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.

Mazzei T, Mini E, Novelli A, Periti P: Chemistry and mode of action of macrolides. J Antimicrob Chemother 1993;31(suppl C):1-9.
Kazama I, Tamada T, Tachi M: Usefulness of targeting lymphocyte Kv1.3-channels in the treatment of respiratory diseases. Inflamm Res 2015;64:753-765.
Hashiba M, Baba S: Efficacy of long-term administration of clarithromycin in the treatment of intractable chronic sinusitis. Acta Otolaryngol Suppl 1996;525:73-78.
Kudoh S: Erythromycin treatment in diffuse panbronchiolitis. Curr Opin Pulm Med 1998;4:116-121.
Yamaya M, Azuma A, Takizawa H, Kadota J, Tamaoki J, Kudoh S: Macrolide effects on the prevention of COPD exacerbations. Eur Respir J 2012;40:485-494.
Wolter J, Seeney S, Bell S, Bowler S, Masel P, McCormack J: Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax 2002;57:212-216.
Sugiyama K, Shirai R, Mukae H, Ishimoto H, Nagata T, Sakamoto N, et al: Differing effects of clarithromycin and azithromycin on cytokine production by murine dendritic cells. Clin Exp Immunol 2007;147:540-546.
Morikawa K, Zhang J, Nonaka M, Morikawa S: Modulatory effect of macrolide antibiotics on the Th1- and Th2-type cytokine production. Int J Antimicrob Agents 2002;19:53-59.
Mu X, Ubagai T, Kikuchi-Ueda T, Tansho-Nagakawa S, Nakano R, Kikuchi H, et al: Effects of erythromycin and rifampicin on immunomodulatory gene expression and cellular function in human polymorphonuclear leukocytes. Chemotherapy 2013;59:395-401.
Hashimoto Y, Kaneda Y, Takahashi N, Akashi S, Arai I, Nakaike S: Clarithromycin inhibits the development of dermatitis in NC/Nga mice. Chemotherapy 2003;49:222-228.
Miyatake H, Taki F, Taniguchi H, Suzuki R, Takagi K, Satake T: Erythromycin reduces the severity of bronchial hyperresponsiveness in asthma. Chest 1991;99:670-673.
Kase K, Hua J, Yokoi H, Ikeda K, Nagaoka I: Inhibitory action of roxithromycin on histamine release and prostaglandin D2 production from beta-defensin 2-stimulated mast cells. Int J Mol Med 2009;23:337-340.
Borszcz PD, Befus D, Moqbel R, Sin DD, Adamko DJ, Man SF, et al: Effects of clarithromycin on inflammatory cell mediator release and survival. Chemotherapy 2005;51:206-210.
de Paulis A, Cirillo R, Ciccarelli A, Condorelli M, Marone G: FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human Fc epsilon RI+ cells. J Immunol 1991;146:2374-2381.
Shimane T, Asano K, Suzuki M, Hisamitsu T, Suzaki H: Influence of a macrolide antibiotic, roxithromycin, on mast cell growth and activation in vitro. Mediators Inflamm 2001;10:323-332.
Kuehn HS, Radinger M, Gilfillan AM: Measuring mast cell mediator release. Curr Protoc Immunol 2010, DOI: 10.1002/0471142735.im0738s91.
Baba A, Tachi M, Maruyama Y, Kazama I: Olopatadine inhibits exocytosis in rat peritoneal mast cells by counteracting membrane surface deformation. Cell Physiol Biochem 2015;35:386-396.
Baba A, Tachi M, Ejima Y, Endo Y, Toyama H, Matsubara M, et al: Anti-allergic drugs tranilast and ketotifen dose-dependently exert mast cell-stabilizing properties. Cell Physiol Biochem 2016;38:15-27.
Kazama I, Maruyama Y, Takahashi S, Kokumai T: Amphipaths differentially modulate membrane surface deformation in rat peritoneal mast cells during exocytosis. Cell Physiol Biochem 2013;31:592-600.
Shimoda T, Liang Z, Suzuki H, Kawana S: Inhibitory effects of antipsychotic and anxiolytic agents on stress-induced degranulation of mouse dermal mast cells. Clin Exp Dermatol 2010;35:531-536.
Odriscoll D, Wilson G, Steer MW: Lucifer yellow and fluorescein isothiocyanate uptake by cells of Morinda citrifolia in suspension cultures is not confined to the endocytotic pathway. J Cell Sci 1991;100:237-241.
Kazama I, Ejima Y, Endo Y, Toyama H, Matsubara M, Baba A, et al: Chlorpromazine-induced changes in membrane micro-architecture inhibit thrombopoiesis in rat megakaryocytes. Biochim Biophys Acta 2015;1848:2805-2812.
Kostadima E, Tsiodras S, Alexopoulos EI, Kaditis AG, Mavrou I, Georgatou N, et al: Clarithromycin reduces the severity of bronchial hyperresponsiveness in patients with asthma. Eur Respir J 2004;23:714-717.
Kees F, Wellenhofer M, Grobecker H: Serum and cellular pharmacokinetics of clarithromycin 500 mg q.d. and 250 mg b.i.d. in volunteers. Infection 1995;23:168-172.
McCarty JM: Clarithromycin in the management of community-acquired pneumonia. Clin Ther 2000;22:281-294; discussion 265.
Kazama I, Maruyama Y, Nakamichi S: Aspirin-induced microscopic surface changes stimulate thrombopoiesis in rat megakaryocytes. Clin Appl Thromb Hemost 2014;20:318-325.
