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5. Abstract

Author

Andries, L. J., Sys, S. U., Meulemans, A. L., Schuurkes, J. A. J., Vanheel, B., Van de Voorde, J., De Smet, P., Li, J., Van Driessche, W., Flamion, B., Foulon, S., Abramow, M., Calders, P., Eechaute, W., Lacroix, E., Weyne, I., Hoeben, D., Burvenich, C., Fransen, P., Andries, L. J., Van Bedaf, D., Demolder, M., Sys, S. U., Ouedraogo, R., Lebrun, P., Herchuelz, A., Antoine, M. -H., Vandenput, S., Votion, D., Anciaux, N., Duvivier, D. H., Art, T., Lekeux, P., Votion, D., Ghafir, Y., Vandenput, S., Art, T., Lekeux, P., Geurts, M., Hermans, E., Maloteaux, J. -M., Perrad, B., Noel, B., Lagache, F., Bister, J. L., Paquay, R., Bister, J. L., Derycke, G., Vandermeir, M. A., Paquay, R., de Brouwer, S., Porret, C. -A., Stergiopulos, N., Meister, J. -J., Verbeke, M., Van de Voorde, J., Lameire, N., De Clerck, N. M., De Schuytter, J., Tytgato, J., Buyse, G., Eggermont, J., Droogmans, G., Nilius, B., Daenens, P., Salomone, S., Feron, O., Dessy, C., Morel, N., Godfraind, T., Aloisi, A. M., Sacerdote, P., Lodi, L., Carli, G., Carobi, C., Garinei, G., Miniaci, U. C., Scotto, P., Sabatino, M., Sardo, P., Iurato, L., La Grutta, V., Bagni, M. A., Cecchi, G., Cecchini, E., Colomo, F., Garzella, P., Bottinelli, R., Harridge, S. D. H., Canepari, M., Reggiani, C., Reggiani, Saltin, Bambagioni, D., Fanò, G., Menchetti, G,, Danieli-Betto, P., Esposito, A., Betto, R., Megighian, A., Midrio, M., Betto, D. Danieli, Esposito, A., Megighian, A., Midrio, M., Orizio, C., Liberati, D., Locatelli, C., De Grandis, D., Veicsteinas, A., Angoli, D., Delia, D., Wanke, E., Bramucci, M., Miano, A., Quassinti, L., Maccari, E., Murri, O., Amici, D., Cibelli, G., Jüngling, S., Schoch, S., Gerdest, H. H., Thiel, G., Demori, I., Bottazzi, C., Voci, A., Fugassa, E., Barreca, A., Minuto, F., Gallo, G., Fulle, S., Belia, S., Menchetti, G., Cacchio, M., Fanò, G., Gastaldi, G., Laforenza, U., Ferrari, G., Rindi, G., Doni, M. G., Padoin, E., Residori, O., Cesaro, M., Toma, L., Rubini, A., Mutinelli, F, Paulesu, L., Romagnolie, R., Cintorino, M., Pippia, P., Meloni, M. A., Sciola, L., Spano, A., Cogoli-Greuter, M., Cogoli, A., Sardini, A., Mintenig, G. M., Valverde, M. A., Sepùlveda, F. V., Gill, D. R., Hyde, S. C., Higgins, C. F., McNaughton, P. A., Spena, A., Arcuri, M. T., Bonofiglio, S., Chimenti, R., Covello, C., De Cicco, T., Mazzulla, S., Martino, G., Tottene, A., Moretti, A., Pietrobon, D., Baccari, M. C., Calamai, F., Staderini, G., Cova, E., Marelli, R., Sommi, P., Ventura, U., Lombardi, A. M., Fabris, R., Pagano, C., Federspil, G., Vettor, R., Mancinelli, R., Tonali, P., Servidei, S., Romani, R., Tringali, A., Azzena, G. B., Mulè, F., Serio, R., Postorino, A., Pagano, C., Rizzato, M., Granzotto, M., Lombardi, A. M., Fabris, R., Vettor, R., Federspil, G., Sommi, P., Ricci, V., Romano, M., Ivey, K. J., Ventura, U., Vacca, G., Papillo, B., Mary, D. A. S. G., Battaglia, A., Grossini, E., Vacca, G., Papillo, B., Battaglia, A., Grossini, E., Accili, E. A., Redaelli, G., DiFrancesco, D., Antoniotti, S., Distasi, C., Lovisolo, D., Munaron, L., Bertaso, F., Assandri, R., Mazzanti, M., Bianchi, L., Arcangeli, A., Faravelli, L., Becchetti, A., Coronello, M., Mini, E., Francini, F., Olivotto, M., Wanke, E., Bigiani, A., Kim, D. -J., Roper, S. D., Carabelli, V., Lovallo, M., Magnelli, V., Zucker, H., Carbone, E., D’Angelo, E., Rossi, P., De