The effects of nabumetone, a cyclooxygenase-2 inhibitor, on cisplatin-induced 5-hydroxytryptamine release from the isolated rat ileum.
In order to elucidate 5-HT release influenced by PGE2 in the background of the anticancer drug-induced emesis, the effect of nabumetone, a COX-2 inhibitor, on the release of 5-HT from the isolated rat ileum was investigated. PGE2 produced a concentration-dependent increase (10(-9) to 10 M) and decrease (10(-8) to 10(-6) M) in 5-HT release. Arachidonic acid also demonstrated a similar bell-shaped 5-HT release. The arachidonic acid-induced 5-HT release at 3 x 10(-6) M (313.04 +/- 25.90%) was significantly inhibited by the concomitant perfusion with BRL10720 (10(-6) M) (161.98 +/- 19.4%, p<0.01), an active metabolite of nabumetone, or indomethacin (3 x 10(-7) M)(190.01 +/- 16.19%, p<0.05). BRL10720 (10(-6) M)(428.57 +/- 51.72%, p<0.05) significantly inhibited the increase in 5-HT release induced by cisplatin (10(-6) M)(748.56 +/- 136.31%), suggesting that PGE2would be involved in cisplatin-induced 5-HT release. The increase in 5-HT release from the isolated ileum 72 hrs after cisplatin administration, in a delayed-emesis animal model, was significantly inhibited by the in vivo 3-day administration of nabumetone or BRL10720, but was not affected by the 3-day administration of dexamethasone. After 72 hours, however, the in vivo 3-days administration of nabumetone, BRL10720 or dexamethasone had no effect on the increase in ileal 5-HT levels induced by cisplatin. The use of COX-2 inhibitors to ameliorate delayed emesis induced by cisplatin-based anticancer chemotherapy has been proposed. On the other hand, there is a possibility that dexamethasone works through a mechanism other than 5-HT release in delayed emesis.
Kudo
C
C
Department of Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Japan.
Minami
M
M
Hirafuji
M
M
Endo
T
T
Hamaue
N
N
Akita
K
K
Murakami
T
T
Kawaguchi
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D002074:Butanones / Q000494:pharmacology*; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology; D015232:Dinoprostone / Q000502:physiology; D004347:Drug Interactions; D007082:Ileum / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D000077430:Nabumetone; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control
D000970:Antineoplastic Agents; D002074:Butanones; D012701:Serotonin; D003907:Dexamethasone; D015232:Dinoprostone; D000077430:Nabumetone; D002945:Cisplatin