KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a β2-adrenergic agonist enhances relaxation of rat airways.
Am J Physiol-Lung Cell Mol Physiol. 2014 Mar;306(6):L476-L486.
Brueggemann LI,1 Haick JM, 1 Neuburg S, 1 Tate S, 1 Randhawa D, 1 Cribbs LL, 2 Byron KL. 1
1Department of Molecular Pharmacology and Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA; and 2Department of Cellular and Molecular Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
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.
Asthma is a major public health problem in the United States, affecting more than 25 million people, including over 7 million children (1). Asthma is characterized by reversible airway obstruction and hyper-responsiveness of the airways to multiple bronchoconstrictor stimuli (2). Bronchorelaxant drugs are routinely administered to relieve airway obstruction, but these treatments are often inadequate (3). The article by Brueggemann et al. (PMID: 24441871) considers novel pharmacological treatment strategies for bronchorelaxation that may represent an improvement over existing therapeutic regimens. It provides evidence that KCNQ potassium channels are expressed and functional in rat airway smooth muscle cells, along with compelling evidence that multiple structurally unrelated pharmacological KCNQ channel activators are effective bronchodilators. A long-acting β2-adrenergic receptor agonist, formoterol, which is commonly used for relief of excessive airway constriction in asthma patients, is also an effective bronchodilator in rat airways, though it does not affect KCNQ potassium currents. More importantly, the bronchorelaxant effects of formoterol are greatly increased and prolonged when it is administered in combination with the clinically used KCNQ channel activator, retigabine, suggesting a new combination therapy with potential for enhanced efficacy.
Although the published study utilized rat airways as a model system, preliminary results suggest that human lungs may respond similarly. As shown in the Figure below, in precision-cut slices from an asthmatic human lung (obtained post-mortem from a subject who died as a result of an asthma attack), histamine (25 nM) induced a profound bronchiolar constriction. Addition of 30 pM formoterol resulted in a very modest relaxation that was delayed for several minutes. Formoterol treatment reproducibly elicited even smaller responses with repeated exposures (not shown), but when formoterol was combined with retigabine (30 µM), the airway relaxed rapidly and more completely (up to 92% relaxation), compared with <20% relaxation with formoterol alone over the same time frame. These results, though preliminary in nature, suggest that the findings from rat airways may ultimately be translated to improved clinical therapies for human asthma patients.
Combination therapy: KCNQ channel activator retigabine, in combination with formoterol, enhances relaxation of an asthmatic human airway. Representative recording of cross sectional airway area from an asthmatic human bronchiole. Histamine (25 nM, blue boxes) was applied twice, followed by 30 min treatment with 30 pM formoterol alone (H + F; 18% relaxation) or 30 pM formoterol plus 30 µM retigabine (H + F + R; 92% relaxation).
- CDC Centers for Disease Control and Prevention: Asthma; www.cdc.gov/asthma/
- National Asthma Education and Prevention Program, Third Expert Panel on the Diagnosis and Management of Asthma. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. Bethesda (MD): National Heart, Lung, and Blood Institute (US); 2007 Aug. Section 2, Definition, Pathophysiology and Pathogenesis of Asthma, and Natural History of Asthma.Available from: http://www.ncbi.nlm.nih.gov/books/NBK7223/
- Wener RR, Bel EH, Frances L, Leiva-Salinas M, Silvestre JF, Ernst A, Anantham D, Cook ML, Bochner BS, Martin-Mateos MA. (2013) Severe refractory asthma: an update. Eur Respir Rev, 22, 227-35.
Acknowledgements: Support for this work was provided by the National Heart, Lung, and Blood
Institute (R01 HL-089564 to K. L. Byron) and by intramural funds from Loyola University Chicago.
Kenneth L. Byron, Ph.D., FAHA
Professor and Assistant Provost for Research
Dept. of Molecular Pharmacology & Therapeutics
Loyola University Chicago Health Sciences Division
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