A nonpeptide vasopressin V_1a receptor antagonist, SR 49059, does not prevent cisplatin‐induced emesis in piglets

Abstract

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, [3H]-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 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 microg and 1500 microg/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.

The role of electrogastrography and gastrointestinal hormones in chemotherapy-related dyspeptic symptoms

“…21,22 Vasopressin and somatostatin are also involved in the onset of emesis, but their roles are not completely understood. 23,24 All these peptides have also been implicated in the pathophysiology of dyspepsia, and their circulating levels have been associated with impaired GI motility, as expressed by delayed gastric emptying time and gastric electrical activity alterations. 25 Because the role of chemotherapy in the onset of GI motility disorders, in addition to minor GI complaints, has not been clarified yet, we sought to investigate the relationship among the development of dyspepsia, EGG abnormalities (as indices of motility disorders), and circulating levels of GI hormones such as substance P, serotonin, vasopressin, and gastrin in cancer patients well-controlled for emesis.…”