A review of the effects of calcium channels blockers on airway smooth muscle activity and respiratory mechanics

Electrophysiological and pharmacological techniques were used to characterize the membrane conductance changes underlying spasmogen-evoked depolarization in airway smooth muscle (ASM). Changes included a transient activation of chloride ion channels and prolonged suppression of potassium ion channels; both changes are triggered by release of internally sequestered calcium ion and in turn cause opening of voltage-dependent calcium channels. The resultant influx of calcium ions contributes to contraction as well as to refilling of the internal calcium ion pool. Bronchodilators, on the other hand, act in part through activation of potassium channels, with consequent closure of calcium channels. The tools used to study ion channels in ASM are described, and the investigations of the roles of ion channels in ASM physiology (autacoid-evoked depolarization and hyperpolarization) and pathophysiology (airway hyperresponsiveness) are summarized. Finally, how the relationship between ion channels and ASM function/dysfunction may relate to the treatment of asthma and related breathing disorders is discussed.

Download Full-text

Store-refilling involves both L-type calcium channels and reverse-mode sodium calcium exchange in airway smooth muscle

European Respiratory Journal ◽

10.1183/09031936.00008507 ◽

2007 ◽

Vol 30 (2) ◽

pp. 269-278 ◽

Cited By ~ 36

Author(s):

S. Hirota ◽

L. J. Janssen

Keyword(s):

Smooth Muscle ◽

Calcium Channels ◽

Airway Smooth Muscle ◽

Reverse Mode ◽

Sodium Calcium ◽

Calcium Exchange ◽

Sodium Calcium Exchange

Download Full-text

Dihydropyridine-sensitive single calcium channels in airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1990.259.6.l468 ◽

1990 ◽

Vol 259 (6) ◽

pp. L468-L480 ◽

Cited By ~ 17

Author(s):

J. F. Worley ◽

M. I. Kotlikoff

Keyword(s):

Smooth Muscle ◽

Calcium Channels ◽

Smooth Muscle Cells ◽

Calcium Channel ◽

Airway Smooth Muscle ◽

Muscle Cells ◽

Membrane Depolarization ◽

Airway Smooth Muscle Cells ◽

Voltage Dependent ◽

Voltage Dependent Calcium Channels

We have identified and characterized single voltage-dependent calcium channels in both acutely dissociated rat bronchial and cultured human tracheobronchial smooth muscle cells using the patch-clamp technique. In both cell types, on-cell membrane patches displayed unitary currents selective for barium ions and exhibited one conductance level (21–26 pS), and the open state probability was increased by membrane depolarization. Unitary barium currents were enhanced by the calcium channel selective agonist, BAY R 5417, and inhibited by the dihydropyridine calcium channel antagonist, nisoldipine (apparent inhibition constant less than 100 nM). Moreover, the degree of nisoldipine inhibition of the rat bronchial smooth muscle channels was increased with membrane depolarization in a manner consistent with the drug interacting with highest affinity to the inactivated channel state. In addition, the sensitivity to BAY R 5417 augmentation and nisoldipine inhibition of depolarization-induced tonic force of intact rat bronchial ring segments was in close agreement to the single channel results. Thus these data suggest that activation of voltage-dependent calcium channels can influence airway contraction and that dihydropyridines may be effective modulators of depolarization-induced increases in bronchial tone. We conclude that both rat and human airway smooth muscle cells have high-conductance voltage-dependent calcium channels that interact in a predictable manner with dihydropyridines and are similar to voltage-dependent calcium channels observed in other smooth muscle cells.

Download Full-text

Repeated airway constrictions in mice do not alter respiratory function

Journal of Applied Physiology ◽

10.1152/japplphysiol.01073.2017 ◽

2018 ◽

Vol 124 (6) ◽

pp. 1483-1490 ◽

Cited By ~ 10

Author(s):

Samuel Mailhot-Larouche ◽

Louis Deschênes ◽

Morgan Gazzola ◽

Katherine Lortie ◽

Cyndi Henry ◽

...

