Novel phosphodiesterase 4 inhibitor T-440 reverses and prevents human bronchial contraction induced by allergen.
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 microM, 2 microM and > 100 microM, respectively. T-440 (10(-6) M to 10(-5) M) and aminophylline (3.3 x 10(-5) M) significantly reversed the 10(-5) M histamine-induced contraction, the efficacy of 10(-6) M T-440 being almost the same as that of 3.3 x 10(-5) M aminophylline. T-440 (10(-6) M to 10(-5) M) and aminophylline (3.3 x 10(-5) M) significantly reversed the 10(-4) M ACh-induced contraction. But their reversal effects on the ACh-induced contraction were weaker than those on the histamine-induced contraction. T-440 (10(-5) M) significantly reversed the contraction induced by allergen in passively sensitized bronchi. The efficacy of the reversal effect of T-440 (10(-5) M) was significantly higher than that of aminophylline (10(-5) 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 (10(-5) M) and aminophylline (3.3 x 10(-5) 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 (10(-6) M to 10(-5) 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.
Fujii
K
K
First Department of Internal Medicine, Kumamoto University School of Medicine, Japan.
Kohrogi
H
H
Iwagoe
H
H
Hamamoto
J
J
Hirata
N
N
Goto
E
E
Kawano
O
O
Wada
K
K
Yamagata
S
S
Ando
M
M
D000109:Acetylcholine / Q000494:pharmacology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000485:Allergens / Q000276:immunology*; D000628:Aminophylline / Q000494:pharmacology; D001980:Bronchi / Q000201:enzymology; D016084:Bronchoconstriction / Q000187:drug effects*; D000242:Cyclic AMP / Q000032:analysis; D005260:Female; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000302:isolation & purification; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000302:isolation & purification; D011728:Pyridones / Q000494:pharmacology*
D000485:Allergens; D007527:Isoenzymes; D009281:Naphthalenes; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; C101791:T 440; D000628:Aminophylline; D006632:Histamine; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000109:Acetylcholine