Huidobro-Toro J P, Chelala C A, Bahouth S, Nodar R, Musacchio J M
Eur J Pharmacol. 1982 Jun 16;81(1):21-34. doi: 10.1016/0014-2999(82)90597-0.
Substance P (SP) caused an immediate and vigorous contraction of the longitudinal smooth muscle layer of the guinea-pig ileum. The contractile response to SP, unlike that to acetylcholine or histamine was not maintained but faded to baseline levels in about 6 min. When 0.3-1.0 nM SP was added the fading time was shorter than 6 min and tachyphylaxis did not develop. Higher concentrations of SP produced fading times of about 6 min that could not be increased even by adding extremely high concentrations of the peptide, up to 1800 nM. Short fading times and the lack of development of tachyphylaxis are the result of the rapid adsorption and/or metabolism of SP. The addition of exogenous peptidases such as pronase, chymotrypsin and an extract of black widow spider venom gland dramatically increased the rate of degradation of SP, shortened the fading response and blocked the development of tachyphylaxis. Tetrodotoxin and atropine reduced the fading time by 25%, while eserine increased its duration several-fold; these findings are consistent with the existence of a cholinergic nerve component in the mediation of some of the effects of SP receptor and, in part, to adsorption and metabolism of the peptide. The magnitude of the tachyphylaxis to SP was proportional to the concentration of the desensitizing dose of the peptide and was specific to SP and to the related peptide physalaemin; no cross-tachyphylaxis towards other agents was found.
P物质（SP）可引起豚鼠回肠纵行平滑肌层立即发生强烈收缩。与乙酰胆碱或组胺引起的收缩反应不同，对SP的收缩反应不能持续，而是在约6分钟内逐渐消退至基线水平。当加入0.3 - 1.0 nM的SP时，消退时间短于6分钟，且不会产生快速耐受性。较高浓度的SP产生的消退时间约为6分钟，即使加入高达1800 nM的极高浓度该肽也无法延长。消退时间短和缺乏快速耐受性是SP快速吸附和/或代谢的结果。加入外源性肽酶如链霉蛋白酶、胰凝乳蛋白酶和黑寡妇蜘蛛毒腺提取物可显著提高SP的降解速率，缩短消退反应并阻止快速耐受性的产生。河豚毒素和阿托品可使消退时间缩短25%，而毒扁豆碱可使其持续时间延长数倍；这些发现与在介导SP受体的某些效应中存在胆碱能神经成分一致，部分与该肽的吸附和代谢有关。对SP的快速耐受性程度与该肽脱敏剂量的浓度成正比，且对SP和相关肽蛙皮素具有特异性；未发现对其他药物的交叉快速耐受性。
