Referenced in: none

Automatically associated channels: Kv7.1 , Kv7.2 , Kv7.3 , Kv7.4 , Kv7.5

Title: KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a β2-adrenergic agonist enhances relaxation of rat airways.

Authors: Lioubov I Brueggemann, Jennifer M Haick, Samantha Neuburg, Shawn Tate, Devjit Randhawa, Leanne L Cribbs, Kenneth L Byron

Journal, date & volume: Am. J. Physiol. Lung Cell Mol. Physiol., 2014 Mar 15 , 306, L476-86

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24441871

Abstract
KCNQ (Kv7 family) potassium (K(+)) channels were recently found in airway smooth muscle cells (ASMCs) from rodent and human bronchioles. In the present study, we evaluated expression of KCNQ channels and their role in constriction/relaxation of rat airways. Real-time RT-PCR analysis revealed expression of KCNQ4 > KCNQ5 > KCNQ1 > KCNQ2 > KCNQ3, and patch-clamp electrophysiology detected KCNQ currents in rat ASMCs. In precision-cut lung slices, the KCNQ channel activator retigabine induced a concentration-dependent relaxation of small bronchioles preconstricted with methacholine (MeCh; EC50 = 3.6 ± 0.3 μM). Bronchoconstriction was also attenuated in the presence of two other structurally unrelated KCNQ channel activators: zinc pyrithione (ZnPyr; 1 μM; 22 ± 7%) and 2,5-dimethylcelecoxib (10 μM; 24 ± 8%). The same three KCNQ channel activators increased KCNQ currents in ASMCs by two- to threefold. The bronchorelaxant effects of retigabine and ZnPyr were prevented by inclusion of the KCNQ channel blocker XE991. A long-acting β2-adrenergic receptor agonist, formoterol (10 nM), did not increase KCNQ current amplitude in ASMCs, but formoterol (1-1,000 nM) did induce a time- and concentration-dependent relaxation of rat airways, with a notable desensitization during a 30-min treatment or with repetitive treatments. Coadministration of retigabine (10 μM) with formoterol produced a greater peak and sustained reduction of MeCh-induced bronchoconstriction and reduced the apparent desensitization observed with formoterol alone. Our findings support a role for KCNQ K(+) channels in the regulation of airway diameter. A combination of a β2-adrenergic receptor agonist with a KCNQ channel activator may improve bronchodilator therapy.