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Respiratory System ◽

Structural Changes ◽

Respiratory Mechanics ◽

Airway Remodeling ◽

Structural Components ◽

Airway Wall ◽

Cell Hyperplasia ◽

Shed Light

It is suggested that the frequent strain the airways undergo in asthma because of repeated airway smooth muscle (ASM)-mediated constrictions contributes to airway wall remodeling. However, the effects of repeated constrictions on airway remodeling, as well as the ensuing impact of this presumptive remodeling on respiratory mechanics, have never been investigated in subjects without asthma. In this study, we set out to determine whether repeated constrictions lead to features that are reminiscent of asthma in mice without asthma. BALB/c mice were subjected to a 30-min constriction elicited by aerosolized methacholine every other day over 6 wk. Forty-eight hours after the last constriction, the mechanics of the respiratory system was evaluated at baseline and in response to incremental doses of nebulized methacholine with the flexiVent. The whole-lung lavages, the tracheas, and the lungs were also collected to evaluate inflammation, the contractile capacity of ASM, and the structural components of the airway wall, respectively. The resistance and the compliance of the respiratory system, as well as the Newtonian resistance and the resistive and elastic properties of the lung tissue, were not affected by repeated constrictions, both at baseline and in response to methacholine. All the other examined features also remained unaltered, except the number of goblet cells in the epithelium and the number of macrophages in the whole-lung lavages, which both increased with repeated constrictions. This study demonstrates that, despite causing goblet cell hyperplasia and a mild macrophagic inflammation, repeated constrictions with methacholine do not lead to structural changes that adversely impact the physiology. NEW & NOTEWORTHY Repeated airway constrictions led to signs of remodeling that are typically observed in asthma, which neither altered respiratory mechanics nor the contractile capacity of airway smooth muscle. These findings shed light on a debate between those claiming that constrictions induce remodeling and those convinced that methacholine challenges are harmless. Insofar as our results with mice relate to humans, the findings indicate that repeated challenges with methacholine can be performed safely.

Download Full-text

Volatile anesthetics interfere with regulation of store-operated calcium channels in airway smooth muscle

European Journal of Anaesthesiology ◽

10.1097/00003643-200406002-00460 ◽

2004 ◽

Vol 21 (Supplement 32) ◽

pp. 126

Author(s):

Y. Prakash ◽

B. Ay ◽

G. Sieck ◽

C. Pabelick

Keyword(s):

Smooth Muscle ◽

Calcium Channels ◽

Airway Smooth Muscle ◽

Volatile Anesthetics

Download Full-text

Endotracheal cuff pressure as an index of airway smooth muscle activity: Comparison with total lung resistance

Respiration Physiology ◽

10.1016/s0034-5687(98)00029-2 ◽

1998 ◽

Vol 112 (2) ◽

pp. 175-184 ◽

Cited By ~ 2

Author(s):

T. Ishikawa ◽

S. Sekizawa ◽

F.B. Sant'Ambrogio ◽

G. Sant'Ambrogio

Keyword(s):

Smooth Muscle ◽

Airway Smooth Muscle ◽

Muscle Activity ◽

Cuff Pressure ◽

Lung Resistance ◽

Activity Comparison ◽

Total Lung Resistance

Download Full-text

Contractile agonists activate voltage-dependent calcium channels in airway smooth muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.1992.263.1.c106 ◽

1992 ◽

Vol 263 (1) ◽

pp. C106-C113 ◽

Cited By ~ 26

Author(s):

M. Tomasic ◽

J. P. Boyle ◽

J. F. Worley ◽

M. I. Kotlikoff

Keyword(s):

Smooth Muscle ◽

Calcium Channels ◽

Smooth Muscle Cells ◽

Calcium Channel ◽

Airway Smooth Muscle ◽

Muscle Cells ◽

Cell Types ◽

State Probability ◽

Airway Smooth Muscle Cells ◽

Channel Currents

To determine whether agents that cause contraction of airway smooth muscle affect sarcolemmal calcium channel activity, unitary calcium channel currents (using Ba2+ as the charge carrier) were recorded in on-cell configuration from acutely dissociated (dog, pig, and ferret) and cultured (human) airway smooth muscle cells. Addition of the contractile agonists methacholine or bradykinin increased the open-state probability of the large-conductance calcium channel 37.2- and 45-fold, respectively. The increase in open-state probability was not due to cellular depolarization because increases occurred in the absence of depolarization. Channel activation by the agonist was determined to result in the favoring of a long (16.5 +/- 5.0 ms) open lifetime for the channel, which was not observed under control conditions, in the absence of BAY K 8644. We also report the unitary calcium channel currents from a second, smaller conductance calcium channel. This channel was present in all cell types and had a mean conductance of 9.5 +/- 0.8 pS (80 mM Ba2+). Exposure of cells to agonist also resulted in an increase in the open-channel probability of the small-conductance calcium channel (10.4-fold), which did not result from cellular depolarization. These experiments demonstrate that the molecular pathways exist between contractile agonist receptors and sarcolemmal calcium channels in airway smooth muscle cells. Because membrane patches were not directly exposed to agonist, receptor-channel linkage probably occurs via a second messenger-coupling pathway.

Download Full-text