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Acid‐sensing ion channel 1 contributes to pulmonary arterial smooth muscle cell depolarization following hypoxic pulmonary hypertension
Author(s) -
Jernigan Nikki L.,
Naik Jay S.,
Resta Thomas C.
Publication year - 2021
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jp282231
Subject(s) - depolarization , pulmonary hypertension , cardiology , medicine , ion channel , hypoxia (environmental) , chemistry , oxygen , organic chemistry , receptor
Pulmonary hypertension is characterized by sustained vasoconstriction and remodelling of the small pulmonary arteries, which is associated with persistent depolarization of the resting membrane potential ( E m ) of pulmonary arterial smooth muscle cells (PASMCs). It is well‐known that the underlying mechanism of this depolarization includes inhibition of K + channels; however, whether other ion channels contribute to this depolarization is unknown. We previously reported that acid‐sensing ion channel 1 (ASIC1), a non‐selective cation channel (NSCC) that conducts both Na + and Ca 2+ , is present in PASMCs and contributes to the development of chronic hypoxia (CH)‐induced pulmonary hypertension. Therefore, we tested the hypothesis that ASIC1‐mediated Na + influx contributes to PASMC E m regulation following CH‐induced pulmonary hypertension. Using sharp electrode intracellular recordings in isolated, pressurized small pulmonary arteries from rats and mice, we show that exposure to CH leads to PASMC membrane depolarization compared with control animals, and this is independent of intraluminal pressure‐induced depolarization. In addition to a decrease in PASMC whole‐cell K + currents following CH, we demonstrate that whole‐cell NSCC currents are increased and essential to the persistent CH‐induced E m depolarization in PASMCs. Both the specific inhibitor of ASIC1, psalmotoxin 1, and global knockout of ASIC1 ( Asic1 –/– ) prevents CH‐induced E m depolarization and largely inhibits whole‐cell NSCC currents, without affecting whole‐cell K + currents. Our results show a combination of factors, including inhibition of K + efflux and augmented Na + influx, mediate CH‐induced PASMC depolarization. Furthermore, this study demonstrates a novel role for ASIC1 in the regulation of E m in PASMCs during CH‐induced pulmonary hypertension.Key points In pulmonary hypertensive patients and animal models of pulmonary hypertension, the resting membrane potential ( E m ) of pulmonary arterial smooth muscle cells (PASMCs) is persistently depolarized. In addition to the well‐established reduction of K + conductance, we show that non‐selective cation channel currents are increased and essential to the persistent E m depolarization in PASMCs following chronic hypoxia (CH)‐induced pulmonary hypertension. The current study provides novel evidence that acid‐sensing ion channel 1 (ASIC1)‐mediated Na + influx induces membrane depolarization and regulates E m in PASMCs following CH exposure. Although fairly quiescent under control conditions, our findings demonstrate a pathological function of ASIC1 in the development of chronic hypoxia‐induced pulmonary hypertension.