Vasopressin V1a and V1b receptor antagonism does not affect the efficacy of tolvaptan in Polycystic Kidney Disease.

Abstract

Vasopressin plays a major role in the pathogenesis of autosomal dominant polycystic kidney disease (PKD), the fourth leading cause of end-stage kidney disease. The vasopressin V2 receptor (V2R) antagonist tolvaptan is the only approved treatment. The role of vasopressin V1a and V1b receptors (V1aR, V1bR) has not been studied. Pkd1^RC/RC mice were allocated to control, and 5 experimental groups treated with tolvaptan, OPC21268 (V1aR antagonist), SSR149415 (V1bR antagonist), tolvaptan plus OPC21268 or tolvaptan plus SSR149415, from 4 to 16 weeks of age, to compare their separate effects on PKD and to determine whether addition of OPC21268 or SSR149415 potentiates or hinders the therapeutic effect of tolvaptan. Tolvaptan significantly reduced total kidney volume (TKV) measured by MRI and rate of TKV growth. OPC21268 had no effect on PKD when administered alone. SSR149415 reduced TKV and TKV growth in female mice only. The sex dependent effect may be due to the increased expression of the V2 and V1b receptors in the kidneys of female compared to male Pkd1^RC/RC mice. When OPC21268 or SSR149415 were administered in combination with tolvaptan, TKV, TKV growth, kidney weights, kidney weights adjusted by body weight, cyst indices and volumes, and plasma urea concentrations were not different from those observed with administration of tolvaptan alone. These results indicate that the beneficial effects of tolvaptan in PKD are mainly mediated by the inhibition of V2 receptors and provide no support for clinical trials of V2R antagonists combined with either V1a or V1b receptor antagonists.