title: Inhibition of native 5-HT3 receptor-evoked contractions in guinea pig and mouse ileum by antimalarial drugs.
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. The 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, correspondingly) 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, correspondingly) 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) 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) 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.
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK. Electronic address: s.p.kelley@kent.ac.uk.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Kelley
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Walsh
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Kelly
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK.
authors.forename: Simerjyot
authors.initials: S
authors.lastname: Muhdar
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Adel-Aziz
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK.
authors.forename: Iain D
authors.initials: ID
authors.lastname: Barrett
authors.affiliation: Medway School of Pharmacy, Universities of Kent and Greenwich Chatham Maritime, UK.
authors.forename: Scott S
authors.initials: SS
authors.lastname: Wildman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000009:adverse effects*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3 / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000009:adverse effects*
chemical_list: D000962:Antimalarials; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists
keywords: 5-HT; Chloroquine; Contractions; Gastrointestinal; Mefloquine; Quinine