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.