Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs

The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess: (i) the effects on colonic contractile motility patterns; and (ii) the mediation of these effects by 5-hydroxytryptamine (5-HT4) receptors. Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain-gauge force transducers that were sutured on the serosal side of the colon. Prucalopride altered colonic contractile motility patterns in a dose-dependent fashion by stimulating high-amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon. Prucalopride was equipotent after oral and intravenous administration, as reflected by the values for the effective dose that induced 50% of maximum effect (95% confidence limits): 0.04 mg kg(-1) p.o. (0.01-0.1 mg kg(-1)) and 0.01 mg kg(-1) i.v. (0.006-0.04 mg kg(-1)). Prucalopride also caused a dose-dependent decrease in the time to the first giant migrating contraction (GMC); at higher doses of prucalopride, the first GMC generally occurred within the first half-hour after treatment. Subcutaneous pretreatment with the 5-HT4 receptor antagonist GR125487 (40 mug kg(-1) bodyweight) completely prevented the effects of orally administered prucalopride (0.31 mg kg(-1) bodyweight). Prucalopride, given orally or intravenously, alters colonic motility in the fasted conscious dog in a dose-dependent fashion. It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating 5-HT4 receptors.