KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a beta2-adrenergic agonist enhances relaxation of rat airways Journal Article

Authors: Brueggemann, L. I.; Haick, J. M.; Neuburg, S.; Tate, S.; Randhawa, D.; Cribbs, L. L.; Byron, K. L.
Article Title: KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a beta2-adrenergic agonist enhances relaxation of rat airways
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 muM). Bronchoconstriction was also attenuated in the presence of two other structurally unrelated KCNQ channel activators: zinc pyrithione (ZnPyr; 1 muM; 22 +/- 7%) and 2,5-dimethylcelecoxib (10 muM; 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 beta2-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 muM) 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 beta2-adrenergic receptor agonist with a KCNQ channel activator may improve bronchodilator therapy.
Keywords: Molecular Pharmacology; Male; Animals; Rats; Patch-Clamp Techniques; Rats, Sprague-Dawley; Acetylcholine/secretion; Adrenergic beta-2 Receptor Agonists/pharmacology; Anthracenes/pharmacology; Asthma/drug therapy/metabolism; Bronchi/drug effects; Bronchoconstriction/drug effects; Bronchoconstrictor Agents/pharmacology; Bronchodilator Agents/pharmacology; Carbamates/pharmacology; Ethanolamines/pharmacology; KCNQ Potassium Channels/agonists; Keratolytic Agents/pharmacology; Membrane Transport Modulators/pharmacology; Methacholine Chloride/pharmacology; Myocytes, Smooth Muscle/drug effects/metabolism; Organometallic Compounds/pharmacology; Phenylenediamines/pharmacology; Potassium Channel Blockers/pharmacology; Pyrazoles/pharmacology; Pyridines/pharmacology; Sulfonamides/pharmacology; KCNQ voltage-activated potassium channel; airway smooth muscle; bronchoconstrictor signal transduction; bronchodilator therapy; precision-cut lung slice
Journal Title: American Journal of Physiology - Lung Cellular Molecular Physiology
Volume: 306
Issue: 6
ISSN: 1522-1504
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: L476
End Page: 86
Language: eng
Notes: GR: R01 HL-089564/HL/NHLBI NIH HHS/United States; JID: 100901229; 0 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone); 0 (2,5-dimethylcelecoxib); 0 (Adrenergic beta-2 Receptor Agonists); 0 (Anthracenes); 0 (Bronchoconstrictor Agents); 0 (Bronchodilator Agents); 0 (Carbamates); 0 (Ethanolamines); 0 (KCNQ Potassium Channels); 0 (Keratolytic Agents); 0 (Membrane Transport Modulators); 0 (Organometallic Compounds); 0 (Phenylenediamines); 0 (Potassium Channel Blockers); 0 (Pyrazoles); 0 (Pyridines); 0 (Sulfonamides); 0W5ETF9M2K (Methacholine Chloride); 12G01I6BBU (ezogabine); 5ZZ84GCW8B (formoterol); N9YNS0M02X (Acetylcholine); R953O2RHZ5 (pyrithione zinc); OID: NLM: PMC3949081 [Available on 03/15/15]; OTO: NOTNLM; PMCR: 2015/03/15 00:00; 2014/01/17 [aheadofprint]; ppublish