Isoenzyme-selective cyclic nucleotide phosphodiesterase inhibitors: Effects on airways smooth muscle

Abstract

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes (I–V) have been demonstrated in airways smooth muscle of several species including man. Theophylline is a non-selective inhibitor of PDE and is a potent relaxant of airways smooth muscle but its use is limited by its toxicity. Consequently, research into new, isoenzyme-selective PDE inhibitors is seen as important. The potential airways smooth muscle relaxant effects of these drugs is discussed in this review. Cyclic AMP PDE (types III and IV) inhibition produces greater relaxation than cyclic GMP PDE (types I and V) inhibition. No PDE II-selective inhibitors have been described. Airways smooth muscle relaxation in vitro, is greater with PDE IV than PDE III inhibitors in guinea-pig and bovine airways whereas PDE III is more important in porcine airways. Both cyclic AMP PDEs are important in human airways. PDE III or IV inhibition can produce additive effects and can augment isoprenaline actions. PDE V inhibition augments sodium nitroprusside-induced effects. There are no reported interactions between cyclic AMP and cyclic GMP PDE inhibitors. In vivo, cyclic AMP PDE inhibitors are more potent bronchodilators than cyclic GMP PDE inhibitors. PDE IV inhibitors have less cardiovascular side-effects. Topical administration may further increase efficacy and selectivity. Clinically PDE III inhibition improves lung function but also affects cardiovascular parameters. Inhaled PDE III/IV inhibitors produce bronchodilation without marked side effects. Potent, selective PDE IV inhibitors are currently being evaluated. In conclusion, isoenzyme-selective PDE inhibitors, especially PDE IV, may be useful airways smooth muscle relaxants in the treatment of lung disorders such as asthma. The potent anti-inflammatory properties of PDE IV inhibitors should also be of benefit in asthma.