The effect of selective and non-selective phosphodiesterase inhibitors on allergen- and leukotriene C-4-induced contractions in passively sensitized human airways

1 Non-selective inhibitors of cyclic nucleotide phosphodiesterase (PDE) blo ck allergen-induced contraction of passively sensitized human airways in vi tro by a dual mechanism involving a direct relaxant effect on smooth muscle and inhibition of histamine and cysteinyl leukotriene (LT) release from ai rways. We investigated the effects of non-selective PDE inhibitors and sele ctive inhibitors of PDE3 and PDE4 in order to determine the involvement of PDE isoenzymes in the suppression of allergic bronchoconstriction. 2 Macroscopically normal airways from 76 patients were sensitized with IgE- rich sera (>250 u ml(-1)) containing specific antibodies against allergen ( Dermatophagoides farinae). Contractile responses of bronchial rings were as sessed using standard organ bath techniques. 3 Passive sensitization caused increased contractile responses to allergen, histamine and LTC4. Non-selective PDE inhibitors (theophylline, 3-isobutyl -1-methylxanthine [IBMX]), a PDE3-selective inhibitor (motapizone), PDE4-se lective inhibitors (RP73401, rolipram, AWD 12-281) and a mixed PDE3/4 inhib itor (zardaverine) all significantly relaxed inherent bronchial tone at res ting tension and to a similar degree. Theophylline, IBMX, zardaverine and t he combination of motapizone and RP73401 inhibited the contractile response s to allergen and LTC4. Pre-treatment with motapizone, RP73401, rolipram or the methylxanthine adenosine receptor antagonist, 8-phenyltheophylline, di d not significantly decrease responses to either allergen or LTC4. 4 We conclude that combined inhibition of PDE3 and PDE4, but not selective inhibition of either isoenzyme or antagonism of adenosine receptors, is eff ective in suppressing allergen-induced contractions of passively sensitized human airways. The relationship between allergen- and LTC4-induced respons es suggests that PDE inhibitors with PDE3 and PDE4 selectivity are likely t o act in part through inhibition of mediator release and not simply through direct relaxant actions on airway smooth muscle.