microcirculation. 2008 Feb;15(2):137-50. 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.
环氧合酶代谢产物11,12 - 环氧二十碳三烯酸（11,12 - EET）具有肾血管作用。已开发出11,12 - EET类似物以确定11,12 - EET的构效关系，并作为研究负责传入小动脉扩张的信号传导机制的工具。我们假设11,12 - EET介导的传入小动脉扩张涉及磷酸蛋白磷酸酶2A（PP2A）和大电导钙激活钾离子（KCa）通道增加。我们评估了化学和/或代谢稳定的11,12 - EET类似物：11,12 - EET - N - 甲基磺酰亚胺（11,12 - EET - SI）、11 - 壬氧基 - 十一碳 - 8（Z） - 烯酸（11,12 - 醚 - EET - 8 - ZE）和11,12 - 反式 - 氧化二十碳 - 8（Z） - 烯酸（11,12 - 四 - EET - 8 - ZE）。评估了传入小动脉的反应。通过肾肌细胞的单细胞通道记录确定了11,12 - EET类似物对KCa通道的激活作用。肾血管反应评估显示，11,12 - EET类似物增加了传入小动脉直径。K + 通道或PP2A抑制消除了对11,12 - EET类似物的血管舒张反应。11,12 - EET类似物激活了肾肌细胞的大电导KCa通道。11,12 - EET类似物使肾肌细胞中的cAMP增加了2倍，PP2A活性增加了3 - 8倍。PP2A抑制并未显著影响11,12 - EET类似物介导的cAMP增加，并且PP2A比PKA更大程度地增加了肾肌细胞KCa通道活性。这些数据支持了11,12 - EET利用PP2A依赖性途径激活大电导KCa通道并扩张传入小动脉的概念。
