ASIC1 mediates enhanced receptor‐mediated vasoconstriction following chronic hypoxia‐induced pulmonary hypertension

Abstract

Increases in pulmonary vascular smooth muscle (VSM) store‐operated Ca2+ entry (SOCE) are implicated in augmented basal VSM intracellular Ca2+([Ca2+]i) and enhanced vasoconstriction in chronic hypoxia (CH)‐induced pulmonary hypertensive rats. Our laboratory has recently characterized a unique role for acid sensing ion channel 1 (ASIC1) in regulating SOCE in pulmonary VSM. The goal of the present study was to determine the physiological importance of ASIC1‐mediated SOCE to receptor‐mediated pulmonary vasoconstriction. We hypothesized that enhanced Ca2+ entry through ASIC1 contributes to increased receptor‐mediated vasoconstriction following CH. To test this hypothesis we examined vasoconstrictor and VSM [Ca2+]i to UTP, endothelin‐1, KCl (depolarizing stimulus), and elevated intraluminal pressure (myogenic) in fura‐2‐loaded, endothelium‐disrupted, pressurized small pulmonary arteries from control and CH rats (4 wk at 0.5 atm). Specific inhibition of ASIC1 with psalmotoxin 1 (PcTX1) attenuated vasoconstriction and increases in VSM [Ca2+]i to UTP and endothelin‐1 in arteries from control and CH rats; normalizing the responses between groups. However, PcTX1 had no effect on depolarization‐ or pressure‐induced vasoconstriction and changes in VSM [Ca2+]i. These studies support a novel role of ASIC1 in elevated receptor‐stimulated vasoconstriction following CH which is likely mediated through increased SOCE.