title: Leukotriene receptor antagonism and augmentation of beta-receptor-mediated events by LY171883.
abstract: LY171883, (1-[2-hydroxy-3-propyl-4-[4(1H-tetrazol-5-yl)butoxy)phenyl]etha none), a leukotriene (LT) D4/E4 receptor antagonist, was assessed in comparison with two well known phosphodiesterase inhibitors, isobutylmethyl-xanthine (IBMX) and theophylline, for its ability to augment beta-receptor-mediated responses. Relaxation of carbachol-contracted guinea-pig trachea by isoprenaline was enhanced by the three agents in a dose-dependent manner. A two-fold enhancement of isoprenaline-induced smooth muscle relaxation was produced by 2.5 microM IBMX, 28 microM LY171883, or 140 microM theophylline. Similar concentrations of IBMX or theophylline did not antagonize LTE4-induced tracheal contractions; LY171883 totally inhibited the response and had significant LTE4 receptor antagonist activity even at 10-fold lower concentrations. Antigen-induced release of histamine and LTC4 from guinea-pig lung was reduced by isoprenaline. Prior treatment with LY171883, IBMX, or theophylline did not enhance this action. Isoprenaline reduced histamine-induced bronchospasm in anaesthetized guinea-pigs. LY171883, 30 mg kg-1, or IBMX, 1 mg kg-1, did not affect the isoprenaline-induced decrease in the histamine response. IBMX, 3 mg kg-1, and theophylline, 30 mg kg-1, augmented the isoprenaline-induced bronchodilation. LTE4-induced bronchoconstriction was not affected by IBMX or theophylline whereas LY171883 antagonized this response at doses as low as 3 mg kg-1. Therefore, in both in-vitro and in-vivo test systems, LY171883 functioned primarily as a leukotriene receptor antagonist with minimal pharmacological activity attributable to its ability to potentiate isoprenaline.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
authors.forename: L E
authors.initials: LE
authors.lastname: Rinkema
authors.forename: C R
authors.initials: CR
authors.lastname: Roman
authors.forename: W L
authors.initials: WL
authors.lastname: Russell
authors.forename: S M
authors.initials: SM
authors.lastname: Spaethe
authors.forename: K G
authors.initials: KG
authors.lastname: Bemis
authors.forename: D P
authors.initials: DP
authors.lastname: Henry
authors.forename: W S
authors.initials: WS
authors.lastname: Marshall
authors.forename: J H
authors.initials: JH
authors.lastname: Fleisch
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000098:Acetophenones / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists; D000818:Animals; D001993:Bronchodilator Agents; D002217:Carbachol / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D017999:Leukotriene E4; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D018077:Receptors, Leukotriene; D013189:SRS-A / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
chemical_list: D000098:Acetophenones; D000318:Adrenergic beta-Agonists; D001993:Bronchodilator Agents; D011971:Receptors, Immunologic; D018077:Receptors, Leukotriene; D013189:SRS-A; D013777:Tetrazoles; D017999:Leukotriene E4; C044660:LY 171883; D002217:Carbachol; D013806:Theophylline; D007545:Isoproterenol; D015056:1-Methyl-3-isobutylxanthine