Kobayashi Y, Hoshikuma K, Nakano Y, Yokoo Y, Kamiya T
Kyowa Hakko Kogyo Co., Ltd., Tsukuba Research Laboratories, Ibaraki, Japan.
Planta Med. 2001 Apr;67(3):244-8. doi: 10.1055/s-2001-12008.
Cardiotonic effects of evodiamine and rutaecarpine, constituents of the fruits of Evodia rutaecarpa Bentham Rutaceae, were evaluated on guinea pig isolated atria. Comparison with capsaicin, a vanilloid receptor agonist, revealed similar positive inotropic and chronotropic activity, as judged from antagonistic effects of the competitive vanilloid receptor (capsaicin receptor) antagonist capsazepine, the non-competitive vanilloid receptor antagonist ruthenium red, the calcitonin gene related peptide antagonist CGRP(8-37), the P2X purinoceptor antagonist PPADS, and various desensitization studies. Evodiamine and rutaecarpine produced transient positive inotropic and chronotropic effects on the guinea-pig isolated atria, followed by a desensitizing effect to additional administration. Dose-response relationships for evodiamine, rutaecarpine and capsaicin were obtained. All the compounds evoked positive inotropic and chronotropic effects in a concentration-dependent manner. Maximal contractions for evodiamine, rutaecarpine and capsaicin were observed at concentrations of 1 microM, 3 microM and 0.3 microM, respectively. The cardiotonic responses evoked by both evodiamine and rutaecarpine were shifted to the right by capsazepine, an established antagonist of vanilloid receptor (capsaicin-receptor). The effects of both evodiamine (1 microM) and rutaecarpine (3 microM) were abolished by pretreatment with a desensitizing dosage of capsaicin (1 microM), developing cross-tachyphylaxis between these compounds. The effects of evodiamine (1 microM), rutaecarpine (3 microM) and capsaicin (0.3 microM) were also significantly reduced by pretreatment with ruthenium red (10 microM) and CGRP (8-37) (10 microM). The effects of evodiamine, rutaecarpine and capsaicin were not affected by pretreatment with PPADS (100 microM), a highly selective P2X purinoceptor antagonist, and the possibility of the involvement of the P2X purinoceptor was excluded. These results suggest that the positive inotropic and chronotropic effects on the guinea-pig isolated right atria induced by both evodiamine and rutaecarpine could be attributed to their interaction with vanilloid receptors and the resultant release of CGRP, a cardiotonic neurotransmitter, from capsaicin-sensitive nerves as with capsaicin.
对吴茱萸果实中的成分吴茱萸碱和吴茱萸次碱对豚鼠离体心房的强心作用进行了评估。与香草酸受体激动剂辣椒素比较，从竞争性香草酸受体（辣椒素受体）拮抗剂辣椒平、非竞争性香草酸受体拮抗剂钌红、降钙素基因相关肽拮抗剂CGRP(8 - 37)、P2X嘌呤受体拮抗剂PPADS的拮抗作用以及各种脱敏研究判断，显示出相似的正性肌力和变时活性。吴茱萸碱和吴茱萸次碱对豚鼠离体心房产生短暂的正性肌力和变时作用，随后对额外给药产生脱敏作用。获得了吴茱萸碱、吴茱萸次碱和辣椒素的剂量 - 反应关系。所有化合物均以浓度依赖性方式引起正性肌力和变时作用。吴茱萸碱、吴茱萸次碱和辣椒素的最大收缩分别在1微摩尔/升、3微摩尔/升和0.3微摩尔/升的浓度下观察到。既定的香草酸受体（辣椒素受体）拮抗剂辣椒平使吴茱萸碱和吴茱萸次碱引起的强心反应向右移位。用脱敏剂量的辣椒素（1微摩尔/升）预处理可消除吴茱萸碱（1微摩尔/升）和吴茱萸次碱（3微摩尔/升）的作用，在这些化合物之间产生交叉快速耐受性。用钌红（10微摩尔/升）和CGRP(8 - 37)（10微摩尔/升）预处理也显著降低了吴茱萸碱（1微摩尔/升）、吴茱萸次碱（3微摩尔/升）和辣椒素（0.3微摩尔/升）的作用。高度选择性的P2X嘌呤受体拮抗剂PPADS（100微摩尔/升）预处理不影响吴茱萸碱、吴茱萸次碱和辣椒素的作用，排除了P2X嘌呤受体参与的可能性。这些结果表明，吴茱萸碱和吴茱萸次碱对豚鼠离体右心房的正性肌力和变时作用可能归因于它们与香草酸受体的相互作用以及由此导致的强心神经递质降钙素基因相关肽从辣椒素敏感神经中释放，与辣椒素的情况相同。
