Effects of granisetron, a 5-HT3 receptor antagonist, on 5-hydroxytryptamine (5-HT) release from the isolated ileum in a delayed-emesis rat model.
We examined the effects of granisetron, a 5-HT3-receptor antagonist, on the release of serotonin (5-hydroxytryptamine, 5-HT) from the isolated ileum and on histopathological changes of the intestine in a delayed-emesis rat model. The rats were studied 72 hours after receiving an intraperitoneal (i.p.) dose of cisplatin (5 mg/kg). The 5-HT content in the isolated ileum 72 hours after administration was significantly higher in the cisplatin group (26.0 +/- 3.0 ng/mg protein, p < 0.001) than in the non-drug control group (9.6 +/- 0.6 ng/mg protein). The increase in 5-HT content in the cisplatin group was significantly inhibited in rats pretreated with granisetron (17.5 +/- 2.2 ng/mg protein, p < 0.05). The release of 5-HT from the isolated ileum was significantly greater in the cisplatin group (11,963.0 +/- 2,104.6 ng x hr/g tissue, p < 0.01) than in the non-drug control group (2,861.0 +/- 210.7 ng x hr/g tissue). The increased 5-HT release from the isolated ileum in the cisplatin group was significantly inhibited in rats pretreated with granisetron (3,359.8 +/- 494.3 ng x hr/g tissue, p < 0.01). Disarrangement of intestinal villi, luminal dilatation of crypts and decreased numbers of goblet cells were observed in the cisplatin group. The group pretreated with granisetron showed mild macroscopic and histopathological changes, but no significant weight loss. The histopathological changes of the intestinal mucosa were apparently associated with the release of 5-HT. Our results suggest that 5-HT release from the enterochromaffin cells, accompanied by histopathological changes of the intestinal mucosa, is involved in the onset of delayed emesis after administration of cisplatin. These findings suggest that treatment with granisetron before the administration of anticancer drugs may prevent delayed emesis and intestinal disturbances associated with anticancer drugs.
Endo
Toru
T
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu 061-0293, Japan.
Hamaue
Naoya
N
Ihira
Emi
E
Teramoto
Yumi
Y
Liu
Yanxia
Y
Hirafuji
Masahiko
M
Minami
Masaru
M
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects; D004195:Disease Models, Animal; D017829:Granisetron / Q000494:pharmacology*; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced / Q000378:metabolism*
D000970:Antineoplastic Agents; D002945:Cisplatin; D017829:Granisetron; D012701:Serotonin; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists