Inhibition of β-adrenoceptor agonist relaxation of airway smooth muscle by Ca2+-activated K+ channel blockers

1993 ◽  
Vol 235 (1) ◽  
pp. 37-43 ◽  
Author(s):  
Jiao-Cheng Huang ◽  
Maria L. Garcia ◽  
John P. Reuben ◽  
Gregory J. Kacsorowski
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
K Channel ◽  
Channel Blockers ◽  
Adrenoceptor Agonist

Expression of dihydropyridine resistance differs in porcine bronchial and tracheal smooth muscle

1994 ◽  
Vol 267 (2) ◽  
pp. L106-L112 ◽  
Author(s):  
T. L. Croxton ◽  
C. Fleming ◽  
C. A. Hirshman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Isometric Tension ◽  
Tracheal Smooth Muscle ◽  
Airway Smooth Muscle Cells ◽  
Channel Blockers ◽  
Response Curves ◽  
Voltage Dependent ◽  
Relaxation Responses ◽  
Ca2 Channels

Voltage-dependent and receptor-operated Ca2+ entry mechanisms have been demonstrated in airway smooth muscle, but their relative importance for maintenance of contraction is unknown. Blockade of voltage-dependent Ca2+ channels (VDC) has produced inconsistent relaxation. We postulated regional variations in Ca2+ handling by airway smooth muscle cells and compared the efficacy of dihydropyridine VDC blockers in tracheas and bronchi. Porcine tracheal smooth muscle strips and bronchial rings were mounted in tissue baths filled with physiological solutions and isometric tension was measured. Tissues were precontracted with carbachol or KCl, and relaxation dose-response curves to nifedipine, Mn2+, or Cd2+ were obtained. Relaxation responses to nifedipine were significantly different in carbachol-contracted tracheas and bronchi. Whereas carbachol-contracted tracheal muscle completely relaxed with 10(-6) M nifedipine, bronchial smooth muscle relaxed < 50%. In contrast, KCl-contracted bronchial muscle was completely relaxed by nifedipine. The nonspecific Ca2+ channel blockers Mn2+ and Cd2+ produced similar relaxation responses in each tissue. Thus VDC are the predominant mechanism for Ca2+ entry in porcine tracheal smooth muscle, but a dihydropyridine-insensitive pathway is functionally important in carbachol-contracted porcine bronchi. Regional variation may account for apparent inconsistencies between previous studies.

scholarly journals Neuroleptics antagonize a calcium-activated potassium channel in airway smooth muscle.

1987 ◽  
Vol 89 (2) ◽  
pp. 339-352 ◽  
Author(s):  
J D McCann ◽  
M J Welsh
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Dissociation Constants ◽  
Rank Order ◽  
K Channel ◽  
Airway Smooth Muscle Cells ◽  
Open Probability ◽  
K Channels ◽  
Channel Inhibition ◽  
Equilibrium Dissociation Constants

We examined the effect of neuroleptics on Ca-activated K channels from dog airway smooth muscle cells. Because these agents inhibit a variety of other Ca-mediated processes, it seemed possible that they might also inhibit Ca-activated K channels. In excised, inside-out patches, several neuroleptics potently and reversibly inhibited the K channel from the internal but not the external surface of the patch. Measurements of the effect on open probability and open- and closed-state durations support a simple kinetic model in which neuroleptics bind to and block the open channel. Inhibition by neuroleptics was moderately voltage dependent, with blockers less potent at hyperpolarizing voltages. The relationship between voltage and the dissociation constant for the blocker suggests that the binding site is one-third of the way across the channel's electrical field. Equilibrium dissociation constants for the drug-channel complex were: haloperidol, 1.0 +/- 0.1 microM; trifluoperazine, 1.4 +/- 0.1 microM; thioridazine, 2.4 +/- 0.1 microM; and chlorpromazine, 2.0 microM. This rank-order potency is different from their potency as calmodulin inhibitors, which suggests that neuroleptics bind to the channel rather than a calmodulin-channel complex.

