In vivo and in vitro characterisation of a nonpeptide vasopressin V1A and V2 receptor antagonist (YM087) in the rat

This paper reports the in vitro and in vivo characterisation of a nonpeptide, orally active, vasopressin V-1A and V-2 receptor antagonist, YM087 (methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilde monohydrochloride) in the rat. YM087 dose dependently displaced the vasopressin VIA receptor antagonist radioligand, I-125-labelled [d(CH2)(5),sarcosine(7)]vasopressin at vasopressin V-1A receptors in liver and kidney medulla membranes and caused a concentration dependent displacement of the vasopressin V-2 receptor antagonist radioligand [H-3]desGly-NH29[d(CH2)(5), D-Ile(2), Ile(4)] vasopressin at vasopressin V-2 receptors in kidney medulla membranes. In vitro binding kinetic studies showed YM087 acted as a competitive antagonist at liver V-1A and kidney V-1A and V-2 vasopressin receptors. Oral administration of YM087 (0.1-3 mg/kg) dose dependently inhibited vasopressin binding to liver V-1A and kidney V-1A and V-2 vasopressin receptors over 24 h. Oral YM087 (1-3 mg/kg/day) for 7 days in normotensive rats caused a dose dependent aquaresis with no effect on systolic blood pressure. These results show that YM087 is an orally effective vasopressin V-1A and V-2 receptor antagonist that may be useful in the treatment of conditions characterised by vasoconstriction and fluid retention such as congestive heart failure. (C) 1999 Elsevier Science B.V. All rights reserved.