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Transient receptor potential vanilloid 4 activation constricts the human bronchus
via the release of cysteinyl leukotrienes
#MMPMID24504097
McAlexander MA
; Luttmann MA
; Hunsberger GE
; Undem BJ
J Pharmacol Exp Ther
2014[Apr]; 349
(1
): 118-25
PMID24504097
show ga
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.
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