Activation of peripheral 5-HT4 receptors attenuates colonic sensitivity to intraluminal distension
Activation of peripheral 5-HT4 receptors attenuates colonic sensitivity to intraluminal distension
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DOI：
10.1111/j.1365-2982.2005.00723.x
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发表时间：
2006-01-01
影响因子：
3.5
通讯作者：
Crowell, MD
中科院分区：
文献类型：
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作者：
Greenwood-Van Meerveld, B;Venkova, K;Crowell, MD
替加色罗是一种5-HT4受体部分激动剂，获批用于治疗便秘女性和慢性便秘男性和女性的肠易激综合征。替加色罗的疗效是基于5-HT 4受体调节肠道蠕动和分泌以及可能的内脏感觉通路的重要性。我们的目的是研究替加色罗对结直肠扩张（CRD）的正常和过度反应模型的结直肠敏感性的影响。以反射性腹部收缩次数为指标，测定不同压力（0-60mmHg）下CRD的内脏反应（VMR）。结肠内注入稀醋酸诱发急性结直肠超敏反应。在三硝基苯磺酸诱导的结肠炎自发消退后，在大鼠中观察到慢性超敏反应。正常敏感结肠的大鼠作为对照。替加色罗（0.1 - 10 mg kg（-1））导致对照大鼠和结肠过敏大鼠的VMR至CRD呈剂量依赖性降低。5-HT 4拮抗剂逆转了替加色罗对结肠正常敏感大鼠的作用，并部分抑制了对结肠过敏大鼠的作用。替加色罗中枢给药无抑制作用。这些结果支持结肠超敏反应可通过替加色罗作用（至少部分通过外周5-HT 4受体）而正常化的假设。
Tegaserod is a 5-HT4 receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5-HT4 receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0-60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid-induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1-10 mg kg(-1)) caused dose-dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5-HT4 antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5-HT4 receptors.