Ca2+ Dynamics and Ca2+ Sensitization in the Regulation of Airway Smooth Muscle Tone

Kumakura, Hiroaki

doi:10.5772/60969

Cited by 4 publications

(18 citation statements)

References 172 publications

(275 reference statements)

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“…We also examined the effects of a combination of SABAs with glycopyrronium on MCh-induced tension and intracellular Ca 2+ concentration. When the SABAs procaterol (0.1–1 nM) and salbutamol (1–10 nM) were applied in the presence of glycopyrronium, the relaxant effect was greater than the sum of the effects of the equivalent concentrations of each agent ( Figure 4 and Figure 5 ), similar to the combined relaxant effect of indecaterol (a LABA) and glycopyrronium shown in previous reports [ 9 , 10 ]. These results demonstrate that pre-exposure to a lower concentration of glycopyrronium markedly enhances the effect of SABAs.…”

Section: Discussionsupporting

confidence: 84%

“…These results demonstrate that pre-administration of a LAMA causes a marked augmentation in the relaxant action of SABAs, and that Ca 2+ signaling due to both Ca 2+ dynamics and Ca 2+ sensitization contributes to this synergistic effect (cross talk between β 2 -adrenoceptors and muscarinic receptors). Recent reports have demonstrated that indacaterol, a LABA, synergistically augments the inhibitory effects of glycopyrronium against muscarinic contraction in airway smooth muscle [ 9 , 10 ]. Moreover, synergistic effects are similarly observed between olodaterol, another LABA, and tiotropium [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…In airway smooth muscle, LABAs and LAMAs act synergistically, enhancing inhibition of muscarinic contraction more than the sum of the effects of each agent [ 9 , 10 ]. Cross talk between these two receptors may contribute to this synergistic effect in airway smooth muscle.…”

Section: Introductionmentioning

confidence: 99%

“…MP is phosphorylated by Rho-kinase, which is an effector of the small G protein RhoA [ 26 , 27 , 28 ] and by C-kinase-potentiated protein phosphatase-1 inhibitor (CPI-17), which is another potential mediator regulated by protein kinase C (PKC) ( Figure 1 ) [ 29 , 30 , 31 ]. Ca 2+ signaling in airway smooth muscle plays an essential role in the pathophysiology of asthma and COPD [ 9 , 10 , 32 , 33 , 34 , 35 , 36 , 37 ].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress

Lhc

Mdcc

et al. 2019

Front. Pharmacol.

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Asthma is a heterogeneous disease of the airways characterized by chronic inflammation associated with bronchial and smooth muscle hyperresponsiveness. Currently, different murine models for the study of asthma show poor bronchial hyperresponsiveness due to a scarcity of smooth muscle and large airways, resulting in a failure to reproduce smooth muscle hyperreactivity. Thus, we aimed to standardize a guinea pig model of chronic allergic lung inflammation mimicking airway smooth muscle hyperreactivity observed in asthmatics (Asth). Animals were randomly divided into a control group (Ctrl), which received saline (0.9% NaCl), and the Asth group, subjected to in vivo sensitization with ovalbumin (OVA) nebulization. Morphological analysis was performed by hematoxylin-eosin staining. Bronchial hyperresponsiveness was evaluated by nebulization time in the fifth, sixth, and seventh inhalations (NT5-7) and tracheal isometric contractions were assessed by force transducer. Total antioxidant capacity was measured by the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method and protein expression by Western blot. Histologically, the Asth group developed peribronchial cellular infiltrate, epithelial hyperplasia and smooth muscle thickening. After the fourth nebulization, the Asth group developed bronchial hyperreactivity. The trachea from the Asth group contracted after in vitro stimulation with OVA, differing from the Ctrl group, which showed no response. Additionally, airway smooth muscle hyperreactivity to carbachol and histamine was observed in the Asth group only in intact epithelium preparations, but not to KCl, and this effect was associated with an augmented production of reactive oxygen species. Moreover, lung inflammation impaired the relaxant potency of isoproterenol only in intact epithelium preparations, without interfering with nifedipine, and it was found to be produced by transforming growth factor-β negative modulation of β adrenergic receptors and, furthermore, big-conductance Ca 2+ -sensitive K + channels. These effects were also associated with increased levels of phosphatidylinositol 3-kinases but not extracellular signal-regulated kinases 1/2 or phosphorylation, and augmented α-actin content as well, explaining the increased smooth muscle mass. Furthermore, pulmonary antioxidant capacity was impaired in the Asth group. Therefore, we developed a standardized and easy-to-use, reproducible guinea pig model of lung inflammation that mimics airway smooth muscle hypercontractility, facilitating the investigation of the mechanisms of bronchial hyperresponsiveness in asthma and new therapeutic alternatives.

