title: Blood pressure-lowering effect of an orally active vasopressin V1 receptor antagonist in mineralocorticoid hypertension in the rat.
abstract: 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)
authors.affiliation: University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Burrell
authors.forename: P A
authors.initials: PA
authors.lastname: Phillips
authors.forename: J M
authors.initials: JM
authors.lastname: Stephenson
authors.forename: J
authors.initials: J
authors.lastname: Risvanis
authors.forename: K A
authors.initials: KA
authors.lastname: Rolls
authors.forename: C I
authors.initials: CI
authors.lastname: Johnston
mesh_terms: D000284:Administration, Oral; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001127:Arginine Vasopressin / Q000378:metabolism; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects*; D003900:Desoxycorticosterone; D005260:Female; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007700:Kinetics; D008638:Mesenteric Arteries / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017483:Receptors, Vasopressin / Q000145:classification; D012965:Sodium Chloride; D013599:Systole; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C068644:OPC 21268; D003900:Desoxycorticosterone; D012965:Sodium Chloride