Blockade of 5-HT-mediated enteric slow EPSPs by BRL 24924: gastrokinetic effects.
Blockade of 5-HT-mediated enteric slow EPSPs by BRL 24924: gastrokinetic effects.
复制标题
BRL 24924 阻断 5-HT 介导的肠慢 EPSP：胃动力作用。
DOI：
10.1152/ajpgi.1989.257.3.g386
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Gershon,MD
中科院分区：
文献类型：
--
作者：
Mawe,GM;Branchek,TA;Gershon,MD
已在细胞内微电极刺穿的肠神经元上从生理学角度鉴定出两种类型的 5-羟色胺 (5-HT) 受体：5-HT1P 和 5-HT3。 5-HT1P 受体的激活会引起与输入电阻增加相关的持久膜去极化，而 5-HT3 受体的刺激会导致短暂的去极化，在此期间输入电阻下降。肌间 II 型超极化后电位 (AH) 神经元中的慢兴奋性突触后电位 (EPSP) 已被证明是由 5-HT1P 受体介导的。目前的实验旨在确定取代的苯甲酰胺 BRL 24924 是否是 5-HT1P 受体的特异性拮抗剂，并可用作研究血清素能神经元在胃肠道运动控制中所起作用的探针。使用细胞内微电极分析 BRL 24924 对豚鼠肌间神经元的影响。 BRL 24924 的微喷射既不模仿 5-HT 的长期反应，也不模仿短暂的反应；然而，BRL 24924 (0.5-1.0 microM) 可逆地拮抗肌间神经元对 5-HT 的持久 5-HT1P 受体介导的反应和 5-HT 介导的慢 EPSP。需要高出 10 倍浓度的 BRL 24924 才能减少 5-HT3 受体介导的短暂反应。 BRL 24924 不影响肌间神经元对 P 物质的反应。这些结果表明 BRL 24924 主要是 5-HT1P 拮抗剂。与其他 5-HT1P 激动剂或拮抗剂不同，BRL 24924 不会阻断 5-[3H]HT 与 5-HT1P 受体的结合。这一观察结果表明，BRL 24924 对 5-HT 生理反应的特异性拮抗作用可能是 5-HT1P 受体与其效应机制偶联作用的结果。 BRL 24924 (0.5-1 mg/kg) 和另一种 5-HT1P 拮抗剂 N-乙酰基-5-羟基色氨酸-5-羟基色氨酸酰胺 (5 mg/kg) 显着增加了 51Cr 标记的液体膳食从小鼠胃中的排空率。相反，5-HT3拮抗剂ICS 205-930 (0.1-0.5 mg/kg)不影响胃排空率。这些观察结果与小鼠胃的内在抑制性神经元被通过 5-HT1P 受体作用的血清素能轴突激活的假设一致。因此，松弛途径中神经元兴奋性驱动的拮抗作用可以解释 BRL 24924 的胃动力作用。
Two types of 5-hydroxytryptamine (5-HT) receptor, 5-HT1P and 5-HT3, have been identified physiologically on enteric neurons impaled by intracellular microelectrodes. Activation of 5-HT1P receptors evokes a long-lasting membrane depolarization associated with an increased input resistance, whereas stimulation of 5-HT3 receptors results in a brief depolarization during which the input resistance falls. Slow excitatory postsynaptic potentials (EPSPs) in myenteric type II-hyperpolarizing afterpotential (AH) neurons have been demonstrated to be mediated by 5-HT1P receptors. The current experiments were done to determine whether the substituted benzamide, BRL 24924, is a specific antagonist at 5-HT1P receptors and can be used as a probe to investigate the role played by serotoninergic neurons in the control of gastrointestinal motility. Intracellular microelectrodes were used to analyze the effects of BRL 24924 on guinea pig myenteric neurons. Microejection of BRL 24924 mimicked neither the long-lasting nor the brief response to 5-HT; however, BRL 24924 (0.5-1.0 microM) reversibly antagonized both the long-lasting 5-HT1P receptor-mediated responses of myenteric neurons to 5-HT and 5-HT-mediated slow EPSPs. A greater than 10-fold higher concentration of BRL 24924 was required to reduce the short-lived responses mediated by 5-HT3 receptors. BRL 24924 did not affect the response of myenteric neurons to substance P. These results indicate that BRL 24924 is primarily a 5-HT1P antagonist. Unlike other 5-HT1P agonists or antagonists, BRL 24924 did not block the binding of 5-[3H]HT to 5-HT1P receptors. This observation suggests that specific antagonism of physiological responses to 5-HT by BRL 24924 may be the result of an action on the coupling of the 5-HT1P receptor to its effector mechanism. BRL 24924 (0.5-1 mg/kg) and another 5-HT1P antagonist, N-acetyl-5-hydroxytryptophyl-5-hydroxytryptophan amide (5 mg/kg), significantly increased the rate of emptying of a 51Cr-labeled liquid meal from the murine stomach. In contrast, the 5-HT3 antagonist, ICS 205-930 (0.1-0.5 mg/kg), did not affect the rate of gastric emptying. These observations are consistent with the hypothesis that intrinsic inhibitory neurons of the murine stomach are activated by serotoninergic axons acting through 5-HT1P receptors. Antagonism of an excitatory drive to neurons in a relaxant pathway may thus explain the gastrokinetic effects of BRL 24924.