Bronchoprotective effect of an intrabronchial administration of cilostazol powder and a nebulized PDE1 and PDE4 inhibitor KF19514 in guinea pigs.
BACKGROUND
Both oral and intravenous inhibitors of cyclic nucleotide phosphodiesterase (PDE) 3 and PDE4 have been shown to have bronchodilator and/or pulmonary antiallergic effects but their adverse effects limit the clinical use. The purpose of the present study was to assess the bronchoprotective effect of intrabronchial administration of a selective PDE3 inhibitor, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quin olinone (cilostazol), in dry power form which is proposed to be desirable rather than propellant-driven metered-dose inhalers.


METHODS
Effect of an intrabronchial administration of cilostazol powder on aerosolized histamine- and antigen-induced leukotriene-mediated bronchoconstriction were examined in anesthetized and artificially ventilated guinea pigs, in comparison with the effects of ultrasonically nebulized 5-phenyl-3-(3-pyridyl)methyl-3H-imidazo[4,5-c] [1,8] naphthyridin-4(5H)-one (KF19514), a selective PDE1/4 inhibitor.


RESULTS
Cilostazol powder and KF19514 solution inhibited histamine- and antigen-induced bronchoconstriction in a dose-dependent manner. When assessing the resulting ED50 values, the activity of cilostazol powder against antigen-induced broncho-constriction was weaker than its antagonism of histamine-induced bronchoconstriction (60.4 vs. 7.0 microg), while those of KF19514 were the opposite (0.40 vs. 2.81 microg/ml).


CONCLUSIONS
These results suggest that intrabronchially administered cilostazol powder has a bronchodilator effect, and ensure that PDE4 inhibitors have an antiallergic activity in addition to their bronchodilator effect.
Third Department of Internal Medicine, Kanazawa University School of Medicine, Japan.
M
M
Fujimura
H
H
Tachibana
S
S
Myou
T
T
Kita
T
T
Matsuda
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000281:Administration, Intranasal; D000818:Animals; D000941:Antigens; D016084:Bronchoconstriction / Q000187:drug effects*; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000077407:Cilostazol; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006632:Histamine; D019344:Lactic Acid / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D009287:Naphthyridines / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases; D011208:Powders; D013777:Tetrazoles / Q000008:administration & dosage / Q000494:pharmacology*
D000941:Antigens; D001993:Bronchodilator Agents; C106878:KF 19514; D009287:Naphthyridines; D011208:Powders; D013777:Tetrazoles; D019344:Lactic Acid; D006632:Histamine; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000077407:Cilostazol