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Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle.
Br J Pharmacol. 1999 Jul; 127(6):1431-7.BJ

Abstract

This study aimed to characterize for the first time in vitro 5-HT4 receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum. In the presence of methysergide (60 microM), 5-HT induced relaxation of methacholine (1 microM)-precontracted muscle strips, yielding a monophasic sigmoidal concentration-relaxation curve (pEC50 7.2+/-0.07). Tetrodotoxin (0.3 microM) did not affect the curve to 5-HT, suggesting the inhibitory 5-HT receptor is located on the smooth muscle. Granisetron (0.3 microM) did also not affect the curve to 5-HT, which excludes the 5-HT3 receptor mediating the relaxation to 5-HT. The presence of methysergide rules out the involvement of 5-HT1, 5-HT2 or 5-HT7 receptors. 5-HT, the selective 5-HT4 receptor agonists R076186, prucalopride (R093877) and SDZ HTF-919 and the 5-HT4 receptor agonists cisapride and 5-MeOT relaxed the muscle strips with a rank order of potency R076186 = 5-HT > cisapride > prucalopride > or = SDZ HTF-919 > 5-MeOT. The selective 5-HT4 receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5-HT, yielding pK(B) estimates of 9.7, 7.9 and 9.1, respectively. The selective 5-HT4 receptor antagonist SB 204070 shifted the curve to 5-HT rightward and depressed the maximal response (apparent pA2 10.6). GR 113808 (10 nM) produced a parallel rightward shift of the curve to the selective 5-HT4 receptor agonists R076186 (pA2 8.8). It is concluded that 5-HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5-HT4 receptors. For the first time, a nonhuman species was shown to exhibit relaxant 5-HT4 receptors in the large intestine.

Authors+Show Affiliations

Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Beerse, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

10455293

Citation

Prins, N H., et al. "Pharmacological Characterization of 5-HT4 Receptors Mediating Relaxation of Canine Isolated Rectum Circular Smooth Muscle." British Journal of Pharmacology, vol. 127, no. 6, 1999, pp. 1431-7.
Prins NH, Van Haselen JF, Lefebvre RA, et al. Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle. Br J Pharmacol. 1999;127(6):1431-7.
Prins, N. H., Van Haselen, J. F., Lefebvre, R. A., Briejer, M. R., Akkermans, L. M., & Schuurkes, J. A. (1999). Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle. British Journal of Pharmacology, 127(6), 1431-7.
Prins NH, et al. Pharmacological Characterization of 5-HT4 Receptors Mediating Relaxation of Canine Isolated Rectum Circular Smooth Muscle. Br J Pharmacol. 1999;127(6):1431-7. PubMed PMID: 10455293.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle. AU - Prins,N H, AU - Van Haselen,J F, AU - Lefebvre,R A, AU - Briejer,M R, AU - Akkermans,L M, AU - Schuurkes,J A, PY - 1999/8/24/pubmed PY - 1999/8/24/medline PY - 1999/8/24/entrez SP - 1431 EP - 7 JF - British journal of pharmacology JO - Br J Pharmacol VL - 127 IS - 6 N2 - This study aimed to characterize for the first time in vitro 5-HT4 receptors in the canine gastrointestinal tract. For this purpose, we used circular muscle strips of the canine isolated rectum. In the presence of methysergide (60 microM), 5-HT induced relaxation of methacholine (1 microM)-precontracted muscle strips, yielding a monophasic sigmoidal concentration-relaxation curve (pEC50 7.2+/-0.07). Tetrodotoxin (0.3 microM) did not affect the curve to 5-HT, suggesting the inhibitory 5-HT receptor is located on the smooth muscle. Granisetron (0.3 microM) did also not affect the curve to 5-HT, which excludes the 5-HT3 receptor mediating the relaxation to 5-HT. The presence of methysergide rules out the involvement of 5-HT1, 5-HT2 or 5-HT7 receptors. 5-HT, the selective 5-HT4 receptor agonists R076186, prucalopride (R093877) and SDZ HTF-919 and the 5-HT4 receptor agonists cisapride and 5-MeOT relaxed the muscle strips with a rank order of potency R076186 = 5-HT > cisapride > prucalopride > or = SDZ HTF-919 > 5-MeOT. The selective 5-HT4 receptor antagonists GR 125487, RS 39604 and GR 113808 competitively antagonized the relaxations to 5-HT, yielding pK(B) estimates of 9.7, 7.9 and 9.1, respectively. The selective 5-HT4 receptor antagonist SB 204070 shifted the curve to 5-HT rightward and depressed the maximal response (apparent pA2 10.6). GR 113808 (10 nM) produced a parallel rightward shift of the curve to the selective 5-HT4 receptor agonists R076186 (pA2 8.8). It is concluded that 5-HT induces relaxation of the canine rectum circular muscle through stimulation of a single population of smooth muscle 5-HT4 receptors. For the first time, a nonhuman species was shown to exhibit relaxant 5-HT4 receptors in the large intestine. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/10455293/Pharmacological_characterization_of_5_HT4_receptors_mediating_relaxation_of_canine_isolated_rectum_circular_smooth_muscle_ L2 - https://doi.org/10.1038/sj.bjp.0702665 DB - PRIME DP - Unbound Medicine ER -