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 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).(ABSTRACT TRUNCATED AT 250 WORDS)