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1. 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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3. Energy Efficient Branch Prediction for the Cell BE SPU

Author

Briejer, M. (author) and Briejer, M. (author)

Abstract

We propose a power e?cient branch predictor for the Cell SPU, which normally depends on compiler inserted hint instructions to predict taken branches. We designed four predictors all using Branch History Table (BHT) to store the Branch Target Address and the prediction, which is computed using a bimodal counter. The Simple Bimodal Predictor (SBP) predecodes instructions in the Instruction Line Bu?er and accesses the BHT only for a branch instruction and ignores hints. For the second design, four ways to combine hints with the SBP are studied, by not or partially overruling hints by the predictor. We also introduce Branch Warnings (BW). The SPU only accesses the predictor when a BW or a hint is executed and hints can be overruled. The Aggressive Bimodal Predictor is an aggressive implementation of the SBP that starts predicting when instructions are fetched from local store. It is not designed for energy e?ciency but to investigate the maximum possible speedup for a branch predictor not using hints. Results show that a SBP in combination with overruling hints (SBP-OH-NLS) and a 256-entry BHT can have a speedup of 18.8%. The Branch Warning predictor is the fastest in some occasions, however a non optimal compiler makes it the worst for others. The SBP has the lowest performance overall. The estimated extra power needed for the SBP and SBP-OH-NLS is about 1% of the total SPE power and even less for the BW-OH-NLS. The energy-delay product is reduced the most for the SBP-OH-NLS., Computer Engineering, Electrical Engineering, Mathematics and Computer Science

Published
2009

15. 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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16. 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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17. Labelling and evaluation of new stabilised neurotensin (8–13) analogues for single photon emission tomography (SPET)

Author

Chavatte, K., Terriere, D., Jeannin, L., Iterbeke, K., Briejer, M., Schuurkes, J., Mertens, J. J. R., Bruyneel, E., Tourwé, D., Leysen, J. E., and Bossuyt, A.

Abstract

Neurotensin(8–13) analogues were biologically stabilised by replacement of the peptide bond between amino acids 8 and 9 by the reduced ψ(CH2-NH) isostere. Diethylenetriaminepentaacetic acid (DTPA) analogues for In-111 labelling and 2-bromo-phenyl-acetyl analogues for radioiodination, showed receptor affinities in the nanomolar range in combination with a biological half life in human plasma up to 275 minutes. Biodistribution studies in male Wistar rats of metabolically stabilised and non-stabilised 111In-DTPA-NT(8–13) analogues showed a major clearance from the blood through the kidneys. 125I-Labelled neurotensin (8–13) analogues showed accumulation up to 2.2% of the injected dose per g tissue in the liver which might be an important disadvantage when diagnosis of tumours in the gut is aimed. Neurotensin(8–13) analogues labelled with In-111 or I-123 may act as new potential peptidergic radiopharmaceuticals for SPET diagnosis of neurotensin receptor (NTR) positive tumours. Copyright © 1999 John Wiley & Sons, Ltd.

Published
1999
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21. Cisapride and structural analogs selectively enhance 5-hydroxytryptamine (5-HT)-induced purinergic neurotransmission in the guinea pig proximal colon.

Author

Briejer, M R, Veen, G J, Akkermans, L M, Lefebvre, R A, and Schuurkes, J A

Abstract

In the guinea pig proximal colon, 5-hydroxytryptamine (5-HT) stimulates neuronal 5-HT1-like receptors to induce relaxations that are mediated by nitric oxide and ATP. In the current study, the effects of cisapride and structural analogs on these 5-HT-induced relaxations were investigated. In the continuous presence of ketanserin (0.3 microM) and tropisetron (3 microM) to block contractions via 5-HT2A, 5-HT3 and 5-HT4 receptors, 5-HT induced relaxations that yielded a biphasic concentration-response curve. Cisapride (0.1-1 microM) enhanced the second phase of the concentration-response curve to 5-HT by about 20% to 40%, whereas from 0.3 microM onwards, it inhibited the first phase. Also in the presence of cisapride (0.3 microM), tetrodotoxin (0.3 microM) abolished the relaxations to 5-HT. Cisapride (0.3 microM) did not affect the concentration-response curves to isoprenaline, nitroglycerin, nitroprusside or exogenous ATP, which demonstrated its specificity. The 5-HT relaxation-enhancing effects of cisapride were not mimicked by phentolamine (1 microM), NAN-190 (0.03 microM), spiperone (1 microM), citalopram (0.3 microM), paroxetine (0.3 microM), pargyline (100 microM) or SDZ 205-557 (0.3 microM). In the presence of the inhibitor of nitric oxide synthesis, NG-nitro-L-arginine (100 microM), cisapride (0.3 microM) still enhanced the remaining relaxations to 5-HT (2-3-fold). However, in the presence of the P2-purinoceptor antagonist suramin (300 microM), cisapride did not enhance the relaxations to 5-HT. In the presence of NG-nitro-L-arginine, the cisapride-enhanced relaxations to 5-HT were inhibited by about 90% by suramin. We conclude that in the guinea pig colon, cisapride selectively facilitates the suramin-sensitive, ATP-mediated part of the relaxation to 5-HT via an unidentified effect on intramural nerves.

