title: Effects of OPC-21268, an orally effective vasopressin V1 receptor antagonist in humans.
abstract: An orally effective, nonpeptide vasopressin V1 receptor antagonist, OPC-21268 was produced for possible human use. We investigated the effects of OPC-21268 on the vascular effects of intra-arterially infused arginine vasopressin in human forearm vessels. The brachial artery was cannulated for drug infusions and direct measurement of arterial pressure. Forearm blood flow was measured by a strain gauge plethysmograph, and forearm vascular resistance was calculated. Arginine vasopressin was infused intra-arterially at doses of 0.02, 0.06, 0.09, 0.2, 0.6, and 1.2 ng/kg/min. The lower doses of arginine vasopressin increased, whereas the higher doses of arginine vasopressin decreased forearm vascular resistance (p less than 0.01). Intra-arterial infusion of phenylephrine at doses of 0.2, 0.4, and 2.4 micrograms/min increased forearm vascular resistance dose-dependently (p less than 0.01). OPC-21268 (50 mg for two, 100 mg for six, and 200 mg for two subjects) given orally did not alter resting arterial pressure, forearm vascular resistance, or heart rate. OPC-21268 decreased vasoconstrictor responses to arginine vasopressin at doses of 0.02 (p less than 0.02) and 0.09 (p less than 0.05) ng/kg/min and augmented vasodilator responses to arginine vasopressin at a dose of 1.2 ng/kg/min (p less than 0.01). However, the vasoconstrictor responses to phenylephrine were not altered by OPC-21268. These results demonstrated that OPC-21268 effectively and specifically antagonized the V1 receptor-mediated vasoconstriction in human forearm resistance vessels. These results suggest that OPC-21268 may be useful therapeutically to antagonize the vasoconstriction caused by arginine vasopressin in some pathological states.
authors.affiliation: Research Institute of Angiocardiology, Faculty of Medicine, Kyushu University, Fukuoka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Imaizumi
authors.forename: S
authors.initials: S
authors.lastname: Harada
authors.forename: Y
authors.initials: Y
authors.lastname: Hirooka
authors.forename: H
authors.initials: H
authors.lastname: Masaki
authors.forename: M
authors.initials: M
authors.lastname: Momohara
authors.forename: A
authors.initials: A
authors.lastname: Takeshita
mesh_terms: D000284:Administration, Oral; D000328:Adult; D057911:Angiotensin Receptor Antagonists; D001127:Arginine Vasopressin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007269:Injections, Intra-Arterial; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology*; D015363:Quinolones / Q000009:adverse effects / Q000494:pharmacology*; D017483:Receptors, Vasopressin; D012039:Regional Blood Flow; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D057911:Angiotensin Receptor Antagonists; D010880:Piperidines; D015363:Quinolones; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; C068644:OPC 21268; D010656:Phenylephrine