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 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)
Burrell
L M
LM
University of Melbourne, Austin Hospital, Heidelberg, Victoria, Australia.
Phillips
P A
PA
Stephenson
J M
JM
Risvanis
J
J
Rolls
K A
KA
Johnston
C I
CI
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
D065092:Antidiuretic Hormone Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C068644:OPC 21268; D003900:Desoxycorticosterone; D012965:Sodium Chloride