Published
1995

25. Evidence for 5-HT7 receptors mediating relaxation of human colonic circular smooth muscle.

Author

Prins NH, Briejer MR, Van Bergen PJ, Akkermans LM, and Schuurkes JA

Subjects
Colon drug effects, Dioxanes pharmacology, Humans, In Vitro Techniques, Muscle, Smooth drug effects, Piperidines pharmacology, Serotonin Antagonists pharmacology, Colon physiology, Muscle, Smooth physiology, Receptors, Serotonin physiology
Abstract

5-HT4 receptors mediate relaxation of human colon circular muscle. However, after 5-HT4 receptor blockade (SB 204070 10 nM), 5-HT still induced a relaxation (pEC50 6.3). 5-HT4 receptors were sufficiently blocked, as the curves to 5-HT obtained in the presence of 10 and 100 nM SB 204070 were indistinguishable. This 5-HT-induced relaxation was tetrodotoxin-insensitive, indicative of a smooth muscle relaxant 5-HT receptor. This, and the rank order of potency (5-CT=5-MeOT=5-HT) suggested involvement of 5-HT1 or 5-HT7 receptors. Mesulergine, a 5-HT7 receptor antagonist at nanomolar concentrations, and a 5-HT1 receptor antagonist at micromolar concentrations, competitively antagonized the 5-HT-induced relaxation (pKB 8.3) and antagonized the relaxation to 5-CT. Methysergide antagonized the 5-HT-induced relaxation (pA2 7.6). It is concluded that the profile of the smooth muscle inhibitory 5-HT receptor resembles that of the 5-HT7 receptor. These data provide the first evidence for functional human 5-HT7 receptors.

Published
1999
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26. Idiopathic constipation: too few stools and too little knowledge.

Author

Briejer MR, Schuurkes JA, and Sarna SK

Subjects
Animals, Chronic Disease, Colon physiopathology, Constipation pathology, Constipation physiopathology, Digestive System innervation, Digestive System pathology, Gastrointestinal Motility drug effects, Humans, Muscle, Smooth innervation, Muscle, Smooth pathology, Receptors, Cholecystokinin agonists, Receptors, Opioid agonists, Serotonin Receptor Agonists therapeutic use, Constipation drug therapy, Gastrointestinal Agents therapeutic use
Abstract

The precise abnormalities of colonic motility patterns in idiopathic constipation, and the alterations at the cellular, neural, myogenic and biochemical levels that underlie these patterns, are not yet understood. One promising approach in the treatment of constipation seems to be to design drugs that can stimulate GMCs to produce mass movements and consequently defaecation. This could possibly be achieved with the selective 5-HT4 receptor agonists prucalopride and SDZ HTF-919, which are currently in advanced clinical trials. Other mechanisms that provide a means to induce GMCs, such as NK1 receptor agonism, deserve further exploration.

Published
1999
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27. Characterization of the contraction to 5-HT in the canine colon longitudinal muscle.

Author

Prins NH, Briejer MR, and Schuurkes JA

Subjects
Animals, Colon physiology, Dogs, Dose-Response Relationship, Drug, Female, In Vitro Techniques, Male, Muscle Contraction, Muscle, Smooth physiology, Receptors, Serotonin physiology, Colon drug effects, Muscle, Smooth drug effects, Receptors, Serotonin drug effects, Serotonin pharmacology, Serotonin Agents pharmacology
Abstract