Filippi, G., Taglietti, V., Faravelli, L., Bianchi, L., Arcangeli, A., Francini, F., Olivotto, M., Wanke, E., Francini, F., Bencini, C., Squecco, R., Guatteo, E., Bacci, A., Franceschetti, S., Avanzini, G., Wanke, E., Magnelli, V., Carbone, E., Mazzanti, M., Assandri, R., Ferroni, A., DiFrancesco, D., Navangione, A., Vellani, V., Rispoli, G., Peres, A., Centinaio, E., Giovannardi, S., Russo, G., Marcotti, W., Prigioni, I., Trequattrini, C., Harper, A. A., Petris, A., Franciolini, F., Zaza, A., Micheletti, M., Brioschi, A., Antonutto, G., Capelli, C., Girardis, M., Zamparo, P., di Prampero, P. E., Antonutto, G., Girardis, M., Tuniz, D., di Prampero, P. E., Filippi, G. M., Troiani, D., Grassi, B., Poole, D. C., Richardson, R. S., Knight, D. R., Erickson, B. K., Wagner, P. D., Aimi, B., Stilli, D., Gallo, P., Sgoifo, A., Lagrasta, C., Olivetti, G., Reali, N., Casti, A., Musso, E., Alloatti, G., Penna, C., Gallo, M. P., Levi, R. C., Fenoglio, I., Appendino, G., Gallo, P., Sgoifo, A., Medici, D., Aimi, B., Manghi, M., Stilli, D., Musso, E., Sgoifo, A., Pasini, E., Gallo, P., Aimi, B., Stilli, D., Ceconi, C., Musso, E., Baldissera, F., Cavallari, P., Locatelli, M., Bartesaghi, R., Gessi, T., Benfenati, F., Valtorta, F., Onofri, F., Poo, M., Greengard, P., Biagini, G., Sala, D., Viani§, P., Kozlov, A. V., Zini, I., Bravin, M., Tempia, F., Strata, P., Brescia, G., Di Benedetto, C., Corsi, P., Cangiano, G., Buttiglione, M., Ambrosini, M., Gennarini, G., Casadio, A., Levi, R. C., Montarolo, P. G., Cesare, P., Stoughton, R., McNaughton, P. A., D’Arcangelo, G., Dodt, H. U., Brancati, A., Zieglgänsberger, W., Errico, P., Ferraresi, A., Barmack, N. H., Pettorossi, V. E., Gasparini, S., D’Ambrosio, R., Janigro, D., DiFrancesco, D., Gritti, I., Marintti, M., Calcaterra, R., Freddi, R., Mancia, M., Imeri, I., Bianchi, S., Mancia, M., Lui, F., Gregory, K. M., Blanks, R. H. I., Giolli, R. A., Benassi, C., Corazza, R., Magherini, P. C., Bardoni, R., Belluzzi, O., Mancinelli, R., Manni, E., Azzena, G. B., Tringali, A., Romani, R., Diana, M., Fratta, W., Manzoni, D., Andre, P., Pompeiano, O., Mazzocchio, R., Rossi, A., Melis, F., Kitura, A., Caria, M. A., Asanuma, H., Melone, M, De Biasi, S, Minelli, A, Conti, F, Minelli, A, Karschin, C, DeBiasi, S, Brecha, N C, Conti, F, Monda, M., Amaro, S., Sullo, A., De Luca, B., Monda, M., Amaro, S., Sullo, A., De Luca, B., Pantò, M. R., Cicirata, F., Parenti, R., Serapide, M. F., Parenti, R., Wassef, M., Cicirata, F., Podda, M. V., Solinas, A., Chessa, G., Deriu, F., Mameli, O., Tolu, E., Pompeiano, O., Andre, P., Manzoni, D., Porro, C. A., Francescato, M. P., Cettolo, V., Diamond, M. E., Baraldi, P., Bazzocchi, M., Rivosecchi, R., Konnerth, A., Rossi, M. L., Martini, M., Pelucchi, B., Fesce, R., Santarelli, L., Schacher, S., Montarolo, P. G., Santarelli, R., Grassi, C., Valente, A., Nisticò, S., Bagetta, G., Azzena, G. B., Scuri, Rossana, Garcia-Gil, Mercedes, Mozzachiodi, Riccardo, Brunelli, Marcello, Stefani, G., Onofri, F., Vaccaro, P., Nielander, H. B., Benfenati, F., Tancredi, V., D’Antuono, M., Siniscalchi, A., Brancati, A., Avoli, M., Vellani, V., Navangione, A., Rispoli, G., Verzè, L., Buffo, A., Rossi, F., Oestreicher, A. B., Gispen, W. H., Strata, P., Zamboni, G., Amici, R., Jones, C. A., Perez, E., Domeniconi, R., Parmeggiani, P. L., Zoli, Michele, Le Novàre, Nicolas, Changeux, Jean -Pierre, Lafortuna, C. L., Reinach, E., Saibene, F., Scotto, P., Zocchi, L., Agostoni, E., and Cremaschi, D.

