Inhibition of colonic motility and defecation by RS-127445 suggests an involvement of the 5-HT2B receptor in rodent large bowel physiology
Inhibition of colonic motility and defecation by RS-127445 suggests an involvement of the 5-HT2B receptor in rodent large bowel physiology
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DOI：
10.1111/j.1476-5381.2009.00155.x
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发表时间：
2009-09-01
影响因子：
7.3
通讯作者：
Sanger, G. J.
中科院分区：
文献类型：
--
作者：
Bassil, A. K.;Taylor, C. M.;Sanger, G. J.
背景：5-HT 2B受体定位于肌间神经系统，但其对运动/感觉神经元的功能尚不清楚。为了探索这些受体的作用，我们进一步表征了5-HT 2B受体拮抗剂RS-127445，并研究了其对排便和排便的影响。实验方法：虽然RS-127445被报道为选择性5-HT 2B受体拮抗剂，但其与5-HT 4受体的任何相互作用尚不清楚;这是使用重组受体和生物分子相互作用检测技术进行检查的。将小鼠离体结肠置于组织浴中，用于等长记录电场刺激（EFS）诱发的神经元收缩，或在管腔内压力梯度下诱导蠕动;测量RS-127445对EFS诱导的和蠕动收缩的影响。在腹膜内注射RS-127445后3小时内测量网底笼中大鼠的粪便排出量，并通过测定血液和脑中RS-127445的游离、未结合分数分别验证有效剂量。关键结果：RS-127445（高达1 μ mol.L-1）不与5-HT 4受体相互作用。RS-127445（0.001-1 mmol.L-1）不影响EFS诱导的结肠收缩，尽管在10 mmol.L-1时收缩减少（至对照的36 ± 8%，n = 4）。RS-127445（0.1-10 mmol.L-1）浓度依赖性降低蠕动频率（n = 4）。RS-127445（1-30 mg.kg（-1））呈剂量依赖性减少粪便排出量，在10和30 mg. kg（-1）剂量下达到显著性（n = 6-11）。在血液和大脑中，>98%的RS-127445是蛋白结合的。结论和影响：RS-127445的高蛋白结合表明，需要相对较高的剂量才能有效。结果表明，5-HT 2B受体紧张性调节结肠运动。英国药理学杂志（2009）158，252-258; doi：10.1111/j.1476-5381.2009.00155.x; 2009年4月9日在线发表
Background: 5-HT2B receptors are localized within the myenteric nervous system, but their functions on motor/sensory neurons are unclear. To explore the role of these receptors, we further characterized the 5-HT2B receptor antagonist RS-127445 and studied its effects on peristalsis and defecation.Experimental approach: Although reported as a selective 5-HT2B receptor antagonist, any interactions of RS-127445 with 5-HT4 receptors are unknown; this was examined using the recombinant receptor and Biomolecular Interaction Detection technology. Mouse isolated colon was mounted in tissue baths for isometric recording of neuronal contractions evoked by electrical field stimulation (EFS), or under an intraluminal pressure gradient to induce peristalsis; the effects of RS-127445 on EFS-induced and on peristaltic contractions were measured. Faecal output of rats in grid-bottom cages was measured over 3 h following i.p. RS-127445 and separately, validation of the effective doses was achieved by determining the free, unbound fraction of RS-127445 in blood and brain.Key results: RS-127445 (up to 1 mu mol.L-1) did not interact with the 5-HT4 receptor. RS-127445 (0.001-1 mmol.L-1) did not affect EFS-induced contractions of the colon, although at 10 mmol.L-1 the contractions were reduced (to 36 + 8% of control, n = 4). RS-127445 (0.1-10 mmol.L-1) concentration-dependently reduced peristaltic frequency (n = 4). RS-127445 (1-30 mg.kg(-1)), dose-dependently reduced faecal output, reaching significance at 10 and 30 mg.kg(-1) (n = 6-11). In blood and brain, >98% of RS-127445 was protein-bound.Conclusions and implications: High-protein binding of RS-127445 indicates that relatively high doses are required for efficacy. The results suggest that 5-HT2B receptors tonically regulate colonic motility. British Journal of Pharmacology (2009) 158, 252-258; doi:10.1111/j.1476-5381.2009.00155.x; published online 9 April 2009