1. Although conscious dogs have often been used for colonic motility studies with 5-hydroxytryptamine (5-HT), the effects of 5-HT on the isolated colon have not been thoroughly characterized yet. The current study was undertaken to characterize the response to 5-HT of the canine isolated colon longitudinal muscle. 2. Longitudinal strips of canine midcolon deprived of (sub)mucosa were prepared for isotonic measurement. 5-HT induced contractions from 3 nM onwards, which were not affected by selective inhibition of 5-HT re-uptake, monoamine oxidase or blockade of alpha-adrenoceptors. Tetrodotoxin (0.3 microM) did not affect the responses to 5-HT, suggesting that smooth muscle 5-HT receptors are involved. The selective 5-HT4 receptor antagonist SB 204070 (10 nM) slightly enhanced contractions to 5-HT and therefore it was included in the organ bath solution in all further experiments. The 5-HT1 and 5-HT2 receptor antagonist methysergide (0.1 microM) depressed the curve to 5-HT, but the selective 5-HT3 receptor antagonist granisetron (0.3 microM) had no effect. 3. Besides 5-HT, alpha-methyl-5-HT (alpha-Me-5-HT), 5-methoxytryptamine (5-MeOT), 2-methyl-5-HT (2-Me-5-HT) and 5-carboxamidotryptamine (5-CT) also induced contractions, with the following rank order of potency (pEC50 values in parentheses): 5-HT (6.9) = alpha-methyl-5-HT (6.9) > 2-Me-5-HT (5.8) = 5-MeOT (5.7) = 5-CT (5.6), indicative of 5-HT2 receptor involvement, alpha-Me-5-HT produced a bell-shaped curve, which was not affected by alpha-adrenoceptor blockade. 5-HT, 5-MeOT, 2-Me-5-HT and 5-CT produced a monophasic concentration-response curve, consistent with an interaction with a single receptor site. 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and tryptamine only induced contractions at a concentration exceeding 1 microM. 4. The selective 5-HT2B receptor antagonist SB 204741 (0.3 microM) did not affect the curve to 5-HT. Ketanserin, cisapride and spiroxatrine behaved as competitive antagonists with pKb values of, respectively, 8.4, 8.1 and 6.7. Spiroxatrine (1 microM) shifted the curve to 5-MeOT rightward yielding an apparent pA2 of 7.1. Other antagonists at 5-HT2A receptors also surmountably inhibited the contractions to 5-HT (apparent pA2 value in parentheses): mesulergine (8.2), cinanserin (8.2), yohimbine (6.2) and mianserin (8.6). However, as well as a rightward shift, methiothepin (8.3), pizotifen (8.6) and spiperone (8.8) also caused a depression of the curve, indicative of "pseudo-irreversible' antagonism. Taken together, the above mentioned affinity estimates most closely corresponded to literature affinity values for 5-HT2A receptors. 5. It was concluded that 5-HT induces contractions of the canine midcolon longitudinal muscle primarily by stimulation of smooth muscle 5-HT2A receptors. The presence of inhibitory 5-HT4 receptors cannot be ruled out.

Published
1997
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28. 5-HT-induced neurogenic relaxations of the guinea-pig proximal colon: investigation into the role of ATP and VIP in addition to nitric oxide.

Author

Briejer MR, Akkermans LM, Meulemans AL, Lefebvre RA, and Schuurkes JA

Subjects
Adenosine Triphosphate analogs & derivatives, Adenosine Triphosphate pharmacology, Animals, Apamin pharmacology, Colon innervation, Female, Guinea Pigs, In Vitro Techniques, Isoproterenol pharmacology, Male, Muscle Relaxation drug effects, Muscle, Smooth innervation, Nitroglycerin pharmacology, Suramin pharmacology, Adenosine Triphosphate physiology, Colon drug effects, Muscle, Smooth drug effects, Nitric Oxide physiology, Serotonin pharmacology, Vasoactive Intestinal Peptide physiology
Abstract

