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Chronic Hypoxia Augments Membrane Depolarization‐Induced Myofilament Ca 2+ ‐Sensitization Through Stimulation of Rho Kinase in Small Pulmonary Arteries
Author(s) -
Broughton Brad R.S.,
Walker Benjimen R.,
Resta Thomas C.
Publication year - 2007
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.21.6.a1437
Subject(s) - sensitization , myofilament , depolarization , rho associated protein kinase , hypoxia (environmental) , stimulation , medicine , chemistry , cardiology , phosphorylation , myocyte , immunology , biochemistry , oxygen , organic chemistry
Rho kinase (ROK)‐dependent Ca 2+ sensitization contributes to pressure‐induced tone in small pulmonary arteries following chronic hypoxia (CH). Since vascular smooth muscle (VSM) membrane potential ( E m ) is depolarized in intrapulmonary arteries from CH vs. control rats over a range of transmural pressures, we hypothesized that CH‐induced pulmonary VSM E m depolarization increases myofilament Ca 2+ sensitivity via stimulation of ROK. To test this hypothesis, we assessed vasoconstrictor responses to depolarizing concentrations of KCl (30–120 mM) in the presence or absence of the ROK inhibitor, HA‐1077 (10 μM), in endothelium‐denuded, pressurized pulmonary arteries (157.0 ± 5.8 μm inner diameter) from control and CH (4 wk at 0.5 atm) rats. Arteries were permeabilized to Ca 2+ with ionomycin and loaded with fura‐2 AM to verify that VSM [Ca 2+ ] i was maintained constant during KCl‐induced vasoconstriction. Consistent with our hypothesis, vasoconstriction to KCl was augmented following CH. Further, ROK inhibition attenuated KCl‐induced vasoconstriction only in CH arteries. However, substantial vasoreactivity remained following ROK inhibition in both groups, suggesting that additional Ca 2+ sensitization pathways contribute to depolarization‐dependent vasoconstriction. We conclude that CH increases E m depolarization‐induced Ca 2+ sensitization in pulmonary VSM through enhanced ROK signaling.