Abstract
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 (10−6 M to 10−5 M) and aminophylline (3.3 × 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 × 10−5 M aminophylline. T-440 (10−6 M to 10−5 M) and aminophylline (3.3 × 10−5M) 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 × 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.
Footnotes
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Send reprint requests to: Hirotsugu Kohrogi, M.D., First Department of Internal Medicine, Kumamoto University School of Medicine, 1-1-1, Honjo, Kumamoto 860, Japan.
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↵1 Supported by Scientific Grants-in-Aid for Scientific Research (C) 02670343 and 06670622 from the Ministry of Education, Science and Culture of Japan. Presented in part at the 1996 American Lung Association/American Thoracic Society International Conference.
- Abbreviations:
- PDE
- phosphodiesterase
- FEV1.0%
- ratio of FEV1.0 (forced expiratory volume in one second) to FVC (forced vital capacity)
- VC
- vital capacity
- cGMP
- cyclic guanosine 3′,5′-monophosphate
- Received March 6, 1997.
- Accepted September 16, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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