15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Vomiting

U46619 is a potent thromboxane A(2) mimetic with emesis-inducing actions that are mediated via prostanoid TP receptors. We investigated its emetic mechanism of action in more detail using the ferret as model animal. The emesis induced by U46619 (30 microg/kg, intraperitoneal) was antagonized significantly by (+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine hydrochloride (CP-99,994; 1 and 10 mg/kg; P < 0.05) and metoclopramide (0.3 and 3 mg/kg), but not by domperidone (3 mg/kg), sulpiride (0.1 mg/kg), ondansetron (0.1 and 1 mg/kg) alone or combined with droperidol (3 mg/kg), GR125487 (1 mg/kg), promethazine (3 mg/kg), or scopolamine (3 mg/kg); GR 125487 (1 mg/kg) prevented the anti-emetic action of metoclopramide (3 mg/kg). U46619 0.3 microg administered into the fourth ventricle rapidly induced emesis. However, bilateral abdominal vagotomy was ineffective in reducing the emetic response (P > 0.05). Our data suggests that U46619 induces emesis via an extra-abdominal mechanism, probably within the brain. Metoclopramide probably has a mechanism of action to prevent U46619-induced emesis via 5-HT(4) receptor activation and NK(1) tachykinin receptor antagonists could be useful to prevent emesis induced by TP receptor activation in man.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antiemetics; Disease Models, Animal; Ferrets; Metoclopramide; Piperidines; Receptors, Thromboxane; Vagotomy; Vomiting

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 microg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E(2), 17-phenyl-omega-trinor prostaglandin E(2), misoprostol and sulprostone), FP (prostaglandin F(2alpha) and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 microg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biphenyl Compounds; Copper Sulfate; Dose-Response Relationship, Drug; Female; Heptanoic Acids; Hydantoins; Injections, Intraperitoneal; Injections, Subcutaneous; Intubation, Gastrointestinal; Male; Nausea; Nicotine; Prostaglandins; Prostaglandins F, Synthetic; Reaction Time; Receptors, Thromboxane; Shrews; Time Factors; Vomiting

The emetic action of the prostanoid TP receptor agonist, 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619; 300 microg/kg, i.p.), was investigated in Suncus murinus. The emetic response was reduced by 76% following bilateral abdominal vagotomy (P<0.001) and by reserpine (5 mg/kg, i.p., 24 h pretreatment; P<0.05) but U46619 administered i.c.v. (30-300 ng) was not emetic, suggesting a peripheral mechanism involving monoamines. However, fenfluramine (5 mg/kg, repeated treatment) and para-chlorophenylalanine (100-400 mg/kg) and ondansetron (0.3-3 mg/kg) were inactive (P>0.05) to reduce U46619-induced emesis precluding a role of 5-HT and 5-HT(3) receptors in the mechanism. Similarly, phentolamine (0.3-3 mg/kg), propranolol (3 mg/kg), and their combination, and metoclopramide (0.3-3 mg/kg), domperidone (0.3-3 mg/kg), droperidol (0.3-3 mg/kg), scopolamine (0.3-3 mg/kg) and promethazine (0.3-3 mg/kg) were inactive (P>0.05) to reduce the retching and vomiting response. However, the tachykinin NK(1) receptor antagonist, (+)-2S,3S(-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpiperidine) (CP-122,721; 1-10 mg/kg) antagonized emesis (P<0.01). In conclusion, U46619-induced emesis appears to be mediated via a predominant peripheral mechanism sensitive to reserpine and is not likely to involve adrenoceptors, dopamine, 5-HT(3), muscarinic or histamine (H(1)) receptors. The action of CP-122,721 to reduce U46619-induced emesis extends the spectrum of anti-emetic action tachykinin NK(1) receptor antagonists to mechanisms involving TP receptors.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Emetics; Female; Male; Piperidines; Receptors, Thromboxane; Shrews; Vagotomy; Vagus Nerve; Vomiting