Effects of K+ channel inhibitors on the basal tone and KCl- or methacholine-induced contraction of mouse trachea

Li, Liang; Paakkari, Ilari; Vapaatalo, Heikki

doi:10.1016/s0014-2999(98)00074-0

Cited by 11 publications

(7 citation statements)

References 24 publications

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“…Furthermore, there was no substantial variation in this response to KCl throughout the various zones of the airway. These results appear to be inconsistent with the robust contractions induced by high KCl in the tracheal or bronchial SMCs from mice or other species (37,38). However, we found that the SMC twitching correlated with the occurrence of slow Ca 2ϩ oscillations within the individual SMCs rather than sustained elevated levels of Ca 2ϩ .…”

Section: Discussioncontrasting

confidence: 91%

Contractility and Ca²⁺ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Bai

Zhang

Sanderson

2007

Am J Respir Cell Mol Biol

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The control and mechanisms of airway smooth muscle cell (SMC) contraction were investigated with a sequential series of lung slices from different generations of the same airway from the cardiac lobe of the mouse lung. Airway contraction was measured by monitoring the changes in airway lumen area with phase-contrast microscopy. Changes in intracellular calcium concentration of the SMCs were studied with a custom-built confocal or two-photon microscope. The distribution of the airway SMCs and the muscarinic Excessive contraction of airway smooth muscle cells (SMCs) is a major cause of airway narrowing in asthma. This change in the contractile function of SMCs frequently occurs secondarily to airway inflammation, which itself can contribute to increased resistance to airflow by thickening of the airway wall or mucus hypersecretion (1). Although inflammatory responses occur throughout the bronchial tree (2-4), the increased responsiveness and resistance due to airway narrowing appears to be more prevalent in the peripheral airways (1, 5-7). Therefore, to understand this localized reaction, it is important to determine if the contractile responses of SMCs vary in different sections of the respiratory tract and if this predisposes the peripheral airways to disease.Because of their small size and inaccessible location, the physiology of intact intrapulmonary airways has been difficult to study. As a result, comparative reports of the contractile responses in proximal and distal airways of different species are CLINICAL RELEVANCEThis study implies that the heterogeneity of airway contraction must be considered when the impact of the hyperreactivity of a diseased airway is evaluated. inconsistent (8-13). In general, the distal airways appeared more contractile than proximal airways and this difference may result from variations in the structure of the airway wall or the heterogeneity in the SMCs (13). However, a fundamental question is whether the contractility of individual SMC varies in different zones of the intrapulmonary airways. It has been shown that the magnitude of airway SMC contraction relates to the frequency of agonist-induced Ca 2ϩ oscillations within the SMCs (14, 15). Consequently, differences in the Ca 2ϩ signaling mechanism of SMC (e.g., agonist receptor distribution or type) could be responsible for the variation in contraction at different airway locations.The aim of this study was to compare the contractile responses of a range of sizes of intrapulmonary airways and correlate these responses with the intracellular Ca 2ϩ signaling of the SMCs. The observations of SMC contraction and Ca 2ϩ signaling in different airway locations have been made possible by the development of techniques to cut thin serial lung slices that can be observed with microscopy. With this approach, we found that methacholine (MCh) induced a concentration-dependent contraction of SMCs in each generation along the length of an airway through the cardiac lobe of a mouse lung. The greatest contractile response occurred in the mids...

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Section: Discussioncontrasting

confidence: 91%

Contractility and Ca²⁺ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Bai

Zhang

Sanderson

2007

Am J Respir Cell Mol Biol

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“…Whether the membrane depolarization induced by the lack of BK channels was sufficient to activate Ca 2ϩ influx via voltage-operated Ca 2ϩ channels is not known, but our finding that baseline airway resistance and baseline pulmonary compliance was not significantly different between BK Ϫ/Ϫ and WT mice argue against this possibility. This view is further supported by the observation that BK channel blockers failed to increase basal tone of the mouse trachea (32). There may, however, be differences between species because BK channel blockers were found to increase basal tone of human bronchi, an effect that was reversed by the Ca 2ϩ channel blocker verapamil (8).…”

Section: Discussionmentioning

confidence: 88%

Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca²⁺‐activated K⁺channel

Sausbier¹,

Zhou

Beier

et al. 2006

FASEB j.

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The unique voltage- and Ca2+-dependent K+ (BK) channel, prominently expressed in airway smooth muscle cells, has been suggested as an important effector in controlling airway contractility. Its deletion in mice depolarized resting membrane potential of tracheal cells, suggesting an increased open-probability of voltage-gated Ca2+ channels. While carbachol concentration-dependently increased the tonic tension of wild-type (WT) trachea, mutant trachea showed a different response with rapid tension development followed by phasic contractions superimposed on a tonic component. Tonic contractions were substantially more dependent on L-type Ca2+ current in mutant than in WT trachea, even though L-type Ca2+ channels were not up-regulated. In the absence of L-type Ca2+ current, half-maximal contraction of trachea was shifted from 0.51 to 1.7 microM. In agreement, cholinergic bronchoconstriction was reduced in mutant lung slices, isolated-perfused lungs and, most impressively, in mutant mice analyzed by body plethysmography. Furthermore, isoprenaline-mediated airway relaxation was enhanced in mutants. In-depth analysis of cAMP and cGMP signaling revealed up-regulation of the cGMP pathway in mutant tracheal muscle. Inhibition of cGMP kinase reestablished normal sensitivity toward carbachol, indicating that up-regulation of cGMP signaling counterbalances for BK channel ablation, pointing to a predominant role of BK channel in regulation of airway tone.

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“…Together, our data suggest that Ca 2ϩ influx through the reverse mode of the NCX contributes substantially to increasing the pool of intracellular Ca 2ϩ necessary for refilling of the SR. Since the removal of extracellular Na ϩ and KB-R7943 had no effect on contractions mediated by KCl [involving L-type Ca 2ϩ channels (22,23,26,31,39) and RhoA/ROCK signaling (9,18,25,30,36)] but significantly reduced agonist-induced contractions (involving those same pathways as well as release of the internal Ca 2ϩ pool), we conclude that the reductions observed during our interventions were due to specific targeting of the reverse mode of the NCX and subsequent refilling of the internal Ca 2ϩ pool. Thus the data are consistent with our hypothesis that Ca 2ϩ influx via the reverse mode of the NCX is essential to the refilling of the SR following Ca 2ϩ mobilization by a variety of physiological agonists.…”

Section: Discussionmentioning

confidence: 99%

“…KCl is widely used to trigger voltage-dependent Ca 2ϩ -influx (22,23,26,31,39) and has also recently been shown to stimulate the RhoA/ROCK signaling pathway (9,18,25,30,36), but it does not evoke Ca 2ϩ release in ASM. To determine whether our interventions targeting the NCX activity had any effect on those signaling events outside of Ca 2ϩ release, we examined contractions triggered by KCl (60 mM).…”

Section: Effect Of Inhibition Of the Ncx On Successive 5-ht-induced Cmentioning

confidence: 99%

The reverse mode of the Na⁺/Ca²⁺ exchanger provides a source of Ca²⁺ for store refilling following agonist-induced Ca²⁺ mobilization

Hirota¹,

Pertens²,

Janssen³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Effects of K+ channel inhibitors on the basal tone and KCl- or methacholine-induced contraction of mouse trachea

Cited by 11 publications

References 24 publications

Contractility and Ca²⁺ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Contractility and Ca²⁺ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca²⁺‐activated K⁺channel

The reverse mode of the Na⁺/Ca²⁺ exchanger provides a source of Ca²⁺ for store refilling following agonist-induced Ca²⁺ mobilization

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Effects of K+ channel inhibitors on the basal tone and KCl- or methacholine-induced contraction of mouse trachea

Cited by 11 publications

References 24 publications

Contractility and Ca2+ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Contractility and Ca2+ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca2+‐activated K+channel

The reverse mode of the Na+/Ca2+ exchanger provides a source of Ca2+ for store refilling following agonist-induced Ca2+ mobilization

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Product

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Contractility and Ca²⁺ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Contractility and Ca²⁺ Signaling of Smooth Muscle Cells in Different Generations of Mouse Airways

Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca²⁺‐activated K⁺channel

The reverse mode of the Na⁺/Ca²⁺ exchanger provides a source of Ca²⁺ for store refilling following agonist-induced Ca²⁺ mobilization