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Abstract. We investigated the effect of FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-1H-imidazol-4-yl)methyl]pyrido[1,2-a]indol-6(7H)-one hydrochloride], a 5-HT 3 -and 5-HT 4 -receptor antagonist, on the emesis induced by motion stimuli, copper sulfate, or cisplatin in either Suncus murinus or ferrets and also clarified the role of the 5-HT 3 and 5-HT 4 receptors in these models. In Suncus murinus, oral administration of FK1052 (100 µg / kg) completely prevented emesis induced by cisplatin (18 mg / kg, i.p.). Intraperitoneal injection of scopolamine (10 mg / kg) and promethazine (32 mg / kg), but not FK1052 (1 mg / kg), significantly reduced the emetic responses by motion stimuli. In ferrets, copper sulfate (40 mg / kg, p.o.)-induced emesis was moderately prevented by FK1052 (3.2 mg / kg), but not by granisetron (3.2 mg / kg). Cisplatin-induced acute (10 mg / kg, i.v.) and delayed (5 mg / kg, i.p.) emesis were significantly reduced by single and multiple intravenous injection of both FK1052 (3.2 mg / kg) and granisetron (3.2 mg / kg), respectively. The present study suggests that FK1052 may be useful against both acute and delayed emesis induced by cancer chemotherapy. Moreover, it is suggested that blockades of 5-HT 3 and 5-HT 4 receptors are not relevant to the control of motion sickness; and furthermore, it suggested that blocking 5-HT 4 receptors in addition to 5-HT 3 receptors does not have an additional effect on the control of cisplatin-induced emesis, but that 5-HT 4 receptors are at least partly involved in the mechanism of emesis induced by copper sulfate.

Abstract. We evaluated the antiemetic effect of zacopride, a potent 5-HT 3 -receptor antagonist with 5-HT 4 -receptor agonist properties, on delayed emesis caused by cisplatin (5 mg / kg, i.p.) in ferrets, compared with granisetron, a selective 5-HT 3 -receptor antagonist. Multiple intravenous injections of zacopride at 1 mg / kg, a dose that completely inhibited acute emesis caused by cisplatin (10 mg / kg, i.v.), significantly reduced delayed emesis. Granisetron (3.2 mg / kg) also reduced delayed emesis but this failed to reach statistical significance. The present study suggests that a combined 5-HT 3 -receptor antagonist / 5-HT 4 -receptor agonist, like zacopride, may be useful against both acute and delayed emesis induced by cancer chemotherapy.

Abstract. Previous studies showed that diphenidol was effective on emetogens-induced pica, eating of non-nutritive substances, in rats, a model analogous to emesis in other species. We evaluated the actual antiemetic activity of diphenidol against four emetic stimuli in the dog and ferret, animals that possess an emetic reflex. In dogs, emetic responses to apomorphine were significantly prevented by diphenidol (3.2 mg / kg, i.v.), whereas diphenidol (3.2 mg / kg, i.v.´2) showed a weak inhibition to the vomiting evoked by cisplatin. In ferrets, diphenidol (10 mg / kg, i.p.) exhibited a weak antiemetic activity on the emesis induced by copper sulfate and had no activity on emesis by loperamide. On the other hand, CP-122,721, a NK 1 -receptor antagonist, significantly reduced the emetic episodes to all four stimuli. These results suggest that the prediction of antiemetic activity of compounds in animals lacking an emetic reflex does not always correspond with actual antiemetic activity.

These results suggest that a selective EP2 receptor agonist could ameliorate the elevation of RV and improve the reduction of VE in rats with functional urethral obstruction caused by stimulation of α1 -adrenoceptors. The mechanism of action might be not potentiation of bladder contraction but rather preferential relief of urethral constriction.