Planta Med 2001; 67(3): 244-248
DOI: 10.1055/s-2001-12008
Original Paper

© Georg Thieme Verlag Stuttgart · New York

The Positive Inotropic and Chronotropic Effects of Evodiamine and Rutaecarpine, Indoloquinazoline Alkaloids Isolated from the Fruits of Evodia rutaecarpa, on the Guinea-Pig Isolated Right Atria: Possible Involvement of Vanilloid Receptors

Yoshinori Kobayashi*, Kiyoko Hoshikuma, Yumiko Nakano, Yoshiharu Yokoo, Toshikazu Kamiya
  • Kyowa Hakko Kogyo Co., Ltd. Tsukuba Research Laboratories, Ibaraki, Japan
Further Information

Publication History

April 13, 2000

September 17, 2000

Publication Date:
31 December 2001 (online)


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 μM, 3 μM and 0.3 μM, 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 μM) and rutaecarpine (3 μM) were abolished by pretreatment with a desensitizing dosage of capsaicin (1 μM), developing cross-tachyphylaxis between these compounds. The effects of evodiamine (1 μM), rutaecarpine (3 μM) and capsaicin (0.3 μM) were also significantly reduced by pretreatment with ruthenium red (10 μM) and CGRP (8-37) (10 μM). The effects of evodiamine, rutaecarpine and capsaicin were not affected by pretreatment with PPADS (100 μM), 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.


  • 1 Kobayashi Y, Nakano Y, Hoshikuma K, Yokoo Y, Kamiya T. The bronchoconstrictive action of evodiamine, an indoloquinazoline alkaloid isolated from the fruits of Evodia rutaecarpa, on guinea-pig isolated bronchus: possible involvement of vanilloid receptors.  Planta Medica. 2000;  66 526-30
  • 2 Miyauchi T, Ishikawa T, Sugishita Y, Saito A, Goto K. Effects of capsaicin on nonadrenergic noncholinergic nerves in the guinea pig atria: role of calcitonin gene-related peptide as cardiac neurotransmitter.  Journal of Cardiovascular Pharmacology. 1987;  10 675-82
  • 3 Saito A, Ishikawa T, Kimura S, Goto K. Role of calcitonin gene-related peptide as cardiotonic neurotransmitter in guinea-pig left atria.  Journal of Pharmacology & Experimental Therapeutics. 1987;  243 731-6
  • 4 Ishikawa T, Okamura N, Saito A, Goto K. Effects of calcitonin gene-related peptide (CGRP) and isoproterenol on the contractility and adenylate cyclase activity in the rat heart.  Journal of Molecular & Cellular Cardiology. 1987;  19 723-7
  • 5 Shoji N, Umeyama A, Takemoto T, Kajiwara A, Ohizumi Y. Isolation of evodiamine, a powerful cardiotonic principle, from Evodia rutaecarpa var. bodinieri (Rutaeceae).  Journal of Pharmaceutical Sciences. 1986;  75 612-3
  • 6 Amann R, Maggi C A. Ruthenium red as a capsaicin antagonist.  Life Science. 1991;  49 849-56
  • 7 Maggi C A, Patacchini R, Santicioli P, Giuliani S, Del Blanco E, Geppetti P, et al. The “efferent” function of capsaicin-sensitive nerves: ruthenium red discriminates between different mechanisms of activation.  European Journal of Pharmacology. 1989;  170 167-77
  • 8 Ziganshin A U, Hoyle C H, Bo X, Lambrecht G, Mutschler E, Baumert H G, Burnstock G. PPADS selectively antagonize P2X-purinoceptor-mediated responses in the rabbit urinary bladder.  British Journal of Pharmacology. 1993;  110 1491-5
  • 9 Rubino A, Burnstock G. Capsaicin-sensitive sensory-motor neurotransmission in the peripheral control of cardiovascular function.  Cardiovascular Research. 1996;  31 467-9
  • 10 Piper A S, Docherty R J. One-way cross-desensitization between P2X purinoceptors and vanilloid receptors in adult rat dorsal root ganglion neurons.  Journal of Physiology. 2000;  523 Pt3 685-96
  • 11 Froldi G, Pandolfo L, Chinellato A, Ragazzi E, Caparrotta L, Fassina G. Dual effect of ATP and UTP on rat atria: which types of receptors are involved?.  Naunyn-Schmiedebergs Archives of Pharmacology. 1994;  349 381-6
  • 12 Fujii I, Kobayashi Y, Hirayama N. Molecular structures of the indole alkaloids, evodiamine and rutaecarpine, from Evodia fruit.  Zeitschrift für Kristallographie. 2000;  766-70

Y. Kobayashi, Ph. D.

Kyowa Hakko Kogyo Co., Ltd.

Tsukuba Research Laboratories

2, Miyukigaoka, Tsukuba-shi

Ibaraki, 305-0841



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