The effectiveness of theophylline (aminophylline) in treating asthma may result in part from nonselective inhibition of multiple isozymes of cyclic nucleotide phosphodiesterase (PDE). The roles for inhibition of different PDE isozymes in the pulmonary antiallergic and bronchodilator effects of theophylline were investigated in anesthetized and ventilated guinea pigs by using the PDE-III-selective inhibitor Cl-930, the PDE-IV-selective inhibitor rolipram and the PDE-V-selective inhibitor zaprinast. Aminophylline, Cl-930 and rolipram inhibited aerosol ovalbumin-induced full [leukotriene (LT) + histamine] and LT-dependent bronchoconstriction, but zaprinast was inactive. At doses producing an equieffective inhibition of antigen-induced full bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of aerosol histamine-induced bronchoconstriction, whereas rolipram produced much less inhibition of histamine-induced bronchoconstriction. At doses producing an equieffective inhibition of antigen-induced LT-dependent bronchoconstriction, aminophylline and Cl-930 produced a similar inhibition of i.v. LTD4-induced bronchoconstriction, whereas rolipram did not inhibit LTD4-induced bronchoconstriction. Acute airway hyperreactivity was evidenced by significant leftward shifts in dose-response curves to i.v. methacholine-induced bronchoconstriction 24 hr after aerosol ovalbumin challenge. Aminophylline and rolipram prevented airway hyperreactivity without causing residual bronchodilation 24 hr after antigen challenge. In contrast, Cl-930 failed to inhibit airway hyperreactivity, but produced substantial residual bronchodilation. The results indicate that PDE-IV inhibition produces pulmonary antiallergic effects in vivo, including the apparent inhibition of LT release, which may contribute to the antiasthmatic actions of theophylline. The results also support previous suggestions that PDE-III inhibition contributes to the bronchodilator effect of theophylline.