Published
1996
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7. Abstracts of papers Pharmacological Meeting

Author

Bax, W. A., Saxena, P. R., Biewenga, Gerreke Ph., de Jong, Jan, Bast, Aalt, Bloemen, Pauline G. M., van den Tweel, Maria C., Henricks, Paul A. J., Engels, Ferdi, Nijkamp, Frans P., Molewijk, H. E., van der Poel, A. M., Olivier, B., Briejer, M. R., Schuurkes, J. A. J., Akkermans, L. M. A., Bruning, T. A., Hendriks, M. G. C., Chang, P. C., Kuypers, E. A. P., van Zwieten, P. A., Cappendijk, S. L. T., de Vries, R., Dzoljic, M. R., Bouwknecht, J. A., Crijns, F. R. L., Huijberts, M. S. P., Boudier, H. A. J. Struijker, Kruzeman, A. C. Nieuwenhuijzen, Wolffenbuttel, B. H. R., de Lannov, L. M., Danser, A. H. J., Schoemakef, R. G., Schalekamp, M. A. D. H., Du, Xiao Y., Schoemaker, Regien G., Saxena, Pramod R., Dubois, E. A., Batink, H. D., Pfaffendorf, M., van Roven, E. A., Garrelds, I. M., de Graaf-in 't Veld, C., Ziilstra, F. J., Jansen, A. P. H., van Wijk, R. Gerth, Gho, B. C. G., Schoemaker, R. G., Lee, C. v. d., Sharma, H. S., Verdouw, P. D., Groenink, L., van der Gugten, J., Zethof, T. J. J., Hasselaar, P., Jansen, J. W. C. M., van Giezen, J. J. J., Dreteler, G. H., Hulkenberq, A., Reinders, J. H., Toorop, G. P., Herremans, A. H. J., Hijzen, T. H., Slangen, J. L., Hessel, E. M., Van Oosterhout, A. J. M., Hofstra, C., Garssen, J., van Loveren, H., Savelkoul, H. F. J., Nijkamp, F. P., Hol, Thorwald, Van Ree, Jan M., Spruijt, Berry M., Hüsken, B. C. P., van Zwieren, P. A., Kalkman, E. A. J., Kam, K. L., Keuzenkamp-Jansen, C. W., De Abreu, R. A., Bökkerink, J. P. M., vd Heijden, M. A. H., Trijbels, J. M. F., Kraneveld, A. D., Buckley, T. L., van Schaik, Y., Koster, A. Sj., Mathôt R. A. A., Van den Aarsen B. C. F. M., Langemeijer M. W. E., Ijzerman A. P., Danhof M., Mohede, Inqe C. M., van Oosterhout, Antoon J. M., Monshouwer, M., Witkamp, R. F., Nijmeijer, S. M., Van Miert, A. S. J. P. A. M., Oosting, J., Janssen, B. J. A., Pijl, A. J., van der Wal, A. C., Mathy, M. -J., Pruimboom, W. M., van Dijk, A. P. M., Tak, C. J. A. M., Bonta, I. L., Wilson, J. H. P., Bac, D. J., Zijlstra, F. J., Hashjin, G. Sadeghi, Folkerts, G., Henricks, P. A. J., Santing, R. E., Pasman, Y., Olymulder, C. G., Roffel, A. F., Zaaqsma, J., Meurs, H., Scheerens, Heleen, Buckley, Theresa L., Van Loveren, Henk, Sipma, H., Duin, M., den Hertog, A., Nelemans, A., Smit, J., Coppes, R. P., Geurtsen, A., Zaagsma, J., Smit, M. J., Leurs, R., Bast, A., Timmerman, H., Stassen, F. R. M., De Mey, J. G. R., ten Berge, R. E. J., Tjon, Guno H. K., De Vries, Taco J., Ronken, Eric, Hogenboom, François, Warden, George, Mulder, Arie H., Schoffelmeer, Anton N. M., Van Bergen, P., Kleline, J. A., Janssen, P. M. L., Van Der Vaart, J. G. M., Kasbergen, C. M., Versteeg, D. H. G., De Wildt, D. J., van de Velde, M. J., Engels, F., van den Berg, C., Vleeming, W., van Amsterdam, J. G. C., Werner, J., van der Zee, L., den Hertoe, A., van Gelderen, E. Marcel, Agteresch, Hendrik J., De Bruijne, Emile L. E., Saxena, Pramod R., van Kats, J. P., Sassen, L. M. A., Admiraal, P. J. J., Verdouw, P. P., van Muiswinkel, F. L., Steinhusch, H. W. M., Drukarch, B., Sloof, J. C., de Vente, J., Vanderschuren, L. J. M. J., Van Ree, J. M., Verkade P., Verkleij A. J., Gispen W. H., Oestreicher A. B., Vermeulen, R. J., Goosen, C., Wolters, E. Ch., Stoof, J. C., Vincent, V. A. M., Schoffelmeer, A. N. M., Steinbush, H. W. M., Berlcenbosch, F., Voss, Hans-Peter, Donnell, David, Wesselman, J. P. M., VanBavel, E., Spaan, J. A. E., Zeilmaker, W. M., van 't Klooster, G. A. E., Horbach, G. J. M. J., Zhang, J., Zhang, J. S., and van Meet, J. C. A.

