Kaori Horikoshi*, Toshihide Yokoyama, Nobuyuki Kishibayashi, Kenji Ohmori,
Akio Ishii and Akira Karasawa
Drug Development Research Laboratories, Pharmaceutical Research Institute,
Kyowa Hakko Kogyo Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun,
Shizuoka 411-8731, Japan
*Corresponding author. FAX: +81-559-86-7430
E-mail: akira.karasawa@kyowa.co.jp
Abstract: To clarify the mechanism for the severe emesis concomitant
with intensive chemotherapy, we investigated the effects of 5-HT3-
and 5-HT4-receptor antagonists on the emesis induced by the high-dose
of cisplatin in Suncus murinus. The emesis induced by 50 mg/kg of
cisplatin was reduced by the oral pretreatment with tropisetron, which is
known as a 5-HT3- and 5-HT4-receptor dual antagonist
in vitro, with the ID50 value of 0.52 mg/kg. On the contrary,
granisetron, a selective 5-HT3-receptor antagonist, did not markedly
inhibit the emesis at up to 30 mg/kg. Moreover, GR125487, a selective 5-HT4-receptor
antagonist, did not inhibit the emesis. However, co-administration of GR125487
and granisetron significantly reduced the number of emetic episodes. The
study of the co-administration of GR125487 with tropisetron showed that
GR125487 did not further enhance the inhibitory effect of tropisetron alone,
suggesting that the anti-emetic effect of tropisetron is mediated via the
blockade of both 5-HT3 and 5-HT4 receptors. These
results suggest that both the 5-HT3 and 5-HT4 receptors
are involved in the emesis induced by the high-dose of cisplatin in Suncus
murinus.
Keywords: Emesis, Cisplatin, 5-HT3 receptor, 5-HT4
receptor, Suncus murinus
Copyright The Japanese Pharmacological Society
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