Effects of RP 73401, a novel, potent and selective phosphodiesterase type 4 inhibitor, on contractility of human, isolated bronchial muscle

1 The aim of this study was to investigate the smooth muscle relaxant effects of the novel, selective phosphodiesterase (PDE) type 4 inhibitor, RP 73401 in comparison with the classical PDE 4 inhibitor, rolipram, the non‐selective PDE inhibitor, theophylline and the β‐adrenoceptor agonist, isoprenaline on the human, isolated bronchus. 2 At resting tone, the rank order of potency (pD2) for the relaxants was RP 73401 ≥ rolipram ≥ isoprenaline > > theophylline. In terms of maximum relaxation produced (Emax) the PDE 4‐selective inhibitors were similar, but the maximal effects (70–75% of theophylline, 3 mM) were lower than that observed with isoprenaline (98% of theophylline, 3 mM) or theophylline itself (100%). 3 On the human isolated bronchus pre‐contracted with acetylcholine (ACh, 0.1 or 1.0 mM), the rank order of potency remained the same. The maximal responses to RP 73401 and rolipram were however markedly reduced (Emax 39.9–46.6%) compared with isoprenaline (Emax 79–85%). 4 In tissues pre‐contracted with ACh (0.1 mM), RP 73401 and rolipram (10−9‐10−7 m) significantly and concentration‐dependently increased tissue sensitivity to isoprenaline. RP 73401 and rolipram were similar in potency. Both selective PDE 4 inhibitors also significantly increased the maximal relaxant effects of isoprenaline. These effects were not observed with the PDE 3 inhibitor, siguazodan. 5 In terms of retention by tissues (an index of duration of action), the onset of action of RP 73401 (2.11 ± 0.53 min) and rolipram (1.70 ± 0.45 min) was significantly slower than that of isoprenaline (0.33 ± 0.06 min) or theophylline (1.17 ± 0.25 min). The retention of RP 73401 (89.0 ± 21.9 min) on the human isolated bronchial tissues after washing was however dramatically longer than that of rolipram (18.3 ± 4.5 min), theophylline (3.43 ± 0.58 min) or isoprenaline (2.81 ± 0.31 min). 6 These data indicate that RP 73401 is a potent and long‐acting relaxant of human bronchial muscle in vitro. RP 73401 is more potent than the classical PDE 4‐selective inhibitor rolipram and the non‐selective PDE inhibitor theophylline and is retained in bronchial tissue for a much longer period of time.