The sympathetic nervous system and the vascular endothelium act in concert to regulate arterial diameter and thus blood flow and pressure. Vasoconstriction triggers a negative feedback response whereby activation of endothelial small (SKCa) and intermediate (IKCa) conductance calciumactivated potassium channels and/or release of endothelium-derived (NO) limit further reductions in vessel diameter. Thus, we have investigated whether small molecule activators of SKCa and IKCa channels can enhance endothelial modulation of nerve-evoked vasoconstriction in the rat perfused mesenteric bed. N-cyclohexyl-N-[2-(3,5-dimethylpyrazol-1-yl)-6-methyl-4-pyrimid-iamine (CyPPA) and naphtho[1,2-d]thiazol-2-ylamine (SKA-31), activators of SKCa and IKCa channels respectively, each caused concentration-dependent, reversible attenuation of nerve-evoked vasoconstriction without altering basal perfusion pressure. Block of NO signaling significantly enhanced nerve-mediated vasoconstriction and prevented the actions of CyPPA but did not significantly affect responses to SKA-31. In contrast, inhibition of transient receptor potential C3 (TRPC3) channels prevented the actions of SKA-31 but was without effect on responses to CyPPA. Selectivity of CyPPA and SKA- 31 for SKCa and IKCa channels was demonstrated using apamin and 1-[(2-chlorophenyl) diphenyl methyl]-1H-pyrazole (TRAM-34) respectively.This data indicates the different functional roles of SKCa and IKCa channels in endotheliumdependent inhibition of nerve-evoked vasoconstriction of mesenteric arteries; SKCa channels appear to be involved in NO-mediated attenuation of vasoconstriction whereas activation of IKCa channels is linked to an NO-independent pathway. The ability of KCa channel activators to suppress nerve-evoked constriction supports the proposal that these channels may provide novel targets for drugs to overcome the endothelial dysfunction and increased sympathetic out-flow associated with the development of hypertension.
10th World Congress for Microcirculation, Kyoto, Japan 25-27 September 2015