OPC-21268 competitively and specifically antagonizes pressor responses to AVP in vivo. Oral administration of OPC-21268 (10 mg/kg) inhibits the vasoconstriction induced by exogenous AVP in a dose- and time-dependent manner and the effect lasts for more than 8 hours at 30 mg/kg[1]. OPC-21268 predominantly exerts a protective effect in areas where the maximum amount of blood-brain barrier breakdown occurs, and it is effective in the treatment of cold-induced vasogenic brain edema. OPC-21268 treatment at the dosages of 200 and 300 mg/kg significantly reduces brain water content in both hemispheres. Swelling of the traumatized hemispheres is also significantly reduced at 200 and 300 mg/kg dosages[2].
In Vitro
The concentration of OPC-21268 that displaces 50% of specific AVP binding (IC50) is 0.4 μM for VI receptors and 100 μM for V2 receptors. The inhibition constant (Ki) of OPC-21268 for V1 receptors (0.14 μM)[1].
Kinase Assay
Liver and kidney plasma membranes are prepared from Sprague-Dawley rats of 300 to 400 g. Various concentrations of AVP and OPC-21268 are incubated with 50 μg of liver membranes or 600 μg of kidney membranes in 0.25 ml of tris buffer (100 mM, pH 8.0) containing 5 mM MgCI2, 1 mM EDTA, 0.1% bovine serum albumin, and 1.9 nM [3H]AVP (53.6 Ci/mmol) in the liver or 3.8 nM [3H]AVP in the kidney. After incubation for 10 min at 37°C (liver membranes) or 4 hours at 4°C (kidney membranes), 3 mL of ice-cold Tris buffer (100 mM, pH 8.0) is added to each assay tube, and bound and free ligands are separated by filtration through a glass microfiber filter and then washed three times. Specific binding is determined by subtraction of the nonspecific binding, which is measured in the presence of 1 μM unlabeled AVP[1].
Cell Assay
Animal Administration
Rats[1] Male Sprague-Dawley rats, 300 to 400 g, are injected with OPC-21268 (0.1, 0.3, 1 mg/kg). OPC-21268 is given 2 min before the injection of AVP at 30 mU/kg i.v., angiotensin II at 0.3 μg/kg i.v., and noradrenaline at 3 μg/kg i.v.[1].
References
[1]. Yamamura Y, et al. OPC-21268, an orally effective, nonpeptide vasopressin V1 receptor antagonist. Science. 1991 Apr 26;252(5005):572-4.
[2]. Bemana I, et al. Treatment of brain edema with a nonpeptide arginine vasopressin V1 receptor antagonist OPC-21268 in rats. Neurosurgery. 1999 Jan;44(1):148-54.
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