PHOSPHODIESTERASE IV INHIBITORS SYNERGISTICALLY POTENTIATE RELAXATION INDUCED BY FORSKOLIN IN GUINEA-PIG TRACHEA

1. β-Adrenoceptor receptor agonists are the principal bronchodilator agents used in the treatment of bronchial asthma. However, the regular use of β-adrenoceptor agonists in asthmatic patients is likely to increase asthma severity because of a defective β-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 β-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 nudeotide PDEIV 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 β-adrenoceptors. Thus, the combination of forskolin and PDE inhibitors would become useful in the treatment of bronchial asthma.