Blood Pressure-Lowering Effect of an Orally Active Vasopressin VI 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 nonpeptide orally effective vasopressin VI receptor antagonist OPC-21268. Binding kinetic studies demonstrated that oral OPC-21268 (30 mg/kg) acted as a competitive antagonist at the vasopressin VI receptor in DOCA-salt and salt control rats. Basal mean intra-arterial blood pressure was 140±4 mmHg (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 Several lines of evidence support a role for arginine vasopressin (AVP) in the development and maintenance of high blood pressure (BP) in the deoxycorticosterone acetate (DOCA)-salt model of hypertension in the rat. Studies in the Brattleboro rat, which is homozygous for hypothalamic diabetes insipidus and unable to synthesize functional AVP, provide indirect evidence for a role of AVP in the pathogenesis of DOCA-salt hypertension. These rats failed to develop hypertension when treated with DOCA and salt unless also treated with exogenous AVP or desaminoD-arginine-8-vasopressin (dDAVP), a V2 agonist with minimal pressor and increased antidiuretic activity. A direct vasopressor role for AVP in the maintenance of hypertension in the DOCA-salt hypertension model is suggested by the finding of elevated plasma AVP levels and a fall in BP with intravenous administration of AVP antiserum or VI receptor antagonist.However, other investigators failed to demonstrate a reduction in BP with acute VI receptor blockade or showed a reduction in BP with acute V2 or acute or chronic V1-V2 receptor antagonism in DOCA-salt hypertension. Thus, the pressor roles of AVP and/or the VI and V2 AVP receptors in both the pathogenesis and maintenance of hypertension in DOCA-salt hypertension in the rat remain unclear. Received August 9,1993; accepted in revised form February 23, 1994. From the University of Melbourne (Australia), Austin Hospital. Correspondence to Dr Louise M. Burrell, University of Melbourne, Austin Hospital, Studley Rd, Heidelberg 3084, Victoria, Australia. 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±l 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 VI 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. (Hypertension. 1994^3 [part l]:737-743.)