Published
1993
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13. Definitionen

Author

Akkermans, L. M. A., Birkner, B., Bleijenberg, G., Coremans, G. E., Enck, P., Erckenbrecht, J. F., Ewe, K., Goei, R., Janssen, L. W. M., Klauser, A. G., Koelz, H. R., Kruis, W., Kuijpers, J. H. C., Müller-Lissner, S. A., Müller-Lobeck, H., Schindlbeck, N. E., Schulz, A., Schuurkes, J. A. J., Smout, A. J. P. M., Sonnenberg, A., Stern, J., Wienbeck, M., Siewert, J. R., editor, Blum, A. L., editor, Müller-Lissner, Stefan A., editor, and Akkermans, Louis M. A., editor

Published
1989
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19. Definitionen

Author

Akkermans, L. M. A., primary, Birkner, B., additional, Bleijenberg, G., additional, Coremans, G. E., additional, Enck, P., additional, Erckenbrecht, J. F., additional, Ewe, K., additional, Goei, R., additional, Janssen, L. W. M., additional, Klauser, A. G., additional, Koelz, H. R., additional, Kruis, W., additional, Kuijpers, J. H. C., additional, Müller-Lissner, S. A., additional, Müller-Lobeck, H., additional, Schindlbeck, N. E., additional, Schulz, A., additional, Schuurkes, J. A. J., additional, Smout, A. J. P. M., additional, Sonnenberg, A., additional, Stern, J., additional, and Wienbeck, M., additional

Published
1989
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30. Selective desensitization of the 5-HT4 receptor-mediated response in pig atrium but not in stomach.

Author

De Maeyer, J. H., Schuurkes, J. A. J., and Lefebvre, R. A.

Subjects
*NEURAL transmission, *TISSUES, *LABORATORY swine, *HEART atrium, *NEUROPHYSIOLOGY
Abstract

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]

Published
2009
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31. Mapping slow waves and spikes in chronically instrumented conscious dogs: automated on-line electrogram analysis.

Author

Wim J. E. P., Lammers, Michiels, B., Voeten, J., Ver Donck, L., and Schuurkes, J. A. J.

