Bronchoprotective Effect of an Intrabronchial Administration of Cilostazol Powder and a Nebulized PDE1 and PDE4 Inhibitor KF19514 in Guinea Pigs

Abstract

Background: Both oral and intravenous inhibitors of cyclic nucleotide phosphodiesterase (PDE) 3 and PDE4 have been shown to have bronchodilator and/or pulmonary antiallergic effects but their adverse effects limit the clinical use. The purpose of the present study was to assess the bronchoprotective effect of intrabronchial administration of a selective PDE3 inhibitor, 6–[4–(1–cyclohexyl–1H–tetrazol–5–yl)butoxy]–3,4–dihydro–2(1H)–quinolinone (cilostazol), in dry power form which is proposed to be desirable rather than propellant–driven metered–dose inhalers. Methods: Effect of an intrabronchial administration of cilostazol powder on aerosolized histamine– and antigen–induced leukotriene–mediated bronchoconstriction were examined in anesthetized and artificially ventilated guinea pigs, in comparison with the effects of ultrasonically nebulized 5–phenyl–3–(3–pyridyl)methyl–3H–imidazo[4,5–c] [1,8] naphthyridin–4(5H)–one (KF19514), a selective PDE1/4 inhibitor. Results: Cilostazol powder and KF19514 solution inhibited histamine– and antigen–induced bronchoconstriction in a dose–dependent manner. When assessing the resulting ED₅₀ values, the activity of cilostazol powder against antigen–induced broncho–constriction was weaker than its antagonism of histamine–induced bronchoconstriction (60.4 vs. 7.0 μg), while those of KF19514 were the opposite (0.40 vs. 2.81 μg/ml). Conclusion: These results suggest that intrabronchially administered cilostazol powder has a bronchodilator effect, and ensure that PDE4 inhibitors have an antiallergic activity in addition to their bronchodilator effect.