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 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.
Dept. of Molecular Pharmacology & Therapeutics, Loyola Univ. Chicago, Stritch School of Medicine, 2160 S. First Ave., Bldg. 102, Rm. 3634, Maywood, IL 60153. kbyron@lumc.edu.
Lioubov I
LI
Brueggemann
Jennifer M
JM
Haick
Samantha
S
Neuburg
Shawn
S
Tate
Devjit
D
Randhawa
Leanne L
LL
Cribbs
Kenneth L
KL
Byron
D000109:Acetylcholine / Q000378:metabolism; D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects*; D016084:Bronchoconstriction / Q000187:drug effects*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D000068759:Formoterol Fumarate; D051656:KCNQ Potassium Channels / Q000819:agonists*; D007641:Keratolytic Agents / Q000494:pharmacology; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology; D016210:Methacholine Chloride / Q000494:pharmacology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology
C112297:10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone; C506698:2,5-dimethylcelecoxib; D058666:Adrenergic beta-2 Receptor Agonists; D000873:Anthracenes; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D002219:Carbamates; D004983:Ethanolamines; D051656:KCNQ Potassium Channels; D007641:Keratolytic Agents; D049990:Membrane Transport Modulators; D009942:Organometallic Compounds; D010655:Phenylenediamines; D026902:Potassium Channel Blockers; D011720:Pyrazoles; D011725:Pyridines; D013449:Sulfonamides; D016210:Methacholine Chloride; C101866:ezogabine; D000109:Acetylcholine; C010423:pyrithione zinc; D000068759:Formoterol Fumarate
KCNQ voltage-activated potassium channel; airway smooth muscle; bronchoconstrictor signal transduction; bronchodilator therapy; precision-cut lung slice