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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

Transient Receptor Potential Vanilloid 4 Activation Constricts the Human Bronchus via the Release of Cysteinyl Leukotrienes

M. Allen McAlexander, Mark A. Luttmann, Gerald E. Hunsberger and Bradley J. Undem
Journal of Pharmacology and Experimental Therapeutics April 2014, 349 (1) 118-125; DOI: https://doi.org/10.1124/jpet.113.210203
M. Allen McAlexander
Respiratory Therapy Area, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (M.A.M., M.A.L., G.E.H.); and Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, Maryland (B.J.U.)
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Mark A. Luttmann
Respiratory Therapy Area, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (M.A.M., M.A.L., G.E.H.); and Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, Maryland (B.J.U.)
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Gerald E. Hunsberger
Respiratory Therapy Area, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (M.A.M., M.A.L., G.E.H.); and Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, Maryland (B.J.U.)
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Bradley J. Undem
Respiratory Therapy Area, GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania (M.A.M., M.A.L., G.E.H.); and Johns Hopkins Medical Institutions, Johns Hopkins University, Baltimore, Maryland (B.J.U.)
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Abstract

Prior studies have demonstrated that the ion channel transient receptor potential vanilloid 4 (TRPV4) is functionally expressed in airway smooth muscle cells and that TRPV4 single nucleotide polymorphisms are associated with airflow obstruction in patients with chronic obstructive pulmonary disease. We sought to use isometric tension measurements in ex vivo airways to determine whether short-term pharmacological activation of TRPV4 with the potent agonist GSK1016790 [N-((1S)-1-{[4-((2S)-2-{[(2,4-dichlorophenyl)sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide] would constrict human bronchial tissue. As predicted, transient receptor potential vanilloid 4 activation in the human airway produces contractions that are blocked by the nonselective transient receptor potential channel blocker ruthenium red. Moreover, the novel TRPV4-selective blocker GSK2334775 [(R)-6-(methylsulfonyl)-3-((4-(pyrrolidin-1-yl)piperindin-1-yl)methyl)-N-(2,2,2,-trifluoro-1-phenylethyl)-2-(3-(trifluoromethyl)phenyl)quinoline-4-carboxamide] inhibited these contractions over a concentration range consistent with its in vitro potency against recombinant and native TRPV4-containing channels. Surprisingly, TRPV4-dependent contractions were also blocked by a 5-lipoxygenase inhibitor and two structurally distinct cysteinyl leukotriene 1 receptor antagonists. In aggregate, our results fail to support the hypothesis that TRPV4 in airway smooth muscle cells regulates airway contractility short term. Rather, we provide pharmacological evidence that TRPV4 activation causes human airway constriction that is entirely dependent upon the production of cysteinyl leukotrienes. Together, these data identify a novel mechanism by which TRPV4 activation may contribute to pathologic remodeling and inflammation, in addition to airflow obstruction, in the diseased human respiratory tract.

Footnotes

    • Received October 4, 2013.
    • Accepted February 4, 2014.
  • This research was supported by the National Institutes of Health National Heart, Lung, and Blood Institute [Grant 5R01-HL062296]; and GlaxoSmithKline Pharmaceuticals.

  • dx.doi.org/10.1124/jpet.113.210203.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 349 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 349, Issue 1
1 Apr 2014
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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

TRPV4 Activation Constricts Human Airways via Cysteinyl Leukotrienes

M. Allen McAlexander, Mark A. Luttmann, Gerald E. Hunsberger and Bradley J. Undem
Journal of Pharmacology and Experimental Therapeutics April 1, 2014, 349 (1) 118-125; DOI: https://doi.org/10.1124/jpet.113.210203

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Research ArticleGastrointestinal, Hepatic, Pulmonary, and Renal

TRPV4 Activation Constricts Human Airways via Cysteinyl Leukotrienes

M. Allen McAlexander, Mark A. Luttmann, Gerald E. Hunsberger and Bradley J. Undem
Journal of Pharmacology and Experimental Therapeutics April 1, 2014, 349 (1) 118-125; DOI: https://doi.org/10.1124/jpet.113.210203
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