Acid Sensing Ion Channel 1 Contributes to Endothelium‐Derived Hyperpolarizing Factor Induced Vasodilation in Small Mesenteric Arteries.

Abstract

Acid sensing ion channel 1 (ASIC1) belongs to the amiloride‐sensitive degenerin/epithelial sodium channel superfamily, and is permeable to both Na+ and Ca2+. ASIC channels have been found to regulate blood pressure through mechanotransduction in arterial baroreceptors and are also pH sensors in carotid body chemoreceptors. ASIC1 is additionally expressed in vascular smooth muscle and endothelial cells in a variety of vascular beds; yet little is known regarding the role of ASIC1 in the regulation of local vascular resistance. Although extracellular H+ is the recognized activator of ASIC1, we have previously shown this channel can be activated following G protein‐coupled receptor stimulation. In small mesenteric arteries, we found that ASIC1 contributes to acetylcholine (ACh)‐induced endothelial cell Ca2+ entry and vasodilation. However, the mechanisms involved in activating ASIC1 and its downstream effects on vasodilation are unknown. We hypothesized that ACh activates ASIC1‐mediated endothelial cell Ca2+ entry to mediate endothelium‐derived hyperpolarizing factor (EDHF)‐type vasodilation through activation of small (SK) and intermittent (IK) conductance Ca2+‐activated K+ channels. To test this hypothesis, we used pressure myography to study the effects of ASIC1 on ACh‐induced vasodilation (10−9 – 10−5 M) of freshly isolated mesenteric arteries (100–200 μm inner diameter), in the presence of Nω‐nitro‐L‐arginine (nitric oxide synthase inhibitor) and indomethacin (cyclooxygenase inhibitor). ACh‐induced vasodilation was abolished by specific inhibitors of SK and IK channels (apamin and TRAM‐34, respectively), confirming that the ACh‐induced dilation is EDHF‐dependent. The specific ASIC1 antagonist, psalmotoxin 1 (PcTX1; 20 nM) similarly blocks the EDHF‐mediated vasodilatory response, suggesting ASIC1 contributes to ACh‐induced vasodilation through an EDHF‐mediated pathway. Future studies will examine the upstream mechanisms involved in activation of endothelial ASIC1 and subsequent downstream effects to mediate EDHF‐dependent vasodilation. These studies suggest a role for ASIC1 as a novel contributor to agonist‐induced mesenteric vasodilation and cardiovascular homeostasis.Support or Funding InformationSupported by National Heart, Lung, and Blood Institute Grants R01 HL‐111084 (to N.L. Jernigan), T32 HL007736 (to T.C. Resta), and R01 HL132883 (to T.C. Resta).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.