In the guinea-pig proximal colon, 5-hydroxytryptamine (5-HT) relaxes the longitudinal muscle by stimulating neuronal 5-HT receptors, which induces the release of nitric oxide (NO). It was investigated whether the inhibitory neurotransmitters adenosine 5'-triphosphate (ATP) and/or vasoactive intestinal polypeptide (VIP) could be involved as well. Antagonists to block the contractile response to 5-HT via 5-HT2, 5-HT3 or 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. ATP, VIP and 5-HT induced concentration-dependent relaxations, in the case of 5-HT yielding a non-monophasic concentration-response curve. Tetrodotoxin (TTX; 300 nM), NG-nitro-L-arginine (L-NNA, 100 microM) and their combination did not inhibit the relaxations induced by VIP (up to 0.3 microM) or 0.3-3 microM ATP but reduced those by 10 microM ATP. Suramin (300 microM) strongly inhibited the relaxations to ATP and VIP. L-NNA and suramin also inhibited the relaxations to 5-HT. In the presence of L-NNA (100 microM), suramin did not significantly inhibit the relaxations to 5-HT. Suramin did not affect the relaxations to isoprenaline, nitroglycerin or exogenous NO (1 microM), demonstrating its specificity. Apamin (30 nM) inhibited both the relaxations to ATP (by 70-100%) and to 5-HT; relaxations to isoprenaline were partially inhibited, indicating a non-specific component in the inhibitory action of apamin. However, relaxations to exogenous VIP (up to 0.3 microM), NO (1 microM) and to nitroglycerin were not inhibited. In the presence of L-NNA (100 microM), apamin inhibited the relaxations to 5-HT only at 30 microM. alpha, beta-methylene-ATP (alpha, beta-Me-ATP; 100 microM) did not desensitize the responses to ATP. Reactive blue 2 affected the relaxations to isoprenaline at concentrations necessary to significantly inhibit the relaxations to ATP (i.e. from 10 microM onwards). Thus, it was not possible to test either alpha, beta-Me-ATP or reactive blue 2 against the relaxations to 5-HT. alpha-Chymotrypsin (0.015 mg.ml-1) and trypsin (0.005 mg.ml-1) almost abolished the relaxations to VIP, but did not affect those to isoprenaline and 5-HT. The VIP receptor antagonists [p-Cl-D-Phe6, Leu17]VIP (1 microM) and VIP10-28 (1 and 3 microM) did not affect the concentration-response curve to VIP and were hence not tested against 5-HT. Phosphoramidon (1 microM) had no effect on the relaxations to VIP or 5-HT.(ABSTRACT TRUNCATED AT 400 WORDS)

Published
1995
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29. Interactions of serotonin with multiple receptors and neurotransmitters in the guinea-pig isolated colon.

Author

Briejer MR, Akkermans LM, and Schuurkes JA

Subjects
Animals, Atropine pharmacology, Dose-Response Relationship, Drug, Drug Interactions, Granisetron pharmacology, Guinea Pigs, Indoles pharmacology, Ketanserin pharmacology, Serotonin Antagonists pharmacology, Tropisetron, Colon drug effects, Neurotransmitter Agents pharmacology, Serotonin pharmacology
Abstract

The motor effects of 5-hydroxytryptamine (5-HT; serotonin) on the guinea-pig isolated proximal colon were studied and analyzed. A classical organ bath setup was used to measure the longitudinal muscle responses isotonically. 5-Hydroxytryptamine induced concentration-dependent contractions which were preceded by relaxations at low concentrations. By means of the neurotoxin, tetrodotoxin, the muscarinic cholinoceptor antagonist, atropine, and selective 5-HT receptor antagonists, it was shown that the contractions to 5-HT are mediated by 5-HT2A receptors, localized on the smooth muscle, and by 5-HT3 and 5-HT4 receptors, localized on cholinergic nerves. The relaxation was abolished by tetrodotoxin and appeared to be mediated by two 5-HT receptor subtypes; the pharmacological profile of the high affinity 5-HT receptor resembled that of 5-HT2C receptors though it displayed also pronounced differences. Subsequently, it was shown that nitric oxide is the mediator released by lower concentrations of 5-HT, while, at higher concentrations, adenosine triphosphate could be involved as an end neurotransmitter as well. No evidence for a peptidergic neurotransmitter, such as vasoactive intestinal polypeptide, was obtained. Results with two 5-HT analogues confirmed the presence of a dual 5-HT receptor system (high and low affinity) regulating each the release of a different neurotransmitter (nitric oxide and adenosine triphosphate, respectively). The above described results stress the important role of 5-HT as a neurotransmitter involved in gastrointestinal motility.

Published
1995

30. Cisapride and a structural analogue, R 76,186, are 5-hydroxytryptamine4 (5-HT4) receptor agonists on the guinea-pig colon ascendens.

