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Effect of GSK1016790A, a potent TRPV4 agonist, on lung endothelial permeability
Author(s) -
Jian MingYuan,
Thorneloe Kevine,
Townsley Mary I.
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.797.5
Subject(s) - chemistry , agonist , pharmacology , lung , medicine , receptor , biochemistry
Activation of the vanilloid transient receptor potential channel TRPV4 with 4α‐phorbol‐12,13‐didecanoate (4αPDD) causes Ca 2+ entry‐dependent lung injury in rat and mouse lung. However, 4αPDD has no impact on pulmonary arterial pressure despite TRPV4 expression in pulmonary vascular smooth muscle. In this study, we compared the effect of GSK1016790A, a potent and selective TRPV4 agonist, with that elicited by 4αPDD. Lungs isolated from wild type or TRPV4 −/− mice were perfused with Earle's buffer/4% albumin at constant flow. The filtration coefficient (K f , an index of endothelial permeability) and hemodynamics were measured before and after GSK1016790A or 4αPDD treatment. At 3nM (n=4), GSK1016790A had little impact on permeability. However, K f increased 5.5‐ and 10.6‐fold with 10nM (n=6) and 30nM (n=5) doses, respectively. The permeability response to GSK1016790A was accompanied a transient increase in pulmonary arterial pressure. In contrast, 4αPDD (10μM, n=4) increased K f 3.2‐fold without a concomitant pressor response. Neither 30nM GSK1016790A (n=4) nor 10μM 4αPDD (n=4) had impact on permeability or perfusion pressure in lungs from TRPV4 −/− mice. In summary, GSK1016790A is a much more potent stimulus than 4αPDD for TRPV4‐mediated acute lung injury and pressor responses in isolated mouse lung. Supported by GlaxoSmithKline and HL066299.