Prins N H, Van Haselen J F, Lefebvre R A, Briejer M R, Akkermans L M, Schuurkes J A
Department of Gastrointestinal Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Br J Pharmacol. 1999 Jul;127(6):1431-7. doi: 10.1038/sj.bjp.0702665.
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.
本研究旨在首次对犬胃肠道中的5-羟色胺4（5-HT4）受体进行体外特性描述。为此，我们使用了犬离体直肠的环形肌条。在存在麦角新碱（60微摩尔）的情况下，5-羟色胺可使乙酰甲胆碱（1微摩尔）预收缩的肌条松弛，产生单相S形浓度-松弛曲线（半数有效浓度的负对数pEC50为7.2±0.07）。河豚毒素（0.3微摩尔）不影响对5-羟色胺的曲线，提示抑制性5-羟色胺受体位于平滑肌上。格拉司琼（0.3微摩尔）也不影响对5-羟色胺的曲线，这排除了5-HT3受体介导对5-羟色胺的松弛作用。麦角新碱的存在排除了5-HT1、5-HT2或5-HT7受体的参与。5-羟色胺、选择性5-HT4受体激动剂R076186、普芦卡必利（R093877）和SDZ HTF-919以及5-HT4受体激动剂西沙必利和5-甲氧基色胺使肌条松弛，其效价顺序为R076186 = 5-羟色胺 > 西沙必利 > 普芦卡必利 > 或 = SDZ HTF-919 > 5-甲氧基色胺。选择性5-HT4受体拮抗剂GR 125487、RS 39604和GR 113808竞争性拮抗对5-羟色胺的松弛作用，其解离常数的负对数pK(B)估计值分别为9.7、7.9和9.1。选择性5-HT4受体拮抗剂SB 204070使对5-羟色胺的曲线右移并降低最大反应（表观拮抗常数pA2为10.6）。GR 113808（10纳摩尔）使对选择性5-HT4受体激动剂R076186的曲线平行右移（pA2为8.8）。结论是，5-羟色胺通过刺激单一群体的平滑肌5-HT4受体诱导犬直肠环形肌松弛。首次证明非人类物种在大肠中存在具有松弛作用的5-HT4受体。
