Premium
A nonpeptide vasopressin V 1a receptor antagonist, SR 49059, does not prevent cisplatin‐induced emesis in piglets
Author(s) -
Grélot Laurent,
Girod Vincent,
Dapzol Julien,
Maffrand Jean Pierre,
SerradeilLe Gal Claudine
Publication year - 2001
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1046/j.1472-8206.2001.00027.x
Subject(s) - antagonist , in vivo , antiemetic , cisplatin , pharmacology , receptor antagonist , chemistry , vasopressin , receptor , endocrinology , medicine , vomiting , biology , chemotherapy , biochemistry , microbiology and biotechnology
We determined the pharmacological and the antiemetic properties of SR 49059, a selective nonpeptide V 1a receptor antagonist, on cisplatin‐induced emesis 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 studies, [ 3 H]‐SR 49059 exhibited high affinity for V 1a receptors in piglet liver membranes ( K d of 0.76 ± 0.12 n M and B max of 138 ± 22 fmol/mg prot.). In vivo, in decerebrate piglets, SR 49059 (1 mg/kg iv) antagonized AVP (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 LVP. After single and repeated iv or icv administration, we studied the antiemetic properties of SR 49059 on cisplatin‐induced emesis in piglets. Animals receiving an emetic dose of cisplatin (5.5 mg/kg, iv) were observed continuously for 60 h. Piglets acting as controls were iv administered with vehicle 15 min prior to cisplatin infusion (T0 –15min ), while experimental animals 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 49059 (500 μg and 1500 μg/side) 1 h prior to cisplatin infusion. In all groups treated with SR 49059, the latency of the first emetic episode and the incidence of vomiting during the acute, the delayed and the cumulative phases 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.