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Background and Purpose: The time dependency of the effect of 5-HT(4) receptor agonists depends on many specific regulatory mechanisms, which vary between tissues. This has important implications with regard to the effects of endogenous 5-HT, as well as to the clinical use of 5-HT(4) receptor agonists, and might contribute to tissue selectivity of agonists.Experimental Approach: The progression and desensitization of 5-HT(4) receptor-mediated responses were evaluated in an organ bath set-up using two, clinically relevant, porcine in vitro models: gastric cholinergic neurotransmission and atrial contractility.Key Results: Exposure of gastric tissue to 5-HT or to the selective 5-HT(4) receptor agonists prucalopride and M0003 results in a sustained non-transient effect during exposure; after washout, the response to a subsequent challenge with 5-HT shows no clear desensitization. Incubation of left atrial tissue with 5-HT resulted in a transient response, leading after washout to a marked desensitization of the subsequent response to 5-HT. The selective 5-HT(4) receptor agonists prucalopride and M0003 induce only very weak atrial responses whereas they are very effective in desensitizing the atrial response to 5-HT. The observations also suggest that the properties of prucalopride and M0003 to bind to and/or activate the 5-HT(4) receptor differ from those of 5-HT. This difference might have contributed to the observed desensitization.Conclusions and Implications: The high potency of prucalopride and M0003 in desensitizing the response to 5-HT together with their low efficacy in the atrium emphasizes the cardiac safety of this class of 5-HT(4) receptor agonists. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine4 (5-HT4) receptors are an interesting target for the management of patients in need of gastrointestinal (GI) promotility treatment. They have proven therapeutic potential to treat patients with GI motility disorders. Lack of selectivity for the 5-HT4 receptor has limited the clinical success of the agonists used until now. For instance, next to their affinity for 5-HT4 receptors, both cisapride and tegaserod have appreciable affinity for other receptors, channels or transporters [e.g. cisapride: human ether-a-go-go-related gene (hERG) is K+ channel and tegaserod: 5-HT1 and 5-HT2 receptors]. Adverse cardiovascular events observed with these compounds are not 5-HT4 receptor-related. Recent efforts have led to the discovery of a series of selective 5-HT4 receptor ligands, with prucalopride being the most advanced in clinical development. The selectivity of these new compounds clearly differentiates them from the older generation compounds by minimizing the potential of target-unrelated side effects. The availability of selective agonists enables the focus to shift to the exploration of 5-HT4 receptor-related differences between agonists. Based on drug- and tissue-related properties (e.g. differences in receptor binding, receptor density, effectors, coupling efficiency), 5-HT4 receptor agonists are able to express tissue selectivity, i.e. behave as a partial agonist in some and as a full agonist in other tissues. Furthermore, the concept of ligand-directed signalling offers great opportunities for future drug development by enlarging the scientific basis for the generation of agonist-specific effects in different cell types, tissues or organs. Selective 5-HT4 receptor agonists might thus prove to be innovative drugs with an attractive safety profile for better treatment of patients suffering from hypomotility disorders. [ABSTRACT FROM AUTHOR]

There is limited data available on the electrical activity of the rectum. An in vivo canine model was developed to record 240 extracellular electrograms simultaneously from the serosal surface of the rectum thereby enabling an off-line reconstruction of the behaviour of the electrical signals. Serosal rectal electrical activity is characterized by brief bursts of action potentials (=spikes) with a frequency of 22 cycles min−1. High-resolution mapping of these signals revealed predominant propagation of these spikes in the longitudinal direction, originating from any site and conducted for a limited time and length before stopping spontaneously, thereby describing a patch of activity. The dimension of the patches in the longitudinal direction was significantly longer than the transversal width (13.6 vs 2.4 mm; P < 0.001). Spike propagation could occur in the aboral (46% of cases), in the oral (34%) or in both directions (20%). A bolus of betanechol (i.v., 0.5 mg kg−1) increased the frequency of the spikes without affecting size, shape or orientation of the patches. As in other parts of the gastrointestinal system, individual spike propagation in the rectum is limited to small areas or patches. The contractile activity of the organ could possibly reflect this underlying pattern of electrical behaviour. [ABSTRACT FROM AUTHOR]

5-Hydroxytryptamine 4 (5-HT4) receptor agonists promote colonic propulsion. The alteration of circular muscle (CM) motility underlying this involves inhibition of contractility via smooth muscle 5-HT4 receptors and proximal colonic motility stimulation, the mechanism of the latter not having been characterized. Our aim was to identify and characterize a 5-HT4 receptor-mediated stimulation of human colon CM contractile activity. 5-HT4 receptor ligands were tested on electrical field stimulation (EFS)-induced contractions of human colonic muscle strips cut in the circular direction (called‘whole tissue’ strips). Additionally, after incubation of tissues with [3H]-choline these compounds were tested on EFS-induced release of tritium in whole tissue strips and in‘isolated’ CM strips, obtained by superficial cutting in the CM layer. Tetrodotoxin and atropine blocked EFS-induced contractions of whole tissue CM strips. Prucalopride (0.3 μmol L−1) evoked a heterogenous response on EFS-induced contraction, ranging from inhibition (most frequently observed) to enhancement. In the release experiments, EFS-induced tritium efflux was blocked by tetrodotoxin. Prucalopride increased EFS-induced tritium and [3H]-acetylcholine efflux in whole tissue and in isolated CM strips. All effects of prucalopride were antagonized by the selective 5-HT4 receptor antagonist GR113808. The results obtained indicate the presence of excitatory 5-HT4 receptors on cholinergic nerves within the CM of human colon. [ABSTRACT FROM AUTHOR]

In seven isolated segments of the feline duodenum, the timings of all spikes and the locations of all spike patches that occurred after 12–16 successive slow waves were analysed. Simultaneous recordings were performed during 1-min periods using 240 extracellular electrodes (24 × 10 array; interelectrode distance 2 mm) positioned onto the serosal surface. In all seven preparations, spikes always occurred during the first half of the slow wave cycle. From preparation to preparation, and within 1-min periods in each preparation, there was limited variation in the spike–spike intervals, in the times between the spikes and the preceding slow wave and in the number of spikes at each electrode site. In contrast, the number of electrode sites that recorded spikes and the number of spike patches both showed great variability between preparations and sometimes within a single preparation. In addition, the location of spikes and spike patches was not random but was significantly concentrated in certain areas, often located along the anti-mesenteric border, while other sites showed little or no spike activity. In conclusion, spikes and spike patches tend to occur significantly in some areas and not in others. This spatial heterogeneity will play a role in intestinal motility. [ABSTRACT FROM AUTHOR]

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 μg 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. [ABSTRACT FROM AUTHOR]