Bronchial anti-spasmogenic effects and selectivity of T-440, phosphodiesterase type 4 inhibitor, in the dog.
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.
Yamagata
S
S
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Wada
K
K
Sugaya
T
T
Oka
K
K
Kaminuma
O
O
Kikkawa
H
H
Ikezawa
K
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001986:Bronchial Spasm / Q000188:drug therapy*; D016084:Bronchoconstriction / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006632:Histamine / Q000494:pharmacology; D007527:Isoenzymes; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use*; D010276:Parasympatholytics / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use*; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D013806:Theophylline / Q000494:pharmacology
D007527:Isoenzymes; D009281:Naphthalenes; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones; D011760:Pyrrolidinones; C101791:T 440; D006632:Histamine; D013806:Theophylline; D020889:Rolipram