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KCNQ (Kv7) potassium channel activators as bronchodilators: combination with a {Beta}2-adrenergic agonist enhances relaxation of rat airways

Significance Statement

Asthma is a major public health problem in the United States, affecting more than 25 million people, including over 7 million children. Asthma is characterized by reversible airway obstruction and hyper-responsiveness of the airways to multiple bronchoconstrictor stimuli. Bronchorelaxant drugs are routinely administered to relieve airway obstruction, but these treatments are often inadequate.The article by Brueggemann et al. (PMCID: PMC3949081) 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 {Beta}2-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 pM) 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.

 

Figure Legend: 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 pM, 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).

KCNQ (Kv7) potassium channel activators as bronchodilators- global medical discovery

 

 

 

 

 

 

 

Journal Reference

Brueggemann LI, Haick JM, Neuburg S, Tate S, Randhawa D, Cribbs LL, Byron KL.

Am J Physiol Lung Cell Mol Physiol. 2014 Mar 15;306(6):L476-86.

Dept. of Molecular Pharmacology & Therapeutics, Loyola Univ. Chicago, Stritch School of Medicine, 2160 S. First Ave., Bldg. 102, Rm. 3634, Maywood, IL 60153. [email protected]

 

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 broncho-constriction 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.

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