Subjects
GASTROINTESTINAL system, ELECTRODES, DOGS, ELECTROPHYSIOLOGY, ELECTRIC resistors
Abstract

Myoelectric recordings from the gastrointestinal (GI) tract in conscious animals have been limited in duration and site. Recently, we have implanted 24 electrodes and obtained electrograms from these sites simultaneously (200 Hz sampling rate; 1.1 MB/min data stream). An automated electrogram analysis was developed to process this large amount of data. Myoelectrical recordings from the GI tract often consist of slow wave deflections followed by one or more action potentials (=spike deflections) in the same traces. To analyze these signals, a first module separates the signal into one containing only slow waves and a second one containing only spikes. The timings of these waveforms were then detected, in real time, for all 24 electrograms, in a separate slow wave detection module and a separate spike-detection module. Basic statistics such as timing and amplitudes and the number of spikes per slow wave were performed and displayed on-line. In summary, with this online analysis, it is possible to study for long periods of time and under various experimental conditions major components of gastrointestinal motility. [ABSTRACT FROM AUTHOR]

Published
2008
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32. 5-HT4 receptor agonists: similar but not the same.

Author

De Maeyer, J. H., Lefebvre, R. A., and Schuurkes, J. A. J.

Subjects
TRYPTAMINE, DRUG receptors, GASTROINTESTINAL motility, GASTROINTESTINAL diseases, CISAPRIDE
Abstract

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]

Published
2008
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33. 5-HT4 receptors located on cholinergic nerves in human colon circular muscle.

Author

Leclere, P. G., Prins, N. H., Schuurkes, J. A. J., and Lefebvre, R. A.

Subjects
ACETYLCHOLINE, CHOLINERGIC mechanisms, NEUROTRANSMITTERS, COLON (Anatomy), TRYPTAMINE
Abstract

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]

Published
2005
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39. 5‐HT4receptors mediating enhancement of contractility in canine stomach; an in vitroand in vivostudy

Author

Prins, N H, Grijn, A van der, Lefebvre, R A, Akkermans, L M A, and Schuurkes, J A J

Abstract

We aimed to study 5‐HT4receptors in canine stomach contractility both in vivoand in vitro.In anaesthetized Beagle dogs, the selective 5‐HT4receptor agonist prucalopride (i.v.) induced dose‐dependent tonic stomach contractions under isobaric conditions, an effect that was antagonized by the selective 5‐HT4receptor antagonist GR 125487 (10 μg kg−1, i.v.).Electrical field stimulation (EFS) of corpus longitudinal muscle strips resulted in atropine‐ and tetrodotoxin‐sensitive contractions (L‐NOARG (0.1 mM) present in all organ bath solutions). Prucalopride increased these contractions (maximal response after single‐dose addition (0.3 μM): 165% of initial value, or after cumulative addition: 188%). In the presence of methysergide (3 μM), 5‐HT also increased EFS‐contractions (after single‐dose addition (0.3 μM): increase to 192%, after cumulative addition: 148%).The selective 5‐HT4receptor antagonists GR 113808 (0.1 μM) or GR 125487 (10 nM) antagonized the prucalopride (0.3 μM)‐induced contraction increments. When EFS‐induced contractions were blocked by atropine or tetrodotoxin, prucalopride was ineffective. In the presence of methysergide (3 μM), the contraction increases to 5‐HT (0.3 μM) were prevented by GR 113808 (0.1 μM).The prucalopride curve (pEC507.9) was shifted in parallel to the right by GR 113808 3 nM(pA29.4). In the presence of methysergide (3 μM), the curve to 5‐HT (pEC508.1) was competitively antagonized by GR 113808, yielding a Schild slope of 0.8±0.2 (pKBof 9.1 with unit Schild slope).In corpus circular muscle strips, the prucalopride (0.3 μM)‐induced augmentation of EFS‐contractions (258%) was also prevented by GR 113808 (0.1 μM) (124%).In conclusion, the effects of 5‐HT4receptor agonists on proximal stomach motor activity in vivocan be explained by an effect on 5‐HT4receptors on cholinergic nerves within the gastric muscle wall.

