Jacques L, Couture R
Département de Physiologie, Faculté de Médecine, Université de Montréal, Québec, Canada.
Eur J Pharmacol. 1990 Aug 2;184(1):9-20. doi: 10.1016/0014-2999(90)90662-p.
The effects of substance P (SP), SP fragments, neurokinin A (NKA), neurokinin B (NKB) and selective agonists for neurokinin receptors were assessed on cutaneous vascular permeability after intrathecal (i.t.) administration in rats. Dose-dependent increases in plasma extravasation were observed with the following rank orders of potency ([p-Glu6]SP-(6-11) greater than SP greater than or equal to SP-(4-11) greater than [p-Glu5,MePhe8,Sar9]SP-(5-11) = [p-Glu5]SP-(5-11) greater than SP-(7-11) and SP greater than NKA greater than NKB). The N-terminal fragments SP-(1-4), SP-(1-7) and SP-(1-9) were inactive up to 65 nmol. The NK-1 receptor selective agonists [( beta-Ala4,Sar9,Met(O2)11]SP-(4-11) and [Pro9,Met(O2)11]SP) were more potent than the NK-2 ([Nle10]NKA-(4-10] and NK-3 ([beta-Asp4,MePhe7]NKB-(4-10) and [MePhe7]NKB) receptor-selective agonists. Plasma extravasation was also increased by i.t. bradykinin (BK, 8.1 nmol) while the fragment BK-(1-8), a potent B1-receptor-selective agonist, produced only a slight effect at 81 nmol. When BK was given after prior i.t. administration of 6.1 nmol of [Thi5.8,D-Phe7]BK, an antagonist of BK at the B2-receptor, the increase in vascular permeability was significantly attenuated. The analogue [Leu8]BK-(1-8) (10.3 nmol), an antagonist of BK at the B1-receptor, failed to modify the BK-induced plasma extravasation. Plasma extravasation induced by SP (6.5 nmol) and BK (8.1 nmol) was abolished in cervically vagotomized rats, and significantly reduced in both spinal rats and in capsaicin-treated animals. Conversely, bilateral adrenalectomy (48 h earlier) and intercollicular decerebration (30 min earlier) had no major effect on the response elicited either by SP or BK. The response to SP remained unaffected by methysergide and hexamethonium but was significantly reduced by methylnitrate atropine and diphenhydramine. Indomethacin significantly enhanced the plasma extravasation induced by SP. These results suggest that SP and BK may play a role as spinal mediators in peripheral vascular permeability through a sensory and cholinergic vagal mechanism involving a spinobulbar pathway. The receptors mediating the response to SP and BK in the spinal cord are of the NK-1 and B2 subtypes, respectively.
在大鼠鞘内注射后，评估了P物质（SP）、SP片段、神经激肽A（NKA）、神经激肽B（NKB）以及神经激肽受体选择性激动剂对皮肤血管通透性的影响。观察到血浆外渗呈剂量依赖性增加，其效力顺序如下（[p - Glu6]SP-(6 - 11)大于SP大于或等于SP-(4 - 11)大于[p - Glu5,MePhe8,Sar9]SP-(5 - 11)=[p - Glu5]SP-(5 - 11)大于SP-(7 - 11)且SP大于NKA大于NKB）。N端片段SP-(1 - 4)、SP-(1 - 7)和SP-(1 - 9)在高达65 nmol时无活性。NK - 1受体选择性激动剂[(β - Ala4,Sar9,Met(O2)11]SP-(4 - 11)和[Pro9,Met(O2)11]SP比NK - 2（[Nle10]NKA-(4 - 10]）和NK - 3（[β - Asp4,MePhe7]NKB-(4 - 10)和[MePhe7]NKB）受体选择性激动剂更有效。鞘内注射缓激肽（BK，8.1 nmol）也可增加血浆外渗，而片段BK-(1 - 8)，一种有效的B1受体选择性激动剂，在81 nmol时仅产生轻微作用。当在鞘内预先给予6.1 nmol的[Thi5.8,D - Phe7]BK（一种BK在B2受体的拮抗剂）后再给予BK时，血管通透性的增加显著减弱。类似物[Leu8]BK-(1 - 8)（10.3 nmol），一种BK在B1受体的拮抗剂，未能改变BK诱导的血浆外渗。在颈迷走神经切断的大鼠中，SP（6.5 nmol）和BK（8.1 nmol）诱导的血浆外渗被消除，在脊髓大鼠和辣椒素处理的动物中显著降低。相反，双侧肾上腺切除术（提前48小时）和间脑间切断术（提前30分钟）对SP或BK引发的反应没有主要影响。对SP的反应不受麦角新碱和六甲铵的影响，但硝酸甲基阿托品和苯海拉明可使其显著降低。吲哚美辛显著增强了SP诱导的血浆外渗。这些结果表明，SP和BK可能通过涉及脊髓 - 延髓通路的感觉和胆碱能迷走神经机制，作为脊髓介质在外周血管通透性中发挥作用。在脊髓中介导对SP和BK反应的受体分别是NK - 1和B2亚型。
