Activators of endothelial calcium-activated potassium channels enhance the availability of NO released in response to shear stress (1079.22)

Nerve‐evoked vasoconstriction of resistance arteries is limited by shear stress‐induced release of endothelium‐derived nitric oxide (NO) and activation of endothelial Ca2+‐activated potassium (KCa) channels. NO and KCa are often regarded as separate pathways for modulation of vascular tone but recent data from our lab indicate small molecule activators of endothelial KCa channels enhance the availability of NO released in response to agonists. In this study we have extended these observations to test the hypothesis that activators of KCa channels can enhance the availability of NO released in response to increases in shear stress caused by nerve‐evoked vasoconstriction. In the rat perfused mesenteric bed, N‐cyclohexyl‐N‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐4‐pyrimid‐iamine (CyPPA; 1‐10 μM), a small molecule activator of small conductance KCa channels (SKCa) did not alter basal perfusion pressure but did cause endothelium‐ and concentration‐dependent attenuation of nerve‐evoked vasoconstriction. Inhibitors of NO synthase, soluble guanylyl cyclase or SKCa channels, significantly enhanced nerve‐mediated vasoconstriction and prevented the effects CyPPA. In contrast, scavengers of superoxide enhanced the ability of CyPPA to limit vasoconstriction. Inhibition of endothelial intermediate conductance KCa channels or cyclooxygenase did not alter nerve‐evoked responses and did not alter the effects of CyPPA whereas Our findings indicate SKCa channel openers can enhance NO‐mediated modulation of nerve‐evoked vasoconstriction without altering basal perfusion. This finding is significant as in vivo such an effect could reduce vasoconstriction whilst avoiding the baroreceptor activation seen with direct vasodilators and thus may reduce blood pressure whilst maintaining the physiological coupling between nerves, endothelium and changes in blood flow. Supported by HSFC. SL is supported by a QEII award from the University of Alberta.