Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human
Tachykinins and tachykinin receptors in the gut, with special reference to NK2 receptors in human
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DOI：
10.1016/j.autneu.2006.02.014
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发表时间：
2006-06-30
影响因子：
2.7
通讯作者：
Maggi, Carlo Alberto
中科院分区：
文献类型：
--
作者：
Lecci, Alessandro;Capriati, Angela;Maggi, Carlo Alberto
速激肽(TKS)、P物质(SP)、神经激肽A(NKA)和B(NKB)是目前研究的动物包括人类肠道运动的重要多肽调节剂。TKS可以在不同水平上调节运动，因为这些肽在投射到环肌和纵肌的胆碱能兴奋性运动神经元、中间神经元以及壁内和壁外感觉神经元中都有表达。SP、NKA和NKB分别通过刺激NK1、NK2和NK3受体而优先发挥作用，但天然TKS对其首选受体的选择性是相对的。此外，SP和NKA在人体肠道中的表达数量相似，足够的刺激可以从肠神经释放类似数量的TKS。此外，一个单一的解剖底物可以表达多种类型的TK受体，因此阻断单一受体类型可能不会在整合的运动模型中揭示功能效应。在分离的人小肠和结肠环状肌条上，NK1和NK2受体都介导收缩效应。事实上，在人类小肠中，电场刺激(EFS)引起的平滑肌电和运动事件可能涉及NK1和NK2受体中的一种或两种，或者主要涉及后一种受体，具体取决于实验条件。相比之下，在人结肠平滑肌中，只有NK2受体介导的对EFS的反应是显著的，一些证据表明该成分是这一水平上的主要兴奋性运动机制。此外，最近在人的结肠粘膜中发现了NK2受体介导的分泌成分。因此，可以推测，阻断NK1和NK2受体对于拮抗外源性给药或内源性释放TKS在小肠引起的运动效应是必要的，而阻断NK2受体将足以扰乱生理运动，并可能扰乱结肠水平的分泌活动。现有证据表明，在健康志愿者中，静脉滴注NKA(25pmoL/kg/min)。刺激小肠运动，引发一系列肠道和非肠道不良事件。选择性NK2受体拮抗剂尼泊尔突变体(8 mg i.v.)可拮抗NKA引起的小肠运动，并防止相关的肠道不良事件。在另一项研究中，相同剂量的nepadutant增加了接受甘油灌肠治疗的健康志愿者在等压球囊扩张期间的结肠-直肠顺应性，揭示了NK2受体介导的结肠平滑肌张力调节成分。然而，nepadutant(16 mg i.v.)延长了NK2受体的阻断。B.i.d。连续8天)对排便习惯没有影响，无论是在运动方面还是在大便一致性方面。综上所述，这些结果表明，即使在TKS的作用及其受体的作用存在显著冗余的情况下，选择性阻断速激肽NK2受体也可以对人类的肠道运动和感觉产生功能影响，但这可以在不破坏生理功能的情况下发生。(C)2006爱思唯尔B.V.保留所有权利。
Tachykinins (TKs), substance P (SP), neurokinin A (NKA) and B (NKB) are important peptide modulators of intestinal motility in animal species studied so far, including humans. Modulation of motility by TKs can occur at various levels, since these peptides are expressed in cholinergic excitatory motor neurons projecting to both circular and longitudinal muscle, interneurons, and intramural and extramural sensory neurons. The effects of SP, NKA and NKB are preferentially mediated through the stimulation of NK1, NK2 and NK3 receptors, respectively; however, the selectivity of natural TKs for their preferred receptors is relative. In addition, SP and NKA are expressed in similar quantities in the human intestine and adequate stimuli can release similar amount of these TKs from enteric nerves. Furthermore, a single anatomical substrate can express more than one TK receptor type, so that the blockade of a single receptor type may not reveal functional effects in integrated models of motility. In isolated human small intestine and colon circular muscle strips, both NK1 and NK2 receptors mediate contractile effects. Indeed, in the human small intestine, smooth muscle electrical and motor events induced by electrical field stimulation (EFS) can involve either or both NK1 and NK2 receptors or these latter receptors predominantly, depending on the experimental conditions. In contrast, in the human colonic smooth muscle, only the NK2 receptor-mediated component of the response to EFS is prominent and some evidence would suggest that this component is the main excitatory motor mechanism at this level. Furthermore, a NK2 receptor-mediated secretory component in the human colonic mucosa has been recently demonstrated. Thus, it could be speculated that the blockade of both NK1 and NK2 receptors will be necessary to antagonise motor effects induced by exogenous administration or endogenous release of TKs in the small intestine, whereas the blockade of the NK2 receptors would be sufficient to disrupt physiological motor and, possibly, secretory activity at the colonic level. Available evidence indicates that, in healthy volunteers, the infusion of NKA (25 pmol/kg/min i.v.) stimulated small intestine motility and precipitated a series of intestinal and non-intestinal adverse events. Nepadutant (8mg i.v.), a selective NK2 receptor antagonist, antagonised small intestine motility induced by NKA and prevented associated intestinal adverse events. In another study, the same dose of nepadutant increased colo-rectal compliance during isobaric balloon distension in healthy volunteers pretreated with a glycerol enema, disclosing a NK2 receptor-mediated component in the regulation of colonic smooth muscle tone. However, the prolonged blockade of NK2 receptors by nepadutant (16mg i.v. b.i.d. for 8days) did not affect bowel habits, neither in term of movements nor of stool consistency. Altogether, these results indicate that, even when there is a significant redundance in the effects of TKs and in the role of their receptors, the selective blockade of tachykinin NK2 receptors can have functional consequences on human intestinal motility and perception, but this can occur without the disruption of the physiological functions. (c) 2006 Elsevier B.V. All rights reserved.