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

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 mu M). Bronchoconstriction was also attenuated in the presence of two other structurally unrelated KCNQ channel activators: zinc pyrithione (ZnPyr; 1 mu M; 22 +/- 7%) and 2,5-dimethylcelecoxib (10 mu M; 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 beta(2)-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 mu M) 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 beta(2)-adrenergic receptor agonist with a KCNQ channel activator may improve bronchodilator therapy.