Studies on the Inhibitory Mechanisms of Serotonin Type 3 Receptor Antagonists for Nausea and Vomitting Caused by Anti-cancer Chemotherapy Drugs

5-羟色胺3型受体拮抗剂抑制抗癌化疗药物引起的恶心、呕吐的机制研究

• 批准号: 02557100
• 负责人: ITOH Zen
• 金额: $ 3.39万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-02557100/
• 关键词: 5-Hydroxytryptamine (5HT); Serotonin type 3 receptor (5HT_3 receptor); 5HT_3 antagonist; Interdigestive migrating contraction (IMC)

Nausea and vomiting are common side effects of anti-cancer chemotherapeutic drugs. Cisplatin (cis-dichloro-diammineplutinum II), an agent highly effective against a variety of cancers (including testicular, ovarian, urinary-bladder, and head and neck cancers), produces the most severe nausea and emesis of any chemotherapeutic agent Cisplatin is known to cause severe damage on the gastrointestinal tract, along which a highly abandunt population of enterochromaffin (EC) cells containing serotonin (5-Hydroxytryptamine, 5HT) are located. 5HT released from EC cells appears to stimulate its receptors on the afferent nerve endings of Vagus that transmits the stimulus caused by 5HT to the area postrema (AP) of the medulla oblongata. The AP is thought to act as a chemoreceptor trigger zone for nausea and emesis. The stimulus triggered by the AP travels through the efferent nerve of Vagus to cause vomiting reflex in the gastrointestinal tract. Recently investigations performed in laboratory anim … More als have revealed that selective antagonists of serotonin S3 (5HT_3) receptors prevent the vomiting induced by cisplatin. However the effect of 5HT_3 antagonist to prevent vomiting reaction in the gastrointestinal tract is unclear. Thus we utilized dogs implanted with force transducers onto the serosa of the gastrointestinal tract in a direction to measure circular muscle contraction, and observed the effect of a series of 5HT_3 antagonists including ICS205-930, BRL43694 and GR38032F. The appearance of phase III interdigestive migrating contractions (IMC) in the gastrointestinal tract is thought to be caused by rhythmicoscillations of circulating motilin levels with peaks occuring every 90-120 min. Infusion of 5HT_3 antagonists prevented the appearance of IMC in the stomach, but not that of IMC in the intestine. However, the disappearance of IMC by 5HT_3 antagonists was not observed in the denervated stomach, indicating that 5HT_3 antagonists prevent the transmission of 5HT stimulus through the afferent nerve of Vagus. Less

恶心和呕吐是抗癌化疗药物的常见副作用。顺铂（cis-dichloro-diammineputinum II），一种对多种癌症非常有效的药物顺铂（包括睾丸癌、卵巢癌、膀胱癌和头颈癌）产生任何化疗剂中最严重的恶心和呕吐。已知顺铂对胃肠道造成严重损害，沿着胃肠道中含有5-羟色胺的肠嗜铬（EC）细胞的高度废弃群体（5-羟色胺，5 HT）。从EC细胞释放的5 HT似乎刺激迷走神经传入末梢上的5 HT受体，迷走神经将5 HT引起的刺激传递到延髓最后区（AP）。AP被认为是恶心和呕吐的化学感受器触发区。由AP触发的刺激通过迷走神经传出神经在胃肠道中引起呕吐反射。最近在实验室动物中进行的研究 ...更多信息 5-羟色胺S_3（5HT_3）受体的选择性拮抗剂可预防顺铂引起的呕吐。但5HT_3拮抗剂对胃肠道呕吐反应的预防作用尚不清楚。因此，我们利用在狗胃肠道浆膜上植入力传感器的方法，以测量环肌收缩，并观察了一系列5 HT_3拮抗剂包括ICS_（205 -930）、BRL_（43694）和GR_（38032）F的作用。胃肠道III相消化间期移行性收缩（IMC）的出现被认为是由胃动素水平的节律性振荡引起的，其峰值每90-120分钟出现一次。在失神经支配的胃中，5-HT受体拮抗剂对IMC的抑制作用不明显，提示5-HT受体拮抗剂可阻断5-HT刺激通过迷走神经传入的传递。少

项目成果

林直 樹,水本 明良,伊藤 漸,: "胃酸分泌抑制による空腹期胃収縮運動正常化" 日本消化器病学会雑誌88, 8 (1991)

Naoki Hayashi、Akira Mizumoto、Susumu Ito：“通过抑制胃酸分泌使禁食期间胃收缩正常化”日本胃肠病学会杂志 88, 8 (1991)

Z.Itoh,A.Mizumoto,Y.Iwanaga,N.Yoshida,K.Torii,K.Wakabyashi: "Involvement of 5ーHydroxytryptamine 3 Receptors in Regulation of Interdigestive Gastric Contractions by Motilin in the Dog" Gastroenterology. (1991)

Z.Itoh、A.Mizumoto、Y.Iwanaga、N.Yoshida、K.Torii、K.Wakabyashi：“5-羟色胺 3 受体参与胃动素调节狗消化间期胃收缩”胃肠病学。

水本 明良,大多和 正浩,近藤 洋一,伊藤 漸,大村 智: "Motilin Agonist,EM523の消化管運動に及ぼす作用" 日本外科学会雑誌92, 9 (1991)

Akira Mizumoto、Masahiro Otawa、Yoichi Kondo、Susumu Ito、Satoshi Omura：“胃动素激动剂 EM523 对胃肠道运动的影响” 日本外科学会杂志 92, 9 (1991)

Yoshida N., Mizumoto A., Iwanaga Y., Itoh Z.: "Effect of 5-hydroxytriptamine 3 receptor antagonists on gastrointestinal motor activity in conscious dogs." J Pharmacol Exp Ther. 256. 272-278 (1991)

Yoshida N.、Mizumoto A.、Iwanaga Y.、Itoh Z.：“5-羟基三胺 3 受体拮抗剂对清醒狗胃肠道运动活动的影响。”

Shibata C, Sasaki I, Matsuno S, Mizumoto A, Itoh Z.: "Colonic motility in innervated and extrinsically denervated loops in dogs." Gastroenterol. 101. 1571-1578 (1991)

Shibata C、Sasaki I、Matsuno S、Mizumoto A、Itoh Z.：“狗的神经支配和外在去神经环中的结肠运动。”