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Role of NADPH oxidase in enhanced membrane depolarization‐induced Ca 2+ ‐sensitization in pulmonary vascular smooth muscle following chronic hypoxia
Author(s) -
Norton Charles Elbert,
Broughton Brad,
Walker Benjimen,
Resta Thomas
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1023.19
Subject(s) - apocynin , depolarization , hypoxic pulmonary vasoconstriction , chemistry , nadph oxidase , vasoconstriction , sensitization , vascular smooth muscle , hypoxia (environmental) , biophysics , membrane potential , medicine , endocrinology , pharmacology , oxygen , biochemistry , reactive oxygen species , biology , smooth muscle , immunology , organic chemistry
Chronic hypoxia (CH) augments membrane depolarization induced myofilament Ca 2+ ‐sensitization in pulmonary vascular smooth muscle (VSM) through O 2 − dependent stimulation of RhoA, a response that may contribute to the vasoconstrictor component of pulmonary hypertension (PH). We hypothesized that NADPH oxidase (NOX)‐derived O 2 − mediates this sensitization. To test our hypothesis, we examined effects of apocynin (30 μM) on vasoreactivity to depolarizing concentrations of KCl in isolated, saline perfused lungs from control and CH (4 wk at 0.5 atm) rats. We additionally measured vasoconstrictor responses to KCl in the presence or absence of the NOX inhibitors apocynin or diphenylene iodonium (10 μM) in endothelium‐disrupted, Ca 2+ permeabilized, small pulmonary arteries from each group. Parallel experiments in pressurized arteries used the fluorescent O 2 − indicator, dihydroethidium, to assess effects of NOX inhibition on depolarization induced O 2 − production. CH augmented KCl‐dependent vasoconstriction in both isolated lungs and arteries and increased O 2 − generation as previously reported. Furthermore, both NOX inhibitors prevented these effects of CH, resulting in normalization of responses to the level of controls. We conclude that NOX is a source of O 2 − responsible for enhanced membrane depolarization‐induced pulmonary VSM Ca 2+ ‐sensitization and vasoconstriction in CH‐induced PH.