Role of STIM1/Orai1-mediated store-operated Ca2+ entry in airway smooth muscle cell proliferation

2011 ◽  
Vol 110 (5) ◽  
pp. 1256-1263 ◽  
Author(s):  
Jin-jing Zou ◽  
Ya-dong Gao ◽  
Shuang Geng ◽  
Jiong Yang
Keyword(s):  
Smooth Muscle ◽  
Mrna Expression ◽  
Airway Smooth Muscle ◽  
Inhibitory Effect ◽  
Airway Smooth Muscle Cell ◽  
Characteristic Change ◽  
Airway Smooth Muscle Cells ◽  
Channel Blockers ◽  
Asthma Patients ◽  
Underlying Mechanisms

Hyperplasia of airway smooth muscle cells (ASMCs) is a characteristic change of chronic asthma patients. However, the underlying mechanisms that trigger this process are not yet completely understood. Store-operated Ca2+ (SOC) entry (SOCE) occurs in response to the intracellular sarcoplasma reticulum (SR)/endoplasmic reticulum (ER) Ca2+ store depletion. SOCE plays an important role in regulating Ca2+ signaling and cellular responses of ASMCs. Stromal interaction molecule (STIM)1 has been proposed as an ER/SR Ca2+ sensor and translocates to the ER underneath the plasma membrane upon depletion of the ER Ca2+ store, where it interacts with Orai1, the molecular component of SOC channels, and brings about SOCE. STIM1 and Orai1 have been proved to mediate SOCE of ASMCs. In this study, we investigated whether STIM1/Orai1-mediated SOCE is involved in rat ASMC proliferation. We found that SOCE was upregulated during ASMC proliferation accompanied by a mild increase of STIM1 and a significant increase of Orai1 mRNA expression, whereas the proliferation of ASMCs was partially inhibited by the SOC channel blockers SKF-96365, NiCl2, and BTP-2. Suppressing the mRNA expression of STIM1 or Orai1 with specific short hairpin RNA resulted in the attenuation of SOCE and ASMC proliferation. Moreover, after knockdown of STIM1 or Orai1, the SOC channel blocker SKF-96365 had no inhibitory effect on the proliferation of ASMCs anymore. These results suggested that STIM1/Orai1-mediated SOCE is involved in ASMC proliferation.

scholarly journals Chloride channel blockers promote relaxation of TEA-induced contraction in airway smooth muscle

2013 ◽  
Vol 49 (0) ◽  
pp. 112-124 ◽  
Author(s):  
Peter D. Yim ◽  
George Gallos ◽  
Jose F. Perez-Zoghbi ◽  
Jacquelyn Trice ◽  
Yi Zhang ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Chloride Channel ◽  
Channel Blockers

Ionic mechanisms and Ca2+ regulation in airway smooth muscle contraction: do the data contradict dogma?

2002 ◽  
Vol 282 (6) ◽  
pp. L1161-L1178 ◽  
Author(s):  
Luke J. Janssen
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Smooth Muscle Contraction ◽  
Channel Blockers ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Spatial And Temporal Heterogeneity ◽  
Voltage Dependent ◽  
Intracellular Ca ◽  
Ionic Mechanisms

In general, excitation-contraction coupling in muscle is dependent on membrane depolarization and hyperpolarization to regulate the opening of voltage-dependent Ca2+ channels and, thereby, influence intracellular Ca2+ concentration ([Ca2+]i). Thus Ca2+ channel blockers and K+ channel openers are important tools in the arsenals against hypertension, stroke, and myocardial infarction, etc. Airway smooth muscle (ASM) also exhibits robust Ca2+, K+, and Cl− currents, and there are elaborate signaling pathways that regulate them. It is easy, then, to presume that these also play a central role in contraction/relaxation of ASM. However, several lines of evidence speak to the contrary. Also, too many researchers in the ASM field view the sarcoplasmic reticulum as being centrally located and displacing its contents uniformly throughout the cell, and they have focused almost exclusively on the initial single [Ca2+] spike evoked by excitatory agonists. Several recent studies have revealed complex spatial and temporal heterogeneity in [Ca2+]i, the significance of which is only just beginning to be appreciated. In this review, we will compare what is known about ion channels in ASM with what is believed to be their roles in ASM physiology. Also, we will examine some novel ionic mechanisms in the context of Ca2+ handling and excitation-contraction coupling in ASM.

