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Intermittent hypoxia increases Rho kinase‐mediated myofilament Ca2+ sensitization in small pulmonary arteries
Author(s) -
Snow Jessica Bayne,
Kanagy Nancy L.,
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.a1438-b
Subject(s) - hypoxic pulmonary vasoconstriction , vasoconstriction , rho associated protein kinase , pulmonary hypertension , medicine , hypoxia (environmental) , endocrinology , endothelin 1 , sensitization , vasodilation , pulmonary artery , chemistry , cardiology , receptor , kinase , oxygen , immunology , biochemistry , organic chemistry
Chronic intermittent hypoxia (IH) associated with sleep apnea increases circulating concentrations of the vasoconstrictor peptide, endothelin‐1 (ET‐1), and elicits pulmonary hypertension. We hypothesized that, similar to chronic sustained hypoxia, IH enhances pulmonary vasoconstrictor reactivity to ET‐1 through Rho kinase (ROK)‐mediated vascular smooth muscle (VSM) Ca 2+ sensitization. To test this hypothesis, we assessed vasoconstrictor responses to ET‐1 (10 −10 –10 −7 M) in the presence or absence of the ROK inhibitor Y‐27632 (10 μM) in endothelium‐denuded, pressurized pulmonary arteries (141 ± 16 μm inner diameter) from IH rats (3 min cycles to 5% O 2 /air flush, 7 hr/day for 4 wk) or air controls (air/air cycling for equal duration). Arteries were permeabilized to Ca 2+ with ionomycin (3 μM) and superfused with a 300 nM Ca 2+ solution. VSM was loaded with fura‐2 AM to verify that the intracellular free Ca 2+ concentration was maintained constant during ET‐1‐induced vasoconstriction. Consistent with our hypothesis, IH augmented ET‐1‐induced vasoconstriction (10 −10 –10 −9 M). Furthermore, ROK inhibition attenuated ET‐1‐mediated constriction in both control (10 −8 M) and CH (10 −10 –10 −7 M) arteries and normalized responses between groups. We conclude that IH enhances ET‐1‐induced, ROK‐dependent Ca 2+ sensitization in pulmonary VSM. (Supported by NIH grants HL‐07736, HL‐77876, HL‐58124 and HL‐63207) 1Pulmonary Vascular Responses to Acute Aypoxia