Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) in the ferret

Emesis induced by inhibitors of type IV cyclic nucleotide phosphodiesterase (PDE IV) has been investigated in the ferret. The PDE IV inhibitors studie d were: RS14203, R-rolipram and CT-2450 (i.e. (R)-N-{4-[1-(3-cyclopentyloxy -4-methoxyphenyl) -2-(4-pyridyl)ethyl]phenyl}N'-ethylurea), in addition to the less active enantiomers S-rolipram and CT-3405. Following oral administ rations, different emetic profiles were observed with time. Emesis induced by RS14203 exhibited a dose-response relationship but no such relationship was seen for R-rolipram or CT-2450. The incidence of emesis was positively influenced by the dose of PDE IV inhibitors administered, allowing a rank o rder of potency: RS14203 > R-rolipram > S-rolipram > CT-2450 > CT-3405. PDE IV inhibitor-induced emesis was abolished by the tachykinin NK1 receptor a ntagonist, CP-99,994. No peripheral release of substance P by PDE IV inhibi tors seems to be involved in triggering the emetic reflex since L-743,310, which only has peripheral NK1 receptor antagonist activity, was without eff ect. The implication of 5-HT3 receptors in PDE IV inhibitor-induced emesis was variable. Our results suggest that the PDE IV inhibitors studied are mi xed peripheral-central emetogens. PDE IV inhibition itself could be plausib le mechanism of action of these agents. However, whether emesis is mediated via a specific isoform of PDE IV remains to be established. (C) 1999 Elsev ier Science Ltd. All rights reserved.