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Pressure‐dependent pulmonary arterieal tone following chronic hypoxia requires depolarization‐induced activation of epidermal growth factor receptor and NADPH oxidase
Author(s) -
Norton Charles Elbert,
Walker Benjimen R.,
Resta Thomas C.
Publication year - 2013
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.27.1_supplement.1140.3
Subject(s) - apocynin , depolarization , nadph oxidase , chemistry , medicine , endocrinology , membrane potential , pulmonary hypertension , biophysics , biology , biochemistry , oxidative stress
Small pulmonary arteries from rats with chronic hypoxia (CH)‐induced pulmonary hypertension exhibit pressure‐induced vascular smooth muscle (VSM) membrane depolarization and elevated tone without a change in intracellular Ca 2+ ([Ca 2+ ] i ). In addition, the epidermal growth factor receptor (EGFR) and NADPH oxidase (NOX) contribute to depolarization‐induced Ca 2+ sensitization in CH pulmonary arteries. Therefore, we hypothesized that pressure‐dependent pulmonary arterial tone following CH requires depolarization‐induced EGFR and NOX activation. To test this hypothesis we measured tone in response to increasing intraluminal pressure steps (5–45 mmHg) in isolated small intrapulmonary arteries (~150 μm diameter) from control and CH (4 wk at 0.5 atm) rats. Arteries were endothelium‐disrupted and loaded with fura‐2 AM to monitor [Ca 2+ ] i . Significant tone was observed at 25, 35, and 45 mmHg in CH (p<0.05) but not control arteries. Consistent with our hypothesis, inhibition of EGFR (AG 1478; 1 μM), NOX (apocynin; 30 μM), or clamping VSM membrane potential with the K + ionophore valinomycin (5 μM) (confirmed using sharp electrodes) abolished tone in CH arteries. Vessel wall [Ca 2+ ] i was unaltered by AG 1478, apocynin, or by increased pressure. We conclude that CH causes pressure‐dependent pulmonary arterial tone through depolarization‐induced EGFR and NOX activation and independently of changes in [Ca 2+ ] i .