Blood pressure-lowering effect of an orally active vasopressin V1 receptor antagonist in mineralocorticoid hypertension in the rat

We studied the contribution of vasopressin to the maintenance of high blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertension in the rat using the non-peptide orally effective vasopressin V1 receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the vasopressin V1 receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140±4 mm Hg (n=12) in DOCA-salt rats compared with 111±2 mm Hg in salt control rats (n=18). Acute oral OPC-21268 (30 mg/kg) significantly (P<.01) reduced mean intra-arterial pressure in DOCA-salt hypertension, with an average maximal decrease of 24±3 mm Hg occurring at 2.5±0.7 hours after dosing. Systolic blood pressure (tail-cuff) in DOCA-salt rats was 178±2 mm Hg. Chronic oral OPC-21268 (30 mg/kg) twice daily for 7 days significantly (P<.01) reduced systolic blood pressure in DOCA-salt hypertension, with an average maximal decrease of 27±5 mm Hg. The antihypertensive effect was reversed 5 days after treatment with OPC-21268 was stopped. In water control rats basal systolic pressure (120±1 mm Hg, n=20) was unchanged by chronic oral OPC-21268 (30 mg/kg twice daily for 7 days), and this was confirmed by direct measurement of mean intra-arterial pressure. After chronic oral OPC- 21268 (30 mg/kg twice daily for 7 days) hepatic V1 receptor binding was significantly reduced for up to 10 hours (P<.05). The results of this study suggest that vasopressin does not play a major role in the regulation of normal blood pressure in the rat but support a role for vasopressin in the maintenance of mineralocorticoid hypertension in the rat. OPC-21268 may be of use in the treatment of hypertensive conditions associated with elevated vasopressin concentrations.