Antidiuretic effects of a nonpeptide vasopressin V(2)-receptor agonist, OPC-51803, administered orally to rats

J Pharmacol Exp Ther. 2000 Dec;295(3):1005-11.

Abstract

OPC-51803 is the first nonpeptide vasopressin (AVP) V(2)-receptor-selective agonist. Its pharmacological profile, including antidiuretic action and receptor binding, was characterized using conscious Brattleboro rats with hereditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations from the liver and kidney, OPC-51803 displaced the [(3)H]AVP binding to V(2)-receptors (K(i) = 49.8 +/- 8.1 nM) more greatly than that to V(1a)-receptors (K(i) = 1061 +/- 60 nM), showing a 21 times higher affinity for V(2)-receptors. At single oral doses of 0.003 to 0.3 mg/kg in female Brattleboro rats, OPC-51803 decreased urine volume (from 10.8 +/- 1.1 to 0.5 +/- 0.2 ml during 0-2 h postdosing) and increased urinary osmolality (from 114 +/- 9 to 432 +/- 114 mOsm/kg) in a dose-dependent manner. During the period of 4-week treatment with OPC-51803, significant and constant antidiuresis was observed. In male Sprague-Dawley rats with normal plasma AVP levels, OPC-51803 at 0.03 to 0.3 mg/kg also produced a dose-dependent antidiuretic action (urine volume: from 2.6 +/- 0.6 to 1.1 +/- 0.2 ml at 0-4 h postdosing). Few changes in urinary parameters, serum parameters, or plasma hormone levels were observed. OPC-51803 did not change blood pressure or heart rate, or inhibit AVP-induced pressor response even at 30 mg/kg p.o. These results demonstrate that OPC-51803 is a V(2)-selective agonist that produces a significant antidiuretic action after single and multiple oral dosing in AVP-deficient and normal AVP states. The data suggest that OPC-51803 is a useful therapeutic drug in the treatment of hypothalamic diabetes insipidus, nocturnal enuresis, and some kinds of urinary incontinence.

MeSH terms

  • Administration, Oral
  • Animals
  • Arginine Vasopressin / metabolism
  • Arginine Vasopressin / pharmacology
  • Benzazepines / administration & dosage
  • Benzazepines / pharmacology*
  • Blood Pressure / drug effects
  • Creatinine / blood
  • Diabetes Insipidus / drug therapy*
  • Diuresis / drug effects*
  • Dose-Response Relationship, Drug
  • Female
  • Kidney / metabolism
  • Liver / metabolism
  • Male
  • Pyrrolidines / administration & dosage
  • Pyrrolidines / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Vasopressin / agonists*

Substances

  • Benzazepines
  • OPC 51803
  • Pyrrolidines
  • Receptors, Vasopressin
  • Arginine Vasopressin
  • Creatinine