A nonpeptide vasopressin V-1a receptor antagonist, SR 49059, does not prevent cisplatin-induced emesis in piglets

We determined the pharmacological and the antiemetic properties of SR 49059 , a selective nonpeptide Via receptor antagonist, on cisplatin-induced emes is in the piglet. Firstly, we clearly demonstrate that SR 49059 is a potent V-1a receptor antagonist in vitro and in vivo in the piglet. In binding st udies, [H-3]-SR 49059 exhibited high affinity for V-1a receptors in piglet liver membranes (K-d Of 0.76 +/- 0.12 nM and B-max of 138 +/- 22 fmol/mg pr ot.). In vivo, in decerebrate piglets, SR 49059 (1 mg/kg iv) antagonized AV P (500 ng/kg iv)-induced hypertension for at least 150 min and also blocked , for at least 270 min at 3 mg/kg iv, the pressor responses to exogenous LV P. After single and repeated iv or icv administration, we studied the antie metic properties of SR 49059 on cisplatin-induced emesis in piglets. Animal s receiving an emetic dose of cisplatin (5.5 mg/kg, iv) were observed conti nuously for 60 h. Piglets acting as controls were iv administered with vehi cle 15 min prior to cisplatin infusion (T0(-15min)), while experimental ani mals received a single iv administration of SR 49059 at the dose of 1 or 3 mg/kg. In additional piglets, we administered SR 49059 (3 mg/kg) every 12 h from T0(-15min) to T48(-15min) (cumulative dose, 15 mg/kg). Another set of animals - observed only during the acute phase - was administered with SR 49059 (10 mg/kg) every 3 h from T0(-15min) to T15(-15min) (cumulative dose, 60 mg/kg). Lastly, 10 piglets were given a bilateral icv injection of SR 4 9059 (500 tg and 1500 mug/side) 1 h prior to cisplatin infusion. In all gro ups treated with SR 49059, the latency of the first emetic episode and the incidence of vomiting during the acute, the delayed and the cumulative phas es remained statistically similar to that observed in controls, suggesting that V-1a receptors are not involved in the onset and completion of nausea and vomiting.