Effects of OPC-21268, an orally effective vasopressin V₁ receptor antagonist in humans

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<0.01). Intra-arterial infusion of phenylephrine at doses of 0.2, 0.4, and 2.4 μg/min increased forearm vascular resistance dose-dependently (p<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<0.02) and 0.09 (p<0.05) ng/kg/min and augmented vasodilator responses to arginine vasopressin at a dose of 1.2 ng/kg/min (p<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.