Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and β2-adrenergic intrinsic efficacy

Kumakura, Hiroaki; Fukunaga, Kentaro; Oguma, Tetsuya

doi:10.1016/j.pharmthera.2015.09.004

Cited by 31 publications

(38 citation statements)

References 93 publications

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“…In the GAA-deficient ASM cells, if VDCC activity is reduced or SOC channels are disrupted, the effects of ␤ 2agonists would be attenuated. This may account for the lack of response to ␤ 2 -agonists in Gaa Ϫ/Ϫ mice as revealed in this study, in keeping with findings that a rise in cAMP upon ␤ 2 -adrenergic receptor activation inhibits VDCCs directly or indirectly in ASM cells (31,32). Since cAMP can inhibit the SOC entry in ASM cells (1,20,52), it would be of great interest to study the potential role of this calcium entry pathway in mediating the defect in ␤ 2 -agonist induced airway relaxation in Gaa Ϫ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 91%

Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice

Keeler

Liu

Zieger

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pompe disease is an autosomal recessive disorder caused by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for hydrolyzing lysosomal glycogen. Deficiency of GAA leads to systemic glycogen accumulation in the lysosomes of skeletal muscle, motor neurons, and smooth muscle. Skeletal muscle and motor neuron pathology are known to contribute to respiratory insufficiency in Pompe disease, but the role of airway pathology has not been evaluated. Here we propose that GAA enzyme deficiency disrupts the function of the trachea and bronchi and this lower airway pathology contributes to respiratory insufficiency in Pompe disease. Using an established mouse model of Pompe disease, the mouse, we compared histology, pulmonary mechanics, airway smooth muscle (ASM) function, and calcium signaling between and age-matched wild-type (WT) mice. Lysosomal glycogen accumulation was observed in the smooth muscle of both the bronchi and the trachea in but not WT mice. Furthermore, mice had hyporesponsive airway resistance and bronchial ring contraction to the bronchoconstrictive agents methacholine (MCh) and potassium chloride (KCl) and to a bronchodilator (albuterol). Finally, calcium signaling during bronchiolar smooth muscle contraction was impaired in mice indicating impaired extracellular calcium influx. We conclude that GAA enzyme deficiency leads to glycogen accumulation in the trachea and bronchi and impairs the ability of lower ASM to regulate calcium and respond appropriately to bronchodilator or constrictors. Accordingly, ASM dysfunction may contribute to respiratory impairments in Pompe disease.

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Section: Discussionsupporting

confidence: 91%

Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice

Keeler

Liu

Zieger

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A recent COPD guideline states that a combination of bronchodilators of different pharmacological classes may improve effectiveness and decrease the risk of adverse reactions compared to increasing the dose of a single bronchodilator [ 2 ]. Long-acting β 2 -adrenoceptor agonists (LABAs) and long-acting muscarinic receptor antagonists (LAMAs) are two types of bronchodilators widely used as therapy for this disease, and there is a pharmacological rationale for the use of a combination of these agents [ 9 , 10 , 11 , 12 ]. Recent studies in patients with COPD have also demonstrated that the LABA/LAMA combination is more effective in improving symptoms and lung function, and reducing exacerbations, than monotherapy with either agent [ 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle

Fukunaga

Kumakura

Oguma

et al. 2016

IJMS

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Long-acting muscarinic antagonists (LAMAs) and short-acting β2-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 μM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K+ (KCa) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+ sensitization mediated by PKC and Ca2+ dynamics mediated by KCa channels. PKC and KCa channels may be molecular targets for cross talk between β2-adrenoceptors and muscarinic receptors.

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“…Thus far, the pharmacological treatment of asthma and COPD mainly relies upon β2 agonists and muscarinic antagonists, which can affect β2-adrenergic and muscarinic receptors, respectively. Through the regulation of signal pathways related to G protein-coupled receptors, the reduction of intracellular calcium, and the subsequent opening of VDCC/NSCC, airway smooth muscle tone could be relaxed [6, 7]. However, numerous studies have indicated that currently available bronchodilators, especially β2-agonists and muscarinic antagonists, have additive effects on safety, desensitization and tolerability [8–10].…”

Section: Introductionmentioning

confidence: 99%

Nelumbo nucifera leaves extracts inhibit mouse airway smooth muscle contraction

Yang¹,

Lü²,

Zhao

et al. 2017

BMC Complement Altern Med

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BackgroundAlkaloids extracted from lotus leaves (AELL) can relax vascular smooth muscle. However, whether AELL has a similar relaxant role on airway smooth muscle (ASM) remains unknown. This study aimed to explore the relaxant property of AELL on ASM and the underlying mechanism.MethodsAlkaloids were extracted from dried lotus leaves using the high temperature rotary evaporation extraction method. The effects of AELL on mouse ASM tension were studied using force measuring and patch-clamp techniques.ResultsIt was found that AELL inhibited the high K+ or acetylcholine chloride (ACh)-induced precontraction of mouse tracheal rings by 64.8 ± 2.9%, or 48.8 ± 4.7%, respectively. The inhibition was statistically significant and performed in a dose-dependent manner. Furthermore, AELL-induced smooth muscle relaxation was partially mediated by blocking voltage-dependent Ca2+ channels (VDCC) and non-selective cation channels (NSCC).ConclusionAELL, which plays a relaxant role in ASM, might be a new complementary treatment to treat abnormal contractions of the trachea and asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12906-017-1674-7) contains supplementary material, which is available to authorized users.

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Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and β2-adrenergic intrinsic efficacy

Cited by 31 publications

References 93 publications

Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice

Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle

Nelumbo nucifera leaves extracts inhibit mouse airway smooth muscle contraction

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Research and development of bronchodilators for asthma and COPD with a focus on G protein/KCa channel linkage and β2-adrenergic intrinsic efficacy

Cited by 31 publications

References 93 publications

Airway smooth muscle dysfunction in Pompe (Gaa−/−) mice

Airway smooth muscle dysfunction in Pompe (Gaa−/−) mice

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and β2-Adrenoceptor Agonists in Airway Smooth Muscle

Nelumbo nucifera leaves extracts inhibit mouse airway smooth muscle contraction

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Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice

Airway smooth muscle dysfunction in Pompe (Gaa^−/−) mice