Bronchial anti-spasmogenic effects and selectivity of T-440, phosphodiesterase type 4 inhibitor, in the dog.

Abstract:

:We investigated the selectivity of T-440 for the inhibition of phosphodiesterases (PDEs) in vitro and for bronchial anti-spasmogenic effects in vivo. Using a fast protein liquid chromatography system, five PDE isozymes, PDE 1, PDE 2, PDE 3, PDE 4 and PDE 5 were prepared from guinea pig and dog tissues. T-440 selectively inhibited PDE 4 with an IC50 of 0.071 microM and 0.13 microM for guinea pig lung and dog trachea, respectively. The IC50 values for all other PDE isozymes were over 20 microM. In contrast, theophylline nonselectively inhibited all the tested PDE isozymes, and the inhibition did not exceed 50%, even at 100 microM. T-440 inhibited the histamine-induced bronchoconstriction of anesthetized dogs in a dose-dependent manner with an ED50 of 0.029 mg/kg, indicating that T-440 is 600 times more potent than theophylline. Both T-440 and theophylline increased LV dp/dt/P (LVP; left ventricular pressure) in anesthetized dogs with ED50 values of 3.6 mg/kg and 4.4 mg/kg, respectively. This potency was 1/125 times the bronchial anti-spasmogenic effects for T-440 and 4.2 times that of theophylline. Rolipram, a PDE 4 inhibitor, also showed selective bronchial anti-spasmogenic effects in anesthetized dogs. These results suggest that T-440, which specifically inhibits PDE 4 activity, has potent and selective bronchial anti-spasmogenic effects.

journal_name

Biol Pharm Bull

authors

Yamagata S,Wada K,Sugaya T,Oka K,Kaminuma O,Kikkawa H,Ikezawa K

doi

10.1248/bpb.20.1261

subject

Has Abstract

pub_date

1997-12-01 00:00:00

pages

1261-5

issue

12

eissn

0918-6158

issn

1347-5215

journal_volume

20

pub_type

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