Salicylate Inhibits Thrombopoiesis in Rat Megakaryocytes by Changing the Membrane Micro-Architecture

Kazama, Itsuro; Baba, Asuka; Endo, Yasuhiro; Toyama, Hiroaki; Ejima, Yutaka; Matsubara, Mitsunobu; Tachi, Masahiro

doi:10.1159/000374039

Cited by 16 publications

(15 citation statements)

References 44 publications

(69 reference statements)

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“…We conducted standard whole-cell patch-clamp recordings using an EPC-9 patch-clamp amplifier system (HEKA Electronics, Lambrecht, Germany) as described previously [13,14,20,21]. The patch pipette resistance was 4-6 MΩ when filled with internal (patch pipette) solution containing (in mM): K-glutamate, 145; MgCl 2 , 2.0; Hepes, 5.0 (pH 7.2 adjusted with KOH).…”

Section: Electrical Setup and Membrane Capacitance Measurementsmentioning

confidence: 99%

“…#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%

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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: Electrical Setup and Membrane Capacitance Measurementsmentioning

confidence: 99%

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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“…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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“…The experiments confirmed the previously defined localization of the Kv1.3-channels in the plasma membranes and intracellular vesicles of lymphocytes, and additionally demonstrated the presence of the channel protein in mitochondria. Other than inflammatory leukocytes, such as T-or B-lymphocytes and macrophages [28,61], Kv1.3-channels are also expressed in the central nervous system, kidney, liver, skeletal muscle, platelets, megakaryocytes, testis, and osteoclasts [62][63][64][65][66][67][68].…”

Section: Kv13-channels Expressed In T Lymphocytesmentioning

confidence: 99%

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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Salicylate Inhibits Thrombopoiesis in Rat Megakaryocytes by Changing the Membrane Micro-Architecture

Cited by 16 publications

References 44 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

Clarithromycin Dose-Dependently Stabilizes Rat Peritoneal Mast Cells

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

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