Maggi C A, Giuliani S, Patacchini R, Santicioli P, Theodorsson E, Barbanti G, Turini D, Giachetti A
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Gastroenterology. 1992 Jan;102(1):88-96. doi: 10.1016/0016-5085(92)91787-5.
The effects of some newly developed tachykinin antagonists that are selective for the neurokinin (NK)-1 (L 668,169) or the NK-2 (MEN 10,207, L 659,877 and R 396) tachykinin receptor on the cholinergic and noncholinergic contraction and on the nonadrenergic noncholinergic relaxation produced by electrical field stimulation (50 Hz) were investigated in mucosa-free circular strips of the human ileum. The strips were contracted by substance P and neurokinin A as well as by selective NK-2-receptor ligands, [beta Ala8]neurokinin A(4-10), and MDL 28,564, the latter peptide being capable of discriminating between NK-2-receptor subtypes. The selectivity of the antagonists for NK-1 or NK-2 receptors was confirmed in pharmacological experiments using substance P, neurokinin A, and [beta Ala8]neurokinin A(4-10) as stimulants. Among the NK-2-selective antagonists, MEN 10,207 displayed the highest affinity, followed by L 659,877 and R 396. The antagonists MEN 10,207 and L 659,877 inhibited the noncholinergic contraction to electrical stimulation in a concentration-dependent manner; L 668,169 and R 396 were poorly effective. Thus the potency of antagonists toward the noncholinergic response closely paralleled their rank order of potency at NK-2 receptors. The cholinergic contraction and nonadrenergic noncholinergic relaxation were not inhibited by the antagonists. Both substance P- and neurokinin A-like immunoreactivities were detected in extracts of the human ileum, and the identity of the corresponding peptides was confirmed by reverse-phase high-performance liquid chromatography. It was concluded that in addition to NK-1 receptors, the circular muscle of the human ileum also contains NK-2 receptors. Activation of the latter is chiefly responsible for the noncholinergic contraction to nerve stimulation.
在人回肠无黏膜环行肌条上，研究了一些新开发的对神经激肽（NK）-1（L 668,169）或NK-2（MEN 10,207、L 659,877和R 396）速激肽受体具有选择性的速激肽拮抗剂，对电场刺激（50 Hz）引起的胆碱能和非胆碱能收缩以及非肾上腺素能非胆碱能舒张的影响。这些肌条可被P物质、神经激肽A以及选择性NK-2受体配体[β丙氨酸8]神经激肽A(4 - 10)和MDL 28,564收缩，后一种肽能够区分NK-2受体亚型。在使用P物质、神经激肽A和[β丙氨酸8]神经激肽A(4 - 10)作为刺激剂的药理实验中，证实了拮抗剂对NK-1或NK-2受体的选择性。在NK-2选择性拮抗剂中，MEN 10,207表现出最高亲和力，其次是L 659,877和R 396。拮抗剂MEN 10,207和L 659,877以浓度依赖方式抑制对电刺激的非胆碱能收缩；L 668,169和R 396效果不佳。因此，拮抗剂对非胆碱能反应的效力与其在NK-2受体上的效力顺序密切平行。拮抗剂未抑制胆碱能收缩和非肾上腺素能非胆碱能舒张。在人回肠提取物中检测到P物质和神经激肽A样免疫反应性，并通过反相高效液相色谱法确认了相应肽的身份。得出的结论是，除NK-1受体外，人回肠环行肌还含有NK-2受体。后者的激活主要负责对神经刺激的非胆碱能收缩。
