Bronchopulmonary actions of 1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), a substituted imidazole, in the guinea pig.
1-(1,2,3,4-tetrahydro-1-naphthylenyl)-1H-imidazole, nitric acid salt (LY150310), was examined for bronchodilator activity in the guinea pig. In guinea pig tracheal preparations, LY150310 competitively antagonized the contractile effects of exogenous histamine and blocked the histamine-mediated component of contractions produced by ovalbumin challenge. LY150310 had little effect on the nonhistamine component of ovalbumin-induced contractions of lung parenchymal strips, but it enhanced the production of prostaglandin (PG) E2 and PGF2 alpha although it partially inhibited thromboxane B2 formation. In other studies, in which postmortem pulmonary gas trapping was used as an index of in vivo airway obstruction, i.v. LY150310 dose-dependently inhibited the bronchospasm produced by aerosols of the divalent cationic ionophore A23187, histamine, 5-hydroxytryptamine, leukotriene D4, methacholine, ovalbumin or platelet activating factor. LY150310 was equal to or more potent than aminophylline in all test systems. Also, orally administered LY150310 inhibited the airway obstruction produced by selected challenge aerosols. In ex vivo studies, LY150310 elevated PGE2 and tended to decrease thromboxane B2 in sodium arachidonate-stimulated whole blood. However, PGE2 and other cyclooxygenase products did not appear to account for in vivo bronchodilation, because combining LY150310 and piroxicam did not alter inhibition of A23187-induced airway obstruction. Our results demonstrate that LY150310 reduces airway obstruction caused by a variety of bronchoconstrictive agents, including A23187 and ovalbumin. Although this substituted imidazole appears to have activity as a histamine H1-receptor antagonist and can alter prostanoid concentrations in vitro and in vivo, its mode of bronchodilation is unclear.
Stengel
P W
PW
Lilly Research Laboratories, Pulmonary Research, Lilly Corporate Center, Indianapolis, Indiana.
Dillard
R D
RD
Cho
H L
HL
Snyder
D W
DW
Spaethe
S M
SM
Pechous
P A
PA
Obenchain
R L
RL
Cockerham
S L
SL
Silbaugh
S A
SA
D000336:Aerosols; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D016085:Bronchoconstrictor Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004347:Drug Interactions; D015777:Eicosanoids / Q000096:biosynthesis / Q000097:blood; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects*; D008297:Male; D010894:Piroxicam / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000378:metabolism; D014132:Trachea / Q000187:drug effects*
D000336:Aerosols; D000970:Antineoplastic Agents; D016085:Bronchoconstrictor Agents; D015777:Eicosanoids; D007093:Imidazoles; D008070:Lipopolysaccharides; D013764:Tetrahydronaphthalenes; C029166:dazoxiben; C060380:LY 150310; D010894:Piroxicam; D013929:Thromboxane B2; D015237:Dinoprost; D015232:Dinoprostone