type4inhibitor, on contractility ofhuman, isolated bronchial muscle

(PDE)type4inhibitor, RP 73401incomparison withtheclassical PDE 4inhibitor, rolipram, thenon-selective PDEinhibitor, theophylline andthefl-adrenoceptor agonist, isoprenaline on thehuman, isolated bronchus. 2 Atresting tone,therankorderofpotency (pD2) fortherelaxants was RP 73401krolipram kisoprenaline> >theophylline. Intermsofmaximumrelaxation produced (Ema,,) thePDE 4-selective inhibitors were similar, butthemaximal effects (70-75%oftheophylline, 3mM)were lowerthanthat observed withisoprenaline (98%oftheophylline, 3mM)ortheophylline itself (100%). 3 Onthehumanisolated bronchus pre-contracted withacetylcholine (ACh,0.1or 1.0mM),therank order ofpotency remained thesame.Themaximalresponses toRP 73401androlipram werehowever markedly reduced (Ema39.9-46.6%) compared withisoprenaline (Ema79-85%). 4 Intissues pre-contracted withACh (0.1 mM),RP 73401androlipram (10-9- 10-7M)significantly andconcentration-dependently increased tissue sensitivity toisoprenaline. RP 73401androlipram were similar inpotency. Bothselective PDE 4 inhibitors alsosignificantly increased themaximalrelaxant effects ofisoprenaline. Theseeffects were notobserved withthePDE 3inhibitor, siguazodan. 5 Intermsofretention bytissues (anindexofduration ofaction), theonsetofaction ofRP 73401 (2.11+0.53 min)androlipram (1.70+0.45 min)was significantly slower thanthatofisoprenaline (0.33+0.06 min) or theophylline (1.17+0.25 min). Theretention ofRP 73401(89.0+21.9 min) on the humanisolated bronchial tissues after washing was however dramatically longer thanthatofrolipram (18.3 +4.5min), theophylline (3.43 +0.58min) orisoprenaline (2.81 +0.31min). 6 These dataindicate that RP73401isapotent andlong-acting relaxant ofhumanbronchial muscle in vitro. RP73401 ismore potent thantheclassical PDE4-selective inhibitor rolipram andthenon-selective PDE inhibitor theophylline andisretained inbronchial tissue fora muchlonger period oftime.