Endothelial Kir channels amplify the actions of endothelium‐dependent vasodilators in systemic resistance arteries

Abstract

Smooth muscle cells (SMCs) in systemic resistance (mesenteric) arteries lack strong inward rectifier K+ (Kir) channels, which are responsible for external K+‐induced dilations of cerebral arteries. Here we report that pressurized, resistance‐sized (3rd‐order branches) mesenteric arteries from mice dilate to an elevation of external K+ from 6 to 14 mM, which is prevented by Kir blockers Ba2+ (100 μM) and ML 133 (20 μM) or removal of the endothelium. Freshly isolated endothelial cells (ECs) exhibited robust Kir currents (‐7 pA/pF at ‐140 mV, 60 mM external K+). Kir channel currents and K+‐induced dilations were absent in myocytes or arteries from EC‐specific Kir2.1 knockout mice. We have recently shown that muscarinic receptor activation causes vasodilation through membrane hyperpolarization via stimulation of EC TRPV4 (transient receptor potential vanilloid 4) and IK (intermediate conductance calcium activated potassium) channels (Sonkusare et al, Science, 2012; Science Signaling, 2014). We therefore tested the hypothesis that EC Kir channels act as amplifiers to this signaling pathway to enhance EC‐dependent vasodilation. Indeed, vasodilation to stimulation of each element of this pathway (muscarinic receptors, TRPV4, IK) was attenuated by EC Kir channel blockers or in the absence of EC‐Kir2.1. These results suggest that EC Kir2.1 channels have a central role in vasodilation to external K+ and endothelial‐dependent vasodilators.