title: Pharmacological characterization of 5-HT4 receptors mediating relaxation of canine isolated rectum circular smooth muscle.
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.affiliation: Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Beerse, Belgium.
authors.forename: N H
authors.initials: NH
authors.lastname: Prins
authors.forename: J F
authors.initials: JF
authors.lastname: Van Haselen
authors.forename: R A
authors.initials: RA
authors.lastname: Lefebvre
authors.forename: M R
authors.initials: MR
authors.lastname: Briejer
authors.forename: L M
authors.initials: LM
authors.lastname: Akkermans
authors.forename: J A
authors.initials: JA
authors.lastname: Schuurkes
mesh_terms: D008735:5-Methoxytryptamine / Q000494:pharmacology; D000818:Animals; D020117:Cisapride / Q000494:pharmacology; D003106:Colon / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000502:physiology; D044422:Receptors, Serotonin, 5-HT4; D012007:Rectum / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D008735:5-Methoxytryptamine; C105050:tegaserod; D020117:Cisapride; C082871:GR 113808