Hashimoto M, Yamamoto Y, Takagi H
Department of Pharmacology, Tsukuba Research Laboratories, Pharmacia & Upjohn, Ibaraki, Japan.
Res Commun Mol Pathol Pharmacol. 1997 Jul;97(1):79-94.
We investigated the effects of KB-2796 (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), a novel calcium channel blocker, on neurogenic inflammation caused by electrical stimulation in the trigeminal ganglion and on cutaneous reactions induced by inflammatory mediators in rats, by measuring plasma extravasation. Neurogenic inflammation was inhibited by pretreatment with capsaicin (25 mg/kg, s.c.) but not indomethacin (10 mg/kg, i.p.), while phosphoramidon (2.5 mg/kg, i.v.) augmented it. KB-2796 (0.1-1 mg/kg, i.v.) significantly inhibited neurogenic inflammation in a dose dependent manner, without affecting histamine-, bradykinin- or substance P-induced cutaneous reactions. Dimetotiazine (0.3 and 1 mg/kg, i.v.), flunarizine (1 mg/kg, i.v.), mepyramine (1 mg/kg, i.v.) and sumatriptan (1 mg/kg, i.v.) significantly inhibited neurogenic inflammation. However, these compounds also showed complete or partial inhibition of histamine-, bradykinin- or substance P-induced reactions. Nifedipine (0.1 mg/kg, i.v.) did not show marked effects on neurogenic inflammation and cutaneous reactions. The present experiments indicate that neurogenic inflammation is presumably mediated not only by neuropeptides released from trigeminal nerve endings but also by secondarily released histamine, and that KB-2796 like sumatriptan may inhibit neurogenic inflammation caused by trigeminal nerve stimulation probably through inhibition of neuropeptide release but its inhibition may be distinct from the calcium blocking action of the 1,4-dihydropyridine type.
我们通过测量血浆外渗，研究了新型钙通道阻滞剂KB - 2796（1 - [双（4 - 氟苯基）甲基] - 4 - （2,3,4 - 三甲氧基苄基）哌嗪二盐酸盐）对三叉神经节电刺激引起的神经源性炎症以及对大鼠炎症介质诱导的皮肤反应的影响。辣椒素（25 mg/kg，皮下注射）预处理可抑制神经源性炎症，但吲哚美辛（10 mg/kg，腹腔注射）则不能，而磷酰胺（2.5 mg/kg，静脉注射）可增强神经源性炎症。KB - 2796（0.1 - 1 mg/kg，静脉注射）以剂量依赖性方式显著抑制神经源性炎症，且不影响组胺、缓激肽或P物质诱导的皮肤反应。二甲替嗪（0.3和1 mg/kg，静脉注射）、氟桂利嗪（1 mg/kg，静脉注射）、美吡拉敏（1 mg/kg，静脉注射）和舒马曲坦（1 mg/kg，静脉注射）均显著抑制神经源性炎症。然而，这些化合物也完全或部分抑制了组胺、缓激肽或P物质诱导的反应。硝苯地平（0.1 mg/kg，静脉注射）对神经源性炎症和皮肤反应未显示出明显作用。本实验表明，神经源性炎症可能不仅由三叉神经末梢释放的神经肽介导，还由继发性释放的组胺介导，并且KB - 2796与舒马曲坦类似，可能通过抑制神经肽释放来抑制三叉神经刺激引起的神经源性炎症，但其抑制作用可能与1,4 - 二氢吡啶类的钙阻断作用不同。
