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 inhibit or, RP 73401 in comparison with the classical PDE 4 inhibitor, rolipra m, the non-selective PDE inhibitor, theophylline and the beta-adrenoce ptor agonist, isoprenaline on the human, isolated bronchus. 2 At resti ng tone, the rank order of potency (pD(2)) for the relaxants was RP 73 401 greater than or equal to rolipram greater than or equal to isopren aline greater than or equal to theophylline. In terms of maximum relax ation produced (E(max)) the PDE 4-selective inhibitors were similar, b ut the maximal effects (70-75% of theophylline, 3 mM) were lower than that observed with isoprenaline (98% of theophylline, 3 mM) or theophy lline itself (100%). 3 On the human isolated bronchus pre-contracted w ith acetylcholine (ACh, 0.1 or 1.0 mM), the rank order of potency rema ined the same. The maximal responses to RP 73401 and rolipram were how ever markedly reduced (E(max) 39.9-46.6%) compared with isoprenaline ( E(max) 79-85%). 4 In tissues pre-contracted with ACh (0.1 mM), RP 7340 1 and rolipram (10(-9)-10(-7) M) significantly and concentration-depen dently increased tissue sensitivity to isoprenaline. RP 73401 and roli pram were similar in potency. Both selective PDE 4 inhibitors also sig nificantly increased the maximal relaxant effects of isoprenaline. The se effects were not observed with the PDE 3 inhibitor, siguazodan. 5 I n 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 7 3401 (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 p otent than the classical PDE 4-selective inhibitor rolipram and the no n-selective PDE inhibitor theophylline and is retained in bronchial ti ssue for a much longer period of time.