Bronchial Anti-spasmogenic Effects and Selectivity of T-440,Phosphodiesterase Type 4 Inhibitor, in the Dog

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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 IC_<50> of 0.071 μM and 0.13 μM for guinea pig lung and dog trachea, respectively. The IC_<50> values for all other PDE isozymes were over 20 μM. In contrast, theophylline nonselectively inhibited all the tested PDE isozymes, and the inhibition did not exceed 50%, even at 100 μM. T-440 inhibited the histamine-induced bronchoconstriction of anesthetized dogs in a dose-dependent manner with an ED_<50> 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 ED_<50> 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.
公益社団法人日本薬学会の論文
1997-12-15