Suppressive effects of diltiazem and verapamil on delayed rectifier K+-channel currents in murine thymocytes

Baba, Asuka; Tachi, Masahiro; Maruyama, Yoshio; Kazama, Itsuro

doi:10.1016/j.pharep.2015.01.009

Cited by 25 publications

(25 citation statements)

References 46 publications

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“…#p < 0.05 vs. Cm before GTP-γ-S internalization. *p < 0.05 vs. ∆Cm in external solution whole-cell membrane capacitance (Cm) [20,21,[39][40][41][42][43][44]. In mast cells, it was also established that the increase in the Cm reflects the degranulating process during exocytosis [13,14,45,46].…”

Section: Effects Of Tranilast and Ketotifen On Whole-cell Membrane Camentioning

confidence: 99%

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

Baba

Tachi²,

Ejima³

et al. 2016

Cell Physiol Biochem

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Background: Anti-allergic drugs, such as tranilast and ketotifen, inhibit the release of chemokines from mast cells. However, we know little about their direct effects on the exocytotic process of mast cells. Since exocytosis in mast cells can be monitored electrophysiologically by changes in the whole-cell membrane capacitance (Cm), the absence of such changes by these drugs indicates their mast cell-stabilizing properties. Methods: Employing the standard patch-clamp whole-cell recording technique in rat peritoneal mast cells, we examined the effects of tranilast and ketotifen on the Cm during exocytosis. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. Results: Relatively lower concentrations of tranilast (100, 250 µM) and ketotifen (1, 10 µM) did not significantly affect the GTP-γ-S-induced increase in the Cm. However, higher concentrations of tranilast (500 µM, 1 mM) and ketotifen (50, 100 µM) almost totally suppressed the increase in the Cm, and washed out the trapping of the dye on the surface of the mast cells. Compared to tranilast, ketotifen required much lower doses to similarly inhibit the degranulation of mast cells or the increase in the Cm. Conclusions: This study provides electrophysiological evidence for the first time that tranilast and ketotifen dose-dependently inhibit the process of exocytosis, and that ketotifen is more potent than tranilast in stabilizing mast cells. The mast cell-stabilizing properties of these drugs may be attributed to their ability to counteract the plasma membrane deformation in degranulating mast cells.

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Section: Effects Of Tranilast and Ketotifen On Whole-cell Membrane Camentioning

confidence: 99%

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

Baba

Tachi²,

Ejima³

et al. 2016

Cell Physiol Biochem

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“…Among them, T lymphocytes predominantly express Kv1.3-channels in their plasma membranes [27,53,54]. In our series of patch-clamp studies using thymus-derived murine lymphocytes (thymocytes), stepwise changes in the membrane potential evoked membrane currents characteristic to Kv-channels [31,[55][56][57][58][59] (Fig. 1).…”

Section: Kv13-channels Expressed In T Lymphocytesmentioning

confidence: 80%

“…Therefore, the membrane features of thymocytes, including their dielectric properties (e), were not likely to change before and after the application of azithromycin. On the other hand, according to our recent study, lipophilic drugs, which persistently decrease the Cm in thymocytes as azithromycin does, do not induce any morphological changes in the plasma membranes of the cells [59]. Additionally, differing from the secretory cells, such as megakaryocytes or mast cells [64,65,113,114], thymocytes do not usually form invaginated folds on their cell surface, which are deeply associated with the exocytotic release of microparticles or secretory granules [115].…”

Section: Immunomodulation By Clarithromycin As a Potent Kv13-channelmentioning

confidence: 83%

“…However, the therapeutic efficacies of these compounds were for the most part observed only in experimental animal models. In our series of patch-clamp studies, in addition to clarithromycin [31], commonly used drugs, such as calcium channel blockers (CCBs) (i.e., nifedipine, benidipine, diltiazem, and verapamil), HMG-CoA reductase inhibitors (statins) (i.e., pravastatin, lovastatin, and simvastatin), and nonsteroidal anti-inflammatory drugs (NSAIDs) (i.e., salicylate, diclofenac, and indomethacin), also effectively suppressed lymphocyte Kv1.3-channel currents [56][57][58][59] (Table 2). According to separate in vitro studies, these drugs exerted immunomodulatory properties besides their anti-hypertensive, anti-cholesterol, and antiinflammatory effects [124][125][126][127][128][129][130][131][132][133][134].…”

Section: Calcium Channel Blockers Statins and Nsaids As Potent Kv1mentioning

confidence: 99%

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Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases

2015

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T lymphocytes predominantly express delayed rectifier K(+)-channels (Kv1.3) in their plasma membranes. Patch-clamp studies revealed that the channels play crucial roles in facilitating the calcium influx necessary to trigger lymphocyte activation and proliferation. Using selective channel inhibitors in experimental animal models, in vivo studies further revealed the clinically relevant relationship between the channel expression and the development of chronic respiratory diseases, in which chronic inflammation or the overstimulation of cellular immunity in the airways is responsible for the pathogenesis. In chronic respiratory diseases, such as chronic obstructive pulmonary disease, asthma, diffuse panbronchiolitis and cystic fibrosis, in addition to the supportive management for the symptoms, the anti-inflammatory effects of macrolide antibiotics were shown to be effective against the over-activation or proliferation of T lymphocytes. Recently, we provided physiological and pharmacological evidence that macrolide antibiotics, together with calcium channel blockers, HMG-CoA reductase inhibitors, and nonsteroidal anti-inflammatory drugs, effectively suppress the Kv1.3-channel currents in lymphocytes, and thus exert anti-inflammatory or immunomodulatory effects. In this review article, based on the findings obtained from recent in vivo and in vitro studies, we address the novel therapeutic implications of targeting the lymphocyte Kv1.3-channels for the treatment of chronic or acute respiratory diseases.

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“…In our previous studies, microscopic changes in megakaryocytes or lymphocytes were precisely monitored by measurement of the whole-cell Cm [22,26,27,28,29,30,31,32]. In mast cells, the degranulating process during exocytosis can be continuously monitored by the increase in Cm [17,18,19,33,34].…”

Section: Resultsmentioning

confidence: 99%

Clarithromycin Dose-Dependently Stabilizes Rat Peritoneal Mast Cells

Kazama¹,

Saito²,

Baba³

et al. 2016

Chemotherapy

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Background: Macrolides, such as clarithromycin, have antiallergic properties. Since exocytosis in mast cells is detected electrophysiologically via changes in membrane capacitance (Cm), the absence of such changes due to the drug indicates its mast cell-stabilizing effect. Methods: Employing the whole-cell patch clamp technique in rat peritoneal mast cells, we examined the effects of clarithromycin on Cm during exocytosis. Using a water-soluble fluorescent dye, we also examined its effect on deformation of the plasma membrane. Results: Clarithromycin (10 and 100 μM) significantly inhibited degranulation from mast cells and almost totally suppressed the GTP-γ-S-induced increase in Cm. It washed out the trapping of the dye on the surface of mast cells. Conclusions: This study provides for the first time electrophysiological evidence that clarithromycin dose-dependently inhibits the process of exocytosis. The mast cell-stabilizing action of clarithromycin may be attributable to its counteractive effect on plasma membrane deformation induced by exocytosis.

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Suppressive effects of diltiazem and verapamil on delayed rectifier K+-channel currents in murine thymocytes

Cited by 25 publications

References 46 publications

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases

Clarithromycin Dose-Dependently Stabilizes Rat Peritoneal Mast Cells

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