Author

Briejer MR, Akkermans LM, Meulemans AL, Lefebvre RA, and Schuurkes JA

Subjects
4-Aminobenzoic Acid pharmacology, Animals, Cisapride, Colon metabolism, Female, Guinea Pigs, Male, Muscle Contraction drug effects, Muscle, Smooth metabolism, Receptors, Serotonin metabolism, Serotonin metabolism, para-Aminobenzoates, Colon drug effects, Muscle, Smooth drug effects, Piperidines pharmacology, Receptors, Serotonin drug effects, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology
Abstract

Unlabelled: The purpose of this study was to investigate whether the effects of cisapride and its close structural analogue R 76,186 on the isolated guinea-pig colon ascendens, are mediated through 5-HT4 receptors. Both cisapride and R 76,186 induced contractions in a concentration-dependent fashion, giving monophasic concentration-response curves (cisapride: EC50 = 1.1 x 10(-7) M, maximum effect = 40.3% of methacholine-induced (3 x 10(-7) M) contractions; R 76,186: EC50 = 2.4 x 10(-8) M, maximum effect = 52.1%). Blockade of either 5-HT2 or 5-HT3 receptors did not affect the responses to cisapride. However, tropisetron (in 5-HT4 receptor-blocking concentrations), and DAU 6285 and SDZ 205-557, two novel selective 5-HT4 receptor antagonists, depressed the concentration-response curve to cisapride (to about 50%), and the curve to R 76,186 was shifted to the right. The apparent pA2 values were 6.6 (tropisetron), 6.3 (DAU 6285), and 7.5 (SDZ 205-557). However, none of these antagonisms was purely competitive as higher concentrations of these antagonists depressed the curve to R 76,186. Desensitization of the 5-HT4 receptor with 5-methoxytryptamine (5-MeOT) inhibited the responses to cisapride, and abolished those to R 76,186. The contractions to cisapride and R 76,186 were sensitive to mutual antagonism, depressing their concentration-response curves., Conclusions: Both cisapride and R 76,186 mediate their contractile effects in the guinea-pig colon ascendens through agonism at the 5-HT4 receptor, though cisapride also uses a non-5-HT mechanism. R 76,186 is a selective and potent 5-HT4 receptor agonist.

Published
1993
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31. Nitric oxide is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens in vitro.

Author

Briejer MR, Akkermans LM, Meulemans AL, Lefebvre RA, and Schuurkes JA

Subjects
Animals, Arginine analogs & derivatives, Arginine pharmacology, Colon drug effects, Female, Guinea Pigs, Hemoglobins pharmacology, In Vitro Techniques, Isoproterenol pharmacology, Male, Methacholine Compounds pharmacology, Muscle Relaxation drug effects, Nitroarginine, Nitroglycerin pharmacology, Muscle, Smooth drug effects, Nitric Oxide pharmacology, Serotonin pharmacology
Abstract

1. In the guinea-pig colon ascendens, 5-hydroxytryptamine (5-HT) induces contractions, mediated by 5-HT2, 5-HT3 and 5-HT4 receptors, and relaxations, through a 5-HT1 receptor subtype, that triggers the release of an inhibitory neurotransmitter. Nitric oxide (NO) is one of the main candidates of NANC inhibitory neurotransmission in the gut. The aim of this study was to establish whether NO is involved in 5-HT-induced relaxations of the guinea-pig colon ascendens. 2. Antagonists to block the contractile responses to 5-HT via 5-HT2, 5-HT3 and 5-HT4 receptors were present throughout the experiments and methacholine was administered to precontract the strips. Under these conditions, 5-HT concentration-dependently induced relaxations from 10 nM onwards (EC50 = 258 (172-387) nM). The relaxations were inhibited by metergoline (10 nM) and methiothepine (100 nM) and abolished by tetrodotoxin (TTX, 320 nM). Guanethidine (3.2 microM) did not affect them. 3. NG-nitro-L-arginine (L-NNA) inhibited the responses to 5-HT (IC50 = 18.7 (13.3-26.3) microM); at the highest 5-HT concentration a maximum inhibition of about 75% was observed with 320 microM L-NNA. This inhibition was reversed with L-arginine. Relaxations to glyceryl trinitrate (GTN) were not inhibited by L-NNA. 4. Haemoglobin (32 microM) inhibited the relaxations to 5-HT and GTN, but not those to isoprenaline (Iso). Methylene blue (10 microM) inhibited the relaxations to 5-HT but did not affect those caused by GTN or Iso. 5. It is concluded that 5-HT induces relaxations that involve NO.We also confirmed that 5-HT induces these relaxations via (a) 5-HT, receptor subtype(s), located on neurones.

Published
1992
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