In vivo and in vitro characterisation of a nonpeptide vasopressin V(1A) and V(2) receptor antagonist (YM087) in the rat

Eur J Pharmacol. 1999 Sep 17;381(1):23-30. doi: 10.1016/s0014-2999(99)00530-0.

Abstract

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-phenylbenzanilide monohydrochloride) in the rat. YM087 dose dependently displaced the vasopressin V(1A) receptor antagonist radioligand, 125I-labelled [d(CH(2))(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 [3H]desGly-NH(2)(9)[d(CH(2))(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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antidiuretic Hormone Receptor Antagonists*
  • Benzazepines / metabolism
  • Benzazepines / pharmacology*
  • Binding, Competitive / drug effects
  • Blood Pressure / drug effects
  • Dose-Response Relationship, Drug
  • Iodine Radioisotopes
  • Kidney / drug effects
  • Kidney / metabolism
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism
  • Male
  • Membranes / drug effects
  • Membranes / metabolism
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / blood
  • Sodium / urine
  • Systole
  • Urination / drug effects
  • Vasopressins / metabolism

Substances

  • Antidiuretic Hormone Receptor Antagonists
  • Benzazepines
  • Iodine Radioisotopes
  • conivaptan
  • Vasopressins
  • Sodium