Published
2001
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40. 5‐HT4receptors on cholinergic nerves involved in contractility of canine and human large intestine longitudinal muscle

Author

Prins, N H, Akkermans, L M A, Lefebvre, R A, and Schuurkes, J A J

Abstract

5‐HT4receptors mediate circular muscle relaxation in both human and canine large intestine, but this phenomenon alone can not explain the improvement in colonic motility induced by selective 5‐HT4receptor agonists in vivo. We set out to characterize 5‐HT4receptor‐mediated effects in longitudinal muscle strips of canine and human large intestine.Electrical field stimulation (EFS) was applied providing submaximal isotonic contractions. L‐NOARG (0.1 mM) was continuously present in the organ bath to preclude nitric oxide‐induced relaxation to EFS.The selective 5‐HT4receptor agonist prucalopride (0.3 μM) enhanced EFS‐evoked contractions, that were antagonized in both preparations by the selective 5‐HT4receptor antagonist GR 113808 (0.1 μM). The prucalopride‐induced increase was present in canine ascending and descending colon, but absent in rectum. Regional differences in response to prucalopride were not observed in human ascending and sigmoid colon and rectum. Incubation with atropine (1 μM) or tetrodotoxin (0.3 μM) inhibited EFS‐induced contractions, which were then unaffected by prucalopride (0.3 μM) in both tissues.In the presence of methysergide (3 μM; both tissues) and granisetron (0.3 μM; only human tissues), 5‐HT (0.3 μM) enhanced EFS‐induced contractions, an effect that was antagonized by GR 113808 (0.1 μM). In the presence of atropine or tetrodotoxin, EFS‐induced contractions were inhibited, leaving 5‐HT (0.3 μM) ineffective in both preparations.This study demonstrates for the first time that in human and canine large intestine, 5‐HT4receptors are located on cholinergic neurones, presumably mediating facilitating release of acetylcholine, resulting in enhanced longitudinal muscle contractility. This study and previous circular muscle strip studies suggest that 5‐HT4receptor agonism facilitates colonic propulsion viaa coordinated combination of inhibition of circumferential resistance and enhancement of longitudinal muscle contractility.

Published
2000
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41. An improved in vitrobioassay for the study of 5‐HT4receptors in the human isolated large intestinal circular muscle

Author

Prins, N H, Shankley, N P, Welsh, N J, Briejer, M R, Lefebvre, R A, Akkermans, L M A, and Schuurkes, J A J

Abstract

Recently, it was demonstrated that 5‐HT induces relaxation of human colon circular muscle through activation of 5‐HT4receptors and 5‐HT7receptors. The aim of the current study was to develop a new in vitrobioassay of human colon that would facilitate the pharmacological analysis of 5‐HT responses mediated solely by 5‐HT4receptors.Contracting circular muscle strips with KCl (80 mM) yielded a stable contractile tension and, in contrast to muscarinic cholinoceptor agonists and histamine, a profound reduction of spontaneous contractility. This allowed the establishment of reproducible, fully‐defined, agonist concentration‐response curves by cumulative dosing. Under these conditions, 5‐HT induced a concentration‐dependent relaxation (pEC507.31, Hill slope 0.91).Neither methysergide (10 μM) nor granisetron (1 μM) affected the 5‐HT‐induced relaxation, suggesting that 5‐HT1, 5‐HT2, 5‐HT3, 5‐ht5, 5‐HT6or 5‐HT7receptors are not involved. The lack of effect of tetrodotoxin (0.3 μM) indicated a direct effect of 5‐HT on the smooth muscle.The selective 5‐HT4receptor antagonists GR 113808, GR 125487 and RS 39604 competitively antagonized the 5‐HT‐induced relaxation (pKB9.43, 10.12 and 8.53, respectively). SB 204070 (1 nM) produced a rightward shift (pA210.34) and depression of the 5‐HT curve. These affinity estimates are similar to those previously reported for 5‐HT4receptors.The selective 5‐HT4receptor agonists, prucalopride and R076186, induced relaxations (pEC507.50 and 7.57, respectively), that were blocked by GR 113808 (3 nM), yielding pA2estimates of 9.31 and 9.21, respectively.To summarise, in KCl (80 mM)‐contracted muscle strips, 5‐HT induces relaxation through activation of a homogeneous smooth muscle 5‐HT4receptor population. This new bioassay allows the focused, pharmacological characterization of human colonic 5‐HT4receptors in vitro.