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Eosinophil Inflammation and Hyperresponsiveness in the Airways as Phenotypes of COPD, and Usefulness of Inhaled Glucocorticosteroids

Kumakura¹,

Hojo

Hashimoto

2019

Front. Pharmacol.

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Background: The differential diagnosis in persistent airway limitation is sometimes not so clear in older adults. Airway eosinophilia and airway hyperresponsiveness may develop in some cases with chronic obstructive lung disease (COPD), independent of asthma. However, little is known about clinical significance of these phenotypes of COPD in detail. Aims and objectives: This clinical study was designed to examine prevalence of airway eosinophilia and airway hyperresponsiveness in COPD who have no symptom and no past history of asthma, and to examine involvement of these pathophysiological features of asthma in the management and therapy for COPD. Methods: Sputum examination via qualitative and quantitative procedures was performed in stable COPD (GOLD 1–3). When sputum eosinophils were qualitatively (≥+) or quantitatively assessed (≥3%), ciclesonide (inhaled glucocorticosteroids) was added on bronchodilators. In cases with FEV 1 ≥ 70% of predicted values, acetylcholine provocation test was examined for assessment of airway hyperresponsiveness. Therapeutic effect was evaluated using spirometry and COPD assessment test (CAT). Results: Sputum eosinophils were observed in 65 (50.4%) of 129 subjects using qualitative analysis; in contrast, lower grade (>0%) and higher grade (≥3%) were observed in 15 (20.3%) and 25 (33.8%) of 74 subjects using quantitative analysis. Airway hyperresponsiveness developed in 46.9% of these subjects with sputum eosinophils. Exacerbations occurred much more frequently in lower-grade airway eosinophilia without ciclesonide than in higher-grade airway eosinophilia with ciclesonide. Airway hyperresponsiveness significantly increased frequency of exacerbations in COPD with both lower and higher grade in airway eosinophilia. Addition of ciclesonide to indacaterol markedly improved lung function (FEV 1 , IC), CAT score, and reliever use in these subjects with airway eosinophilia determined by qualitative analysis. However, ciclesonide was less effective in improving these values in subjects with airway hyperresponsiveness than in those without airway hyperresponsiveness. Conclusions: Airway eosinophilia and airway hyperresponsiveness are complicated with 25–50% of COPD that have no symptom and history for asthma. These phenotypes of COPD are closely related to symptom stability and reactivity to glucocorticosteroids. These phenotypes may play key roles for advancement of the management and therapy of this disease.

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Ca2+ Dynamics and Ca2+ Sensitization in the Regulation of Airway Smooth Muscle Tone

Abstract: Airway smooth muscle tone is ultimately generated by phosphorylation of myosin light chain, which is regulated by the balance between concentrations of Ca + and

Cited by 4 publications

References 172 publications

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

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

A Guinea Pig Model of Airway Smooth Muscle Hyperreactivity Induced by Chronic Allergic Lung Inflammation: Contribution of Epithelium and Oxidative Stress

Eosinophil Inflammation and Hyperresponsiveness in the Airways as Phenotypes of COPD, and Usefulness of Inhaled Glucocorticosteroids

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