INVESTIGATION INTO THE ROLE OF PHOSPHODIESTERASE-IV IN BRONCHORELAXATION, INCLUDING STUDIES WITH HUMAN BRONCHUS

1 We have investigated the role of cyclic nucleotide phosphodiesterase IV (PDE IV) in the relaxation of human bronchus and guinea-pig trachea in vitro and in guinea-pigs in vivo. 2 Functional studies showed that the selective PDE IV inhibitors, rolipram and denbufylline, relaxed human and guinea-pig preparations in vitro. 3 Two clinically used xanthine non-selective PDE inhibitors, theophylline and pentoxifylline, were also effective in these preparations, but were much less potent than the selective agents used. 4 The rank order of potency for the four PDE inhibitors in both species was similar. 5 Biochemical studies indicated that PDE IV was the major PDE isoform present in the human bronchial tissue. PDEs I, II and V were also identified. 6 Theophylline and pentoxifylline were, as expected. non-selective inhibitors of the human enzymes, but there was a good correlation between PDE IV inhibitory and bronchorelaxation potencies, suggesting that PDE IV inhibition is important for the clinical bronchodilator activities of the two xanthine compounds. 7 We have confirmed the ability of selective PDE IV inhibitors to cause bronchodilatation in guinea-pigs in vivo. 8 We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic.