Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine
Antisecretory actions of a novel vasoactive intestinal polypeptide (VIP) antagonist in human and rat small intestine
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DOI：
10.1038/sj.bjp.0706128
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发表时间：
2005-04-01
影响因子：
7.3
通讯作者：
Burleigh, DE
中科院分区：
文献类型：
--
作者：
Banks, MR;Farthing, MJG;Burleigh, DE
1 血管活性肠肽 (VIP) 已被证明存在于肠粘膜神经元中，并引起肠上皮细胞分泌氯离子。这些发现表明 VIP 是一种分泌运动神经递质。现在，随着 PG 97 - 269 的开发，这种作用可能得到证实，PG 97 - 269 是一种高亲和力、选择性的 VIP 1 型 (VPAC1) 受体拮抗剂，由肠上皮细胞表达。我们使用体外和体内肠道分泌模型评估了这种新型化合物的 VIP 拮抗作用和抗分泌潜力。2 将人结肠细胞系 (T-84) 的单层以及大鼠空肠和人回肠的肌肉剥离制剂设置在 Ussing 室中，用于记录跨上皮电阻和短路电流。使用室被修改以允许对粘膜神经元进行电刺激。在体内灌注的大鼠空肠中研究了PG 97 - 269 对肠毒素诱导的分泌的影响。3 PG 97 - 269 竞争性拮抗T-84 单层中的VIP。在大鼠空肠和人回肠中，对 VIP 的反应以及大鼠空肠对粘膜神经元电刺激的反应均受到抑制。4 在灌注的大鼠空肠中，PG 97 - 269 消除了 VIP 对液体和电解质运输的影响，并减弱了霍乱毒素和大肠杆菌热不稳定毒素诱导的净液体和电解质分泌。5 PG 97 - 269 是肠细胞 VIP 的竞争性拮抗剂受体并有效抑制大鼠和人肠粘膜对 VIP 的反应。对粘膜神经元电刺激和肠毒素的腔内应用的分泌反应的拮抗意味着 VIP 在这些过程中的分泌作用。
1 Vasoactive intestinal peptide ( VIP) has been demonstrated in intestinal mucosal neurones and elicits chloride secretion from enterocytes. These findings have led to the proposal that VIP is a secretomotor neurotransmitter. Confirmation of such a role may now be possible with the development of PG 97 - 269, a high-affinity, selective antagonist of VIP type 1 (VPAC1) receptor, which is expressed by gut epithelial cells. We have evaluated the VIP antagonism and antisecretory potential of this novel compound using in vitro and in vivo models of intestinal secretion.2 Monolayers of the human colonic cell line (T-84) and muscle-stripped preparations of rat jejunum and human ileum were set up in Ussing chambers for recording of transepithelial resistance and short-circuit current. Ussing chambers were modified to allow electrical stimulation of mucosal neurones. Effects of PG 97 - 269 on enterotoxin-induced secretion were investigated in perfused rat jejunum in vivo.3 PG 97 - 269 competitively antagonised VIP in T-84 monolayers. In rat jejunum and human ileum, responses to VIP were inhibited as were responses of rat jejunum to electrical stimulation of mucosal neurons.4 In perfused rat jejunum, PG 97 - 269 abolished the effects of VIP on fluid and electrolyte transport and attenuated cholera toxin and Escherichia coli heat labile toxin-induced net fluid and electrolyte secretion.5 PG 97 - 269 is a competitive antagonist of enterocyte VIP receptors and effectively inhibits responses of rat and human intestinal mucosa to VIP. Antagonism of secretory responses to electrical stimulation of mucosal neurons and lumenal application of enterotoxins imply a secretory role for VIP in these processes.