Published
2000
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42. Pharmacological characterization of 5‐HT4receptors mediating relaxation of canine isolated rectum circular smooth muscle

Author

Prins, N H, Van Haselen, J F W R, Lefebvre, R A, Briejer, M R, Akkermans, L M A, and Schuurkes, J A J

Abstract

This study aimed to characterize for the first time in vitro5‐HT4receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum.In the presence of methysergide (60 μM), 5‐HT induced relaxation of methacholine (1 μM)‐precontracted muscle strips, yielding a monophasic sigmoidal concentration‐relaxation curve (pEC507.2±0.07).Tetrodotoxin (0.3 μM) did not affect the curve to 5‐HT, suggesting the inhibitory 5‐HT receptor is located on the smooth muscle. Granisetron (0.3 μM) did also not affect the curve to 5‐HT, which excludes the 5‐HT3receptor mediating the relaxation to 5‐HT. The presence of methysergide rules out the involvement of 5‐HT1, 5‐HT2or 5‐HT7receptors.5‐HT, the selective 5‐HT4receptor agonists R076186, prucalopride (R093877) and SDZ HTF‐919 and the 5‐HT4receptor agonists cisapride and 5‐MeOT relaxed the muscle strips with a rank order of potency R076186=5‐HT>cisapride>prucaloprideSDZ HTF‐919>5‐MeOT.The selective 5‐HT4receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5‐HT, yielding pKBestimates of 9.7, 7.9 and 9.1, respectively. The selective 5‐HT4receptor antagonist SB 204070 shifted the curve to 5‐HT rightward and depressed the maximal response (apparent pA210.6). GR 113808 (10 nM) produced a parallel rightward shift of the curve to the selective 5‐HT4receptor agonists R076186 (pA28.8).It is concluded that 5‐HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5‐HT4receptors. For the first time, a non‐human species was shown to exhibit relaxant 5‐HT4receptors in the large intestine.

Published
1999
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46. Use of plasma ionized calcium levels and Ca2+ substitution response patterns as prognostic parameters for ileus and survival in colic horses.

Author

Delesalle C, Dewulf J, Lefebvre RA, Schuurkes JA, Van Vlierbergen B, and Deprez P

Subjects
Abdomen, Acute blood, Abdomen, Acute drug therapy, Abdomen, Acute veterinary, Animals, Colic blood, Colic complications, Colic drug therapy, Female, Gastroesophageal Reflux blood, Gastroesophageal Reflux complications, Gastroesophageal Reflux veterinary, Hematocrit veterinary, Horse Diseases drug therapy, Horse Diseases epidemiology, Horse Diseases etiology, Horses, Hydrogen-Ion Concentration, Hypocalcemia blood, Hypocalcemia complications, Hypocalcemia drug therapy, Ileus epidemiology, Ileus etiology, Male, Multivariate Analysis, Prognosis, Survival Analysis, Calcium blood, Calcium therapeutic use, Colic veterinary, Horse Diseases blood, Hypocalcemia veterinary, Ileus veterinary
Abstract

Objective: Hypocalcaemia is a common finding in horses with enterocolitis and severe gastrointestinal disorders. The aims of this study were to investigate in colic horses 1)the parameters related to hypocalcaemia, 2)the influence of hypocalcaemia on outcome and 3)the possible beneficial effect of Ca2+ substitution., Design: Randomized controlled trial., Setting: Intensive care unit., Patients: One hundred forty-four horses that were admitted with an acute abdomen during a 1.5 year period were enrolled and daily evaluated for clinical criteria and whole blood ionized Ca2+ levels. Colic horses with hypocalcaemia were randomly assigned to receive Ca2+., Interventions: Analysis of heparinised whole blood samples. Horses that were assigned to be treated received 400 mEq Ca2+ diluted in 10L of Ringer's lactate solution every 24 h until low reference range limits were obtained or until death., Measurements and Main Results: 88% of all colic patients showed blood ionized Ca2+ levels below the reference range at the time of admission. Multivariable analysis revealed that the presence of reflux, signs of endotoxaemia, increased Packed Cell Volume (PCV), alkalinization of pH and the interaction PCV/pH all predispose colic horses to low ionized Ca2+ levels at the time of admission. The Odds for developing ileus during hospitalization are +/- 11.94 times larger for horses in the "very low" calcaemia interval, in comparison with normocalcaemic horses. The Odds for fatal outcome are respectively +/- 9.82 and 8.33 times larger for horses in the "very low" and "low" calcaemia interval. Ca2+ substitution increased the probability of survival, provided that Ca2+ levels could be normalized. The lack of an upward calcaemia response, despite repetitive Ca2+ substitutions, can be guarded as a poor ominous sign., Conclusions: Hypocalcaemia in colic horses is of prognostic relevance both with regard to survival as to the probability of development of ileus during hospitalization. This study shows the importance of routine measurement of ionized calcium levels in colic horses. Moreover, correction of hypocalcaemia seems to improve clinical outcome.

Published
2005

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