Kazama I, Maruyama Y, Murata Y: Suppressive effects of nonsteroidal anti-inflammatory drugs diclofenac sodium, salicylate and indomethacin on delayed rectifier K+-channel currents in murine thymocytes. Immunopharmacol Immunotoxicol 2012;34:874-878.
Kazama I, Maruyama Y, Matsubara M: Benidipine persistently inhibits delayed rectifier K(+)-channel currents in murine thymocytes. Immunopharmacol Immunotoxicol 2013;35:28-33.
Kazama I, Maruyama Y: Differential effects of clarithromycin and azithromycin on delayed rectifier K(+)-channel currents in murine thymocytes. Pharm Biol 2013;51:760-765.
Kazama I, Baba A, Maruyama Y: HMG-CoA reductase inhibitors pravastatin, lovastatin and simvastatin suppress delayed rectifier K(+)-channel currents in murine thymocytes. Pharmacol Rep 2014;66:712-717.
Baba A, Tachi M, Maruyama Y, Kazama I: Suppressive effects of diltiazem and verapamil on delayed rectifier K+-channel currents in murine thymocytes. Pharmacol Rep 2015;67:959-964.
Kazama I, Baba A, Endo Y, Toyama H, Ejima Y, Matsubara M, et al: Salicylate inhibits thrombopoiesis in rat megakaryocytes by changing the membrane micro-architecture. Cell Physiol Biochem 2015;35:2371-2382.
Fernandez JM, Neher E, Gomperts BD: Capacitance measurements reveal stepwise fusion events in degranulating mast cells. Nature 1984;312:453-455.
Lorenz D, Wiesner B, Zipper J, Winkler A, Krause E, Beyermann M, et al: Mechanism of peptide-induced mast cell degranulation: translocation and patch-clamp studies. J Gen Physiol 1998;112:577-591.
Neher E: The influence of intracellular calcium concentration on degranulation of dialysed mast cells from rat peritoneum. J Physiol 1988;395:193-214.
Penner R: Multiple signaling pathways control stimulus-secretion coupling in rat peritoneal mast cells. Proc Natl Acad Sci USA 1988;85:9856-9860.
LaPlaca MC, Prado GR, Cullen D, Simon CM: Plasma membrane damage as a marker of neuronal injury. Conf Proc IEEE Eng Med Biol Soc 2009;2009:1113-1116.
Kawasaki Y, Saitoh T, Okabe T, Kumakura K, Ohara-Imaizumi M: Visualization of exocytotic secretory processes of mast cells by fluorescence techniques. Biochim Biophys Acta 1991;1067:71-80.
Zampini P, Riviera AP, Tridente G: In vitro inhibition of histamine release from mouse mast cells and human basophils by an anthranilic acid derivative. Int J Immunopharmacol 1983;5:431-435.
Hachisuka H, Nomura H, Sakamoto F, Mori O, Okubo K, Sasai Y: Effect of antianaphylactic agents on substance-P induced histamine release from rat peritoneal mast cells. Arch Dermatol Res 1988;280:158-162.
Kakegawa H, Matsumoto H, Satoh T: Activation of hyaluronidase by metallic salts and compound 48/80, and inhibitory effect of anti-allergic agents on hyaluronidase. Chem Pharm Bull (Tokyo) 1985;33:642-646.
Gruber BL: Mast cells in the pathogenesis of fibrosis. Curr Rheumatol Rep 2003;5:147-153.
Kazama I, Tamada T, Nakajima T: Macroscopic haemoglobinuria associated with Mycoplasma pneumoniae infection successfully treated by clarithromycin. Infez Med 2015;23:74-78.
Hoek KL, Cassell GH, Duffy LB, Atkinson TP: Mycoplasma pneumoniae- induced activation and cytokine production in rodent mast cells. J Allergy Clin Immunol 2002;109:470-476.
Williams CM, Galli SJ: The diverse potential effector and immunoregulatory roles of mast cells in allergic disease. J Allergy Clin Immunol 2000;105:847-859.
Mandic Z: Voltammetric study of the partitioning of macrolide antibiotics at the water/nitrobenzene interface: relationship to the pharmacokinetic profiling of macrolides. ADMET DMPK 2014;2:168-178.
Zuckerman JM: Macrolides and ketolides: azithromycin, clarithromycin, telithromycin. Infect Dis Clin North Am 2004;18:621-649.
Anderson R, Theron AJ, Feldman C: Membrane-stabilizing, anti-inflammatory interactions of macrolides with human neutrophils. Inflammation 1996;20:693-705.
Apodaca G: Modulation of membrane traffic by mechanical stimuli. Am J Physiol Renal Physiol 2002;282:F179-F190.
Cruse G, Duffy SM, Brightling CE, Bradding P: Functional KCa3.1 K+ channels are required for human lung mast cell migration. Thorax 2006;61:880-885.
Patel A, Sharif-Naeini R, Folgering JR, Bichet D, Duprat F, Honore E: Canonical TRP channels and mechanotransduction: from physiology to disease states. Pflugers Arch 2010;460:571-581.
Kawakubo T, Naruse K, Matsubara T, Hotta N, Sokabe M: Characterization of a newly found stretch-activated KCa,ATP channel in cultured chick ventricular myocytes. Am J Physiol 1999;276:H1827-H1838.
Tasaka K, Mio M, Fujisawa K, Aoki I: Role of microtubules on Ca2+ release from the endoplasmic reticulum and associated histamine release from rat peritoneal mast cells. Biochem Pharmacol 1991;41:1031-1037.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.