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

The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess: (i) the effects on colonic contra ctile motility patterns; and (ii) the mediation of these effects by 5-hydro xytryptamine (5-HT4) receptors. Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain-gauge force transduce rs that were sutured on the serosal side of the colon. Prucalopride altered colonic contractile motility patterns in a dose-dependent fashion by stimu lating high-amplitude clustered contractions in the proximal colon and by i nhibiting contractile activity in the distal colon. Prucalopride was equipo tent after oral and intravenous administration, as reflected by the values for the effective dose that induced 50% of maximum effect (95% confidence l imits): 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 o f prucalopride, the first GMC generally occurred within the first half-hour after treatment. Subcutaneous pretreatment with the 5-HT4 receptor antagon ist 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 cons cious dog in a dose-dependent fashion. It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patte rns by stimulating 5-HT4 receptors.