Pharmacological profile of orally administered YM087, a vasopressin antagonist, in conscious rats

1. YM087 is a newly synthesized non-peptide arginine vasopressin (AVP) antagonist that shows high affinity for both V(1A) and V₂ receptors. In the present study, the V(1A) and V₂ receptor antagonist effects of orally administered YM087 were assessed in conscious rats. 2. In conscious rats, orally administered YM087 (0.1, 0.3 and 1.0 mg/kg) did not affect basal blood pressure, but YM087 dose-dependently inhibited 30 mU/kg, i.v., AVP-induced pressor responses. This inhibition lasted for over 8 h following the oral administration of the highest dose of YM087 (1 mg/kg). 3. In rats deprived of water and food for 16-18 h, oral administration of YM087 (0.1, 0.3, 1 and 3 mg/kg) dose-dependently increased urine volume and reduced urine osmolality, with associated increases in urinary sodium and potassium excretion. However, these increases in electrolyte excretion were lower than those seen at comparable diuretic doses of furosemide (3, 10, 30 and 100 mg/kg, p.o.). 4. Oral administration of YM087 (0.3, 1 and 3 mg/kg) produced a dose-dependent increase in urine volume in rats allowed free access to water, with the diuretic effect peaking 2-4 h post-dosing at all dose levels. The diuretic effect of YM087 was sustained 8-10 h after a dose of 3 mg/kg; this is in contrast with the transient diuresis seen after furosemide (100 mg/kg, p.o.) dosing. 5. The present results demonstrate that YM087 is an orally active AVP antagonist with potent and long-lasting effects. YM087 suppressed V(1A) receptor-mediated pressor responses to AVP with minimal effects on basal haemodynamics and exerted a diuretic effect without increased electrolyte excretion by inhibiting V₂ receptor-mediated water reabsorption.