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

1, beta-Adrenoceptor receptor agonists are the principal bronchodilato r agents used in the treatment of bronchial asthma, However, the regul ar use of beta-adrenoceptor agonists in asthmatic. patients is likely to increase asthma severity because of a defective beta-adrenoceptor f untcion. Bronchodilators that bypass this defective function are there fore needed, 2, Our objectives in this study were: (i) to assess the e ffects of an agent that directly activates adenylate cyclase (forskoli n) on guinea-pig tracheal smooth muscle; (ii) to study the interaction s between selective cyclic nucleotide phosphodiesterase (PDE) inhibito rs acid forskolin by measuring isometric tension; and (iii) to compare these results with the interaction between PDE inhibitors and terbuta line, a beta-adrenoceptor agonist, 3, The relaxant effects of forskoli n alone, which if now under development as a new bronchodilator fur br onchial asthma therapy, were slightly weaker than those of terbutaline on guinea-pig tracheal smooth muscle, 4, Both denbufylline and Ra 20- 1724, cyclic nucleotide PDEIV inhibitors, synergistically increased th e relaxant effects of forskolin and terbutaline, while other PTE isozy me inhibitors (amrinone, vinpocetine acid zaprinast) had only a minor influence, 5, In conclusion, a good synergistic interaction between Fo rskolin and PDE IV inhibitors, especially denbufylline, may provide a means for bypassing beta-adrenoceptors. Thus, the combination of forsk olin and PDE IV inhibitors would become useful in the treatment of bro nchial asthma.