S. Nakamura et al., Antidiuretic effects of a nonpeptide vasopressin V-2-receptor agonist, OPC-51803, administered orally to rats, J PHARM EXP, 295(3), 2000, pp. 1005-1011
Citations number
29
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
OPC-51803 is the first nonpeptide vasopressin (AVP) V-2-receptor-selective
agonist. Its pharmacological profile, including antidiuretic action and rec
eptor binding, was characterized using conscious Brattleboro rats with here
ditary diabetes insipidus and Sprague-Dawley rats. In membrane preparations
from the liver and kidney, OPC-51803 displaced the [H-3]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-recepto
rs. 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 durin
g 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 t
reatment 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 change
s in urinary parameters, serum parameters, or plasma hormone levels were ob
served. OPC-51803 did not change blood pressure or heart rate, or inhibit A
VP-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 anti
diuretic 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 enuresi
s, and some kinds of urinary incontinence.