Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus

Abstract

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 guineapigs in vivo. 8 We conclude that our study has provided further evidence that selective PDE IV inhibitors could act as bronchodilators in the clinic.

Relaxation of guinea‐pig trachea by cyclic AMP phosphodiesterase inhibitors and their enhancement by sodium nitroprusside

“…Intracellular concentrations of cyclic AMP and cyclic GMP are also determined by their rate of hydrolysis, catalyzed by a related group of phosphodiesterase (PDE) isoenzyme families, PDE I-PDE V (Beavo & Reifsnyder, 1990). In tracheal smooth muscle, members of all five families have been identified Shahid et al, 1991;de Boer et al, 1992;Cortijo et al, 1993). Of these, PDE's I, II, and III can utilize both cyclic AMP and cyclic GMP as substrate, PDE IV is a cyclic AMP-specific PDE and PDE V a cyclic GMP-specific PDE (Beavo, 1988;Beavo & Reifsnyder, 1990).…”

The effect of a novel orally active selective PDE4 isoenzyme inhibitor (CDP840) on allergen-induced responses in asthmatic subjects

“…PDE4 inhibitors are effective in inhibiting microvascular leakage induced by a variety of proinflammatory mediators [26]. There is also evidence that, as well as enhancing nonadrenergic noncholinergic (NANC) relaxation [27], PDE4 inhibitors may have direct bronchodilatory effects [28,29]. No selective PDE4 inhibitor has yet been evaluated for its anti-inflammatory effects in man.…”

The Pharmacology of Two Novel Long-Acting Phosphodiesterase 3/4 Inhibitors, RPL554 [9,10-Dimethoxy-2(2,4,6-trimethylphenylimino)-3-(N-carbamoyl-2-aminoethyl)-3,4,6,7-tetrahydro-2H-pyrimido[6,1-a]isoquinolin-4-one] and RPL565 [6,7-Dihydro-2-(2,6-diisopropylphenoxy)-9,10-dimethoxy-4H-pyrimido[6,1-a]isoquinolin-4-one]

“…Airway smooth muscle relaxation is observed following inhibition of PDE3 or PDE4 in canine (Torphy et al, 1988;Torphy and Undem, 1991), guinea pig trachea (Raeburn et al, 1993;Spina et al, 1995), and human airway preparations (de Boer et al, 1992;Rabe et al, 1995), which is primarily thought to be mediated by PDE3 (Cortijo et al, 1993). RPL554 and RPL565 both caused a concentration-and timedependent inhibition of contractile responses elicited by EFS.…”