title: Interaction of local anaesthetics with histamine H1 receptors in guinea-pig ileum.
abstract: The interaction of amine local anaesthetics and related compounds with histamine H1 receptors was investigated in guinea-pig ileal longitudinal muscle. Quinacrine, chloroquine, tetracaine and procaine inhibited [3H]mepyramine binding to solubilized membrane from ileal muscle with pKi values of 5.27 +/- 0.11, 5.66 +/- 0.01, 4.28 +/- 0.08 and 3.97 +/- 0.11, respectively. The pKB values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 5.49 +/- 0.11, 6.14 +/- 0.09, 4.86 +/- 0.06 and 4.58 +/- 0.06, respectively, in reasonable agreement with the pKi values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H1 receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization. The results suggested that most of these local anaesthetics interacted competitively at histamine H1 receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allosterically and inhibited desensitization through a separate action.
authors.affiliation: Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Horio
authors.forename: T
authors.initials: T
authors.lastname: Nagare
authors.forename: Y
authors.initials: Y
authors.lastname: Ishida
authors.forename: H
authors.initials: H
authors.lastname: Moritoki
mesh_terms: D000779:Anesthetics, Local / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002738:Chloroquine / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006168:Guinea Pigs; D006632:Histamine / Q000633:toxicity; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D007553:Isotope Labeling; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011343:Procaine / Q000378:metabolism / Q000494:pharmacology; D011738:Pyrilamine / Q000378:metabolism / Q000494:pharmacology; D011796:Quinacrine / Q000378:metabolism / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013748:Tetracaine / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D013748:Tetracaine; D011343:Procaine; D006632:Histamine; D002738:Chloroquine; D011796:Quinacrine; D011738:Pyrilamine