Phosphodiesterase IV inhibitors synergistically potentiate relaxation induced by forskolin in guinea-pig trachea.
1. Beta-adrenoceptor receptor agonists are the principal bronchodilator agents used in the treatment of bronchial asthma. However, the regular use of beta-adrenoceptor agonists in asthmatic patients is likely to increase asthma severity because of a defective beta-adrenoceptor function. Bronchodilators that bypass this defective function are therefore needed. 2. Our objectives in this study were: (i) to assess the effects of an agent that directly activates adenylate cyclase (forskolin) on guinea-pig tracheal smooth muscle; (ii) to study the interactions between selective cyclic nucleotide phosphodiesterase (PDE) inhibitors and forskolin by measuring isometric tension; and (iii) to compare these results with the interaction between PDE inhibitors and terbutaline, a beta-adrenoceptor agonist. 3. The relaxant effects of forskolin alone, which is now under development as a new bronchodilator for bronchial asthma therapy, were slightly weaker than those of terbutaline on guinea-pig tracheal smooth muscle. 4. Both denbufylline and Ro 20-1724, cyclic nucleotide PDE IV inhibitors, synergistically increased the relaxant effects of forskolin and terbutaline, while other PDE isozyme inhibitors (amrinone, vinpocetine and zaprinast) had only a minor influence. 5. In conclusion, a good synergistic interaction between forskolin and PDE IV inhibitors, especially denbufylline, may provide a means for bypassing beta-adrenoceptors. Thus, the combination of forskolin and PDE inhibitors would become useful in the treatment of bronchial asthma.
Tanizawa
M
M
Second Department of Internal Medicine, Nagoya University, School of Medicine, Japan.
Watanabe
T
T
Kume
H
H
Yamaki
K
K
Miyamoto
K
K
Takagi
K
K
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004357:Drug Synergism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013726:Terbutaline / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects*
D001993:Bronchodilator Agents; D010726:Phosphodiesterase Inhibitors; D005576:Colforsin; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D013726:Terbutaline