Large conducting potassium channel reconstituted from airway smooth muscle

1992 ◽  
Vol 262 (3) ◽  
pp. L327-L336 ◽  
Author(s):  
D. Savaria ◽  
C. Lanoue ◽  
A. Cadieux ◽  
E. Rousseau
Keyword(s):  
Smooth Muscle ◽  
Lipid Bilayers ◽  
Airway Smooth Muscle ◽  
Single Channel ◽  
Specific Inhibitor ◽  
Physiological Role ◽  
Membrane Receptors ◽  
K Channel ◽  
Open Probability ◽  
K Channels

Microsomal fractions were prepared from canine and bovine airway smooth muscle (ASM) by differential and gradient centrifugations. Surface membrane vesicles were characterized by binding assays and incorporated into planar lipid bilayers. Single-channel activities were recorded in symmetric or asymmetric K+ buffer systems and studied under voltage and Ca2+ clamp conditions. A large-conductance K(+)-selective channel (greater than 220 pS in 150 mM K+) displaying a high Ca2+, low Ba2+, and charybdotoxin (CTX) sensitivity was identified. Time analysis of single-channel recordings revealed a complex kinetic behavior compatible with the previous schemes proposed for Ca(2+)-activated K+ channels in a variety of biological surface membranes. We now report that the open probability of the channel at low Ca2+ concentration is enhanced on in vitro phosphorylation, which is mediated via an adenosine 3',5'-cyclic monophosphate-dependent protein kinase. In addition to this characterization at the molecular level, a second series of pharmacological experiments were designed to assess the putative role of this channel in ASM strips. Our results show that 50 nM CTX, a specific inhibitor of the large conducting Ca(2+)-dependent K+ channel, prevents norepinephrine transient relaxation on carbamylcholine-precontracted ASM strips. It was also shown that CTX reversed the steady-state relaxation induced by vasoactive intestinal peptide and partially antagonized further relaxation induced by cumulative doses of this potent bronchodilatator. Thus it is proposed that the Ca(2+)-activated K+ channels have a physiological role because they are indirectly activated on stimulation of various membrane receptors via intracellular mechanisms.

Mechanisms of neurotensin-induced inhibition in rat ileal smooth muscle

1992 ◽  
Vol 263 (5) ◽  
pp. G767-G774 ◽  
Author(s):  
H. D. Allescher ◽  
H. Fick ◽  
V. Schusdziarra ◽  
M. Classen
Keyword(s):  
Smooth Muscle ◽  
Channel Blocker ◽  
Inhibitory Concentration ◽  
Longitudinal Muscle ◽  
Inhibitory Effect ◽  
Repetitive Stimulation ◽  
K Channel ◽  
Channel Blockers ◽  
Organ Bath ◽  
Dependent Inhibition

The aim of the present study was to determine the mechanisms of neurotensin-induced inhibition in ileal smooth muscle. Isolated rat ileal smooth muscle strips were stimulated in an organ bath using carbachol (CCH) or by KCl depolarization. Neurotensin produced a concentration-dependent inhibition of muscle contraction [mean inhibitory concentration (IC50): 2.8 x 10(-9) M], which was not blocked by phentolamine (10(-6) M), hexamethonium (10(-4) M), indomethacin (10(-6) M), nordihydroguaretic acid (10(-6) M), or tetrodotoxin (10(-6) M). The inhibitory effect of neurotensin during CCH stimulation was blocked concentration dependently in the presence of the K(+)-channel blocker apamin. By contrast, other K(+)-channel blockers such as 9-aminoacridine (10(-6) M to 3 x 10(-5) M), 4-aminopyridine (10(-4) M to 5 x 10(-3) M), tetraethylammonium (10(-4) M to 10(-1) M), or glibenclamide (10(-5) M) were ineffective. The presence of the Ca(2+)-channel antagonist nitrendipine (IC50: 2.4 x 10(-9) M) or verapamil (IC50: 1.1 x 10(-7) M) also blocked the neurotensin inhibitory effect. Ileal contraction, induced by the Ca(2+)-channel activator BAY K 8644 (10(-7) M), was completely inhibited by neurotensin. After depletion of internal Ca2+ stores by repetitive stimulation with CCH and caffeine in Ca(2+)-free buffer, reintroduction of external Ca2+ restored neurotensin inhibition of the contraction induced by CCH. These results demonstrate that the inhibitory effect of neurotensin in rat ileum longitudinal muscle is apamin sensitive and cannot be observed in the presence of the Ca(2+)-channel blockers nitrendipine or verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

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