Effects of novel, nonpeptide vasopressin antagonists on progressive nephrosclerosis in rats.

Effects of novel, nonpeptide vasopressin V1 and V2 receptor antagonists on partially nephrectomized and salt-loaded spontaneously hypertensive rats (SHR), which develop severe hypertension and progressive nephrosclerosis, were investigated. SHR were 5/6-nephrectomized and fed a high salt diet. The rats were divided into four groups: group 1 was an untreated control, group 2 received the V1 antagonist OPC-21268, group 3 received the V2 antagonist OPC-31260, and group 4 received both the V1 and V2 antagonists. The V1 antagonist alone or combined with the V2 antagonist significantly decreased the increase in blood pressure (BP) of groups 2 and 4 rats, but the V2 antagonist alone did not reduce the increase in BP of the group 3 rats. The V2 antagonist alone or combined with the V1 antagonist induced a significant diuresis of rats in groups 3 and 4. The increase in urinary protein excretion and the progression of renal hyaline arteriolosclerosis were attenuated by the V1 antagonist with or without the V2 antagonist in rats in groups 2 and 4, but not by the V2 antagonist alone in rats in group 3. This implies that the progressive nephrosclerosis in SHR with partial renoablation and salt-loading was associated with V1 agonism.