Van Geldre L A, Lefebvre R A
Heymans Institute of Pharmacology, Ghent University, De Pintelaan 185, B-9000 Gent, Belgium.
Curr Pharm Des. 2004;10(20):2483-97. doi: 10.2174/1381612043383890.
Gastrointestinal (GI) smooth muscle cell activity is controlled by contractile cholinergic neurons and relaxant non-adrenergic non-cholinergic (NANC) neurons in the myenteric plexus between the circular and longitudinal muscle layer. Decreased or increased NANC relaxation might be involved in the pathophysiology of functional GI motility disorders. Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO) are the primary inhibitory NANC neurotransmitters. As classic neurotransmitters, VIP is stored in vesicles in the nerve endings, while NO is synthetized on demand by the neuronal isoform of NO synthase (nNOS). The VIP/nNOS co-localization in myenteric neurons, reported for various regions of the GI tract in different species, suggests that VIP and NO are co-transmitters. At the presynaptic level, VIP and NO can induce each others release. Most clear-cut evidence for this mechanism was obtained in isolated myenteric ganglia where VIP induced NO release, and NO facilitated VIP release. At the postsynaptic level, many studies support that VIP and NO are parallel co-transmitters, acting via the adenylate cyclase/3'5' adenosine cyclic monophosphate (cAMP) and guanylate cyclase/3'5' cyclic guanosine monophosphate pathway respectively. Mainly based on results obtained in isolated GI smooth muscle cells, a serial postsynaptic VIP/NO interaction model was proposed, whereby VIP is the principle neurotransmitter, acting partially via a VPAC receptor and the adenylate cyclase/cAMP pathway but also by induction of muscular NO production. Recent results suggest that the capacity of VIP to release NO from isolated smooth muscle cells is related to the induction of inducible NOS (iNOS) in the cells during the isolation procedure. The relative contribution of NO and VIP to GI NANC relaxation differs upon tissue and nerve firing frequency, so that interference with either of them will lead to varying effects.
胃肠道（GI）平滑肌细胞的活动受环形肌层和纵形肌层之间肌间神经丛中收缩性胆碱能神经元和舒张性非肾上腺素能非胆碱能（NANC）神经元的控制。NANC舒张功能的降低或增强可能参与了功能性胃肠动力障碍的病理生理过程。血管活性肠肽（VIP）和一氧化氮（NO）是主要的抑制性NANC神经递质。作为经典神经递质，VIP储存在神经末梢的囊泡中，而NO则由神经元型一氧化氮合酶（nNOS）按需合成。在不同物种胃肠道的各个区域均有报道，VIP/nNOS在肌间神经元中共定位，这表明VIP和NO是共同递质。在突触前水平，VIP和NO可相互诱导释放。在分离的肌间神经节中获得了关于这一机制的最明确证据，其中VIP诱导NO释放，而NO促进VIP释放。在突触后水平，许多研究支持VIP和NO是平行的共同递质，分别通过腺苷酸环化酶/3',5'-环磷酸腺苷（cAMP）和鸟苷酸环化酶/3',5'-环磷酸鸟苷途径发挥作用。主要基于在分离的胃肠道平滑肌细胞中获得的结果，提出了一个连续的突触后VIP/NO相互作用模型，即VIP是主要神经递质，部分通过VPAC受体和腺苷酸环化酶/cAMP途径发挥作用，但也通过诱导肌肉产生NO发挥作用。最近的结果表明，VIP从分离的平滑肌细胞中释放NO的能力与分离过程中细胞中诱导型一氧化氮合酶（iNOS）的诱导有关。NO和VIP对胃肠道NANC舒张的相对贡献因组织和神经放电频率而异，因此对它们任何一个的干扰都会导致不同的效应。
