Yoshida T, Mio M, Tasaka K
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Okayama University, Japan.
Biochem Pharmacol. 1992 Feb 4;43(3):513-7. doi: 10.1016/0006-2952(92)90572-z.
When primary cultured bovine adrenocortical cells were treated with substance P (SP) at concentrations higher than 10 pM, cortisol output increased in a dose-dependent fashion. Although other neurokinins, such as neurokinin A (NKA) and neurokinin B (NKB), were also effective in secreting cortisol, SP was the most potent among the tested neurokinins, the potency order being SP greater than NKA much greater than NKB. This suggests that the NK-1 type receptor on adrenocortical cells may be the site of action of SP on cortisol secretion. The maximal response in SP-induced cortisol secretion was comparable to that elicited by adrenocorticotropic hormone (ACTH). SP-induced cortisol secretion was dependent upon extracellular Ca2+ concentrations, and 45Ca2+ uptake into adrenocortical cells treated with SP was long-lasting. While, in the case of ACTH, 45Ca2+ uptake proceeded transiently, the increase in intracellular cAMP content was much greater compared with that of SP. Although KT-5720, an inhibitor of protein kinase A, inhibited potently ACTH-induced cortisol secretion, SP-induced secretin was not affected by this inhibitor at all. On the other hand, calmodulin inhibitors, such as calmidazolium, trifluoperazine and N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, were not more effective in inhibiting SP-induced cortisol secretion than secretion induced by ACTH. The present study indicates that SP may be one of the physiological stimulants of cortisol secretion and that an increase in intracellular Ca2+ concentration and the subsequent activation of calmodulin may precede SP-induced cortisol secretion.
当用浓度高于10 pM的P物质（SP）处理原代培养的牛肾上腺皮质细胞时，皮质醇分泌呈剂量依赖性增加。尽管其他神经激肽，如神经激肽A（NKA）和神经激肽B（NKB），在分泌皮质醇方面也有作用，但在测试的神经激肽中，SP的作用最强，其效力顺序为SP大于NKA远大于NKB。这表明肾上腺皮质细胞上的NK-1型受体可能是SP对皮质醇分泌的作用位点。SP诱导的皮质醇分泌的最大反应与促肾上腺皮质激素（ACTH）引起的反应相当。SP诱导的皮质醇分泌依赖于细胞外Ca2+浓度，用SP处理的肾上腺皮质细胞对45Ca2+的摄取是持久的。而对于ACTH，45Ca2+摄取是短暂的，与SP相比，细胞内cAMP含量的增加要大得多。尽管蛋白激酶A抑制剂KT-5720能有效抑制ACTH诱导的皮质醇分泌，但SP诱导的分泌完全不受该抑制剂影响。另一方面，钙调蛋白抑制剂，如氯氮草、三氟拉嗪和N-（6-氨基己基）-5-氯-1-萘磺酰胺，在抑制SP诱导的皮质醇分泌方面并不比抑制ACTH诱导的分泌更有效。本研究表明，SP可能是皮质醇分泌的生理刺激物之一，细胞内Ca2+浓度的增加以及随后钙调蛋白的激活可能先于SP诱导的皮质醇分泌。
