HMG-CoA reductase inhibitors pravastatin, lovastatin and simvastatin suppress delayed rectifier K+-channel currents in murine thymocytes

Kazama, Itsuro; Baba, Asuka; Maruyama, Yoshio

doi:10.1016/j.pharep.2014.03.002

Cited by 31 publications

(49 citation statements)

References 20 publications

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“…In our previous studies, such microscopic changes in these cells were most precisely monitored by measurement of the whole-cell membrane capacitance (Cm) [16,28,29,30,31]. In mast cells, it was also established that the increase in the Cm well indicates the degranulating process during exocytosis [9,32,33].…”

Section: Resultsmentioning

confidence: 99%

Olopatadine Inhibits Exocytosis in Rat Peritoneal Mast Cells by Counteracting Membrane Surface Deformation

Baba¹,

Tachi²,

Maruyama³

et al. 2015

Cell Physiol Biochem

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Backgroud/Aims: Besides its anti-allergic properties as a histamine receptor antagonist, olopatadine stabilizes mast cells by inhibiting the release of chemokines. Since olopatadine bears amphiphilic features and is preferentially partitioned into the lipid bilayers of the plasma membrane, it would induce some morphological changes in mast cells and thus affect the process of exocytosis. Methods: Employing the standard patch-clamp whole-cell recording technique, we examined the effects of olopatadine and other anti-allergic drugs on the membrane capacitance (Cm) in rat peritoneal mast cells 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: Low concentrations of olopatadine (1 or 10 µM) did not significantly affect the GTP-γ-S-induced increase in the Cm. However, 100 µM and 1 mM olopatadine almost totally suppressed the increase in the Cm. Additionally, these doses completely washed out the trapping of the dye on the cell surface, indicating that olopatadine counteracted the membrane surface deformation induced by exocytosis. As shown by electron microscopy, olopatadine generated inward membrane bending in mast cells. Conclusion: This study provides electrophysiological evidence for the first time that olopatadine dose-dependently inhibits the process of exocytosis in rat peritoneal mast cells. Such mast cell stabilizing properties of olopatadine may be attributed to its counteracting effects on the plasma membrane deformation in degranulating mast cells.

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Section: Resultsmentioning

confidence: 99%

Olopatadine Inhibits Exocytosis in Rat Peritoneal Mast Cells by Counteracting Membrane Surface Deformation

Baba¹,

Tachi²,

Maruyama³

et al. 2015

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%

“…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%

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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HMG-CoA reductase inhibitors pravastatin, lovastatin and simvastatin suppress delayed rectifier K+-channel currents in murine thymocytes

Abstract: This study demonstrated for the first time that statins inhibit thymocyte Kv1.3-channels. The slow inactivation patterns induced by lovastatin and simvastatin may be associated with their accumulation in the plasma membranes.

Cited by 31 publications

References 20 publications

Olopatadine Inhibits Exocytosis in Rat Peritoneal Mast Cells by Counteracting Membrane Surface Deformation

Olopatadine Inhibits Exocytosis in Rat Peritoneal Mast Cells by Counteracting Membrane Surface Deformation

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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