Kelley, Stephen P., Walsh, Jacqueline M., Kelly, Mark C., Muhdar, Simerjyot, Adel-Aziz, Mohammed, Barrett, Iain D. and Wildman, Scott S. (2014) Inhibition of native 5-HT3 receptor-evoked contractions in Guinea pig and mouse ileum by antimalarial drugs. European Journal of Pharmacology, 738. pp. 186-191. ISSN 0014-2999 (doi:https://doi.org/10.1016/j.ejphar.2014.05.043)

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Abstract

Quinine, Chloroquine and mefloquine are commonly used to treat malaria; however with associated gastrointestinal (GI) side-effects. These drugs act as antagonists at recombinant 5-HT3 receptors and modulate gut peristalsis. These gastrointestinal side effects may be the result of antagonism at intestinal 5-HT3 receptors. Ileum from male C57BL/6 mice and guinea pigs was mounted longitudinally in organ baths. Concentration-response curves for 5-HT and the selective 5-HT3 agonist 2-Me-5-HT were obtained with 5-HT (pEC50=7.57±0.33, 12) more potent (P=0.004) than 2-Me-5-HT (pEC50=5.45±0.58, n=5) in mouse ileum. There was no difference in potency of 5-HT (pEC50=5.42±0.15, n=8) and 2-Me-5-HT (pIC50=5.01±0.55, n=11) in guinea pig ileum (P>0.05). Quinine, Chloroquine or mefloquine was applied for 10 min and inhibitions prior to submaximal agonist application. In mouse ileum, quinine, chloroquine and mefloquine antagonised 5-HT-induced contractions (pIC50=4.9±0.17, n=7; 4.76±0.14,n=5; 6.21±0.2, n=4, respectively) with mefloquine most potent (P<0.05). Quinine, chloroquine and mefloquine antagonised 2-me-5-HT-induced contractions (pIC50=6.35±0.11,n=8; 4.64±0.2, n=7; 5.11± 0.22, n=6, respectively) with quinine most potent (P<0.05). In guinea-pig ileum, quinine, chloroquine and mefloquine antagonised 5-HT-induced contractions (pIC50=5.02±0.15, n=6; 4.54±0.1, n=7; 5.32±0.13, n=5, respectively) and 2-me-5-HT-induced contractions (pIC50=4.62±0.25, n=5; 4.56±0.14, n=6; 5.67±0.12, n=4, respectively) with chloroquine least potent against 5-HT and mefloquine most potent against 2-me-5-HT (P<0.05). These results support previous studies identifying anti-malarial drugs as antagonists at recombinant 5-HT3 receptors and may also demonstrate the ability of these drugs to influence native 5-HT3 receptor-evoked contractile responses which may account for their associated GI side-effects.

Item Type:	Article
Additional Information:	[1] Received date: 5 December 2013, Revised date: 22 May 2014, Accepted date: 23 May 2014. [2] Available online 1 June 2014 - In Press, Accepted Manuscript. [3] Cite this article as: Stephen P. Kelley, Jacqueline Walsh, Mark C. Kelly, Simerjyot Muhdar, Mohammed Adel-Aziz, Iain D. Barrett, Scott S. Wildman, Inhibition of native 5-HT 3 receptor-evoked contractions in Guinea pig and mouse ileum by antimalarial drugs, European Journal of Pharmacology, http://dx.doi.org/10.1016/j.ejphar.2014.05.043. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to customers [Elsevier] are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [4] Note to users: "Accepted manuscripts are Articles in Press that have been peer reviewed and accepted for publication by the Editorial Board of this publication. They have not yet been copy edited and/or formatted in the publication house style, and may not yet have the full ScienceDirect functionality, e.g., supplementary files may still need to be added, links to references may not resolve yet etc. The text could still change before final publication. Although accepted manuscripts do not have all bibliographic details available yet, they can already be cited using the year of online publication and the DOI, as follows: author(s), article title, Publication (year), DOI. Please consult the journal's reference style for the exact appearance of these elements, abbreviation of journal names and use of punctuation. When the final article is assigned to an volumes/issues of the Publication, the Article in Press version will be removed and the final version will appear in the associated published volumes/issues of the Publication. The date the article was first made available online will be carried over.
Uncontrolled Keywords:	5-HT, quinine, chloroquine, mefloquine, gastrointestinal, contractions
Subjects:	R Medicine > RS Pharmacy and materia medica
Faculty / School / Research Centre / Research Group:	Faculty of Engineering & Science > Medway School of Pharmacy Faculty of Engineering & Science > School of Science (SCI)
Related URLs:	Publisher
Last Modified:	17 Oct 2016 09:12
URI:	http://gala.gre.ac.uk/id/eprint/11528

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