Vol. 284, Issue 1, 162-169, 1998

Novel Phosphodiesterase 4 Inhibitor T-440 Reverses and Prevents Human Bronchial Contraction Induced by Allergen¹

Kazuhiko Fujii, Hirotsugu Kohrogi, Hajime Iwagoe, Junji Hamamoto, Naomi Hirata, Eisuke Goto, Osamu Kawano, Kazuteru Wada, Shinsuke Yamagata and Masayuki Ando

First Department of Internal Medicine and the Department of Laboratory Medicine, Kumamoto University School of Medicine and Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Kumamoto, Japan

To study the roles of phosphodiesterase (PDE) 4 in the human airways, we examined the effect of the novel PDE4 inhibitor T-440 in the isolated human bronchus. T-440 inhibited PDE4 extracted from human bronchial smooth muscle. IC₅₀ values for the effect of T-440, rolipram (a PDE4 inhibitor) and theophylline on PDE4 activity of the bronchial tissues were 0.08 µM, 2 µM and >100 µM, respectively. T-440 (10⁶ M to 10⁵ M) and aminophylline (3.3 × 10⁵ M) significantly reversed the 10⁵ M histamine-induced contraction, the efficacy of 10⁶ M T-440 being almost the same as that of 3.3 × 10⁵ M aminophylline. T-440 (10⁶ M to 10⁵ M) and aminophylline (3.3 × 10⁵ M) significantly reversed the 10⁴ M ACh-induced contraction. But their reversal effects on the ACh-induced contraction were weaker than those on the histamine-induced contraction. T-440 (10⁵ M) significantly reversed the contraction induced by allergen in passively sensitized bronchi. The efficacy of the reversal effect of T-440 (10⁵ M) was significantly higher than that of aminophylline (10⁵ M). T-440 and aminophylline significantly relaxed the basal tension, but pretreatment with T-440 or aminophylline did not significantly prevent histamine- or ACh-induced contraction. In contrast, both T-440 (10⁵ M) and aminophylline (3.3 × 10⁵ M) prevented the contraction induced by allergen, which suggests that PDE4 inhibitor inhibits the release of chemical mediators probably from bronchial mast cells in the allergic response. T-440 (10⁶ M to 10⁵ M) caused the accumulation of cAMP at the concentration that relaxed histamine-induced contraction. Thus selective PDE4 inhibitor is a candidate for the treatment of asthma.