T. Hirano et al., Effects of the V-2-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats, J PHARM EXP, 292(1), 2000, pp. 288-294
Citations number
33
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
This study was conducted to characterize the diuretic effect of OPC-41061,
a nonpeptide vasopressin V-2-receptor antagonist, and furosemide by adminis
tering each alone and in combination in conscious male rats. OPC-41061 at 1
and 10 mg/kg and furosemide at 10 and 100 mg/kg dose-dependently increased
urine volume to the same extent. The high dose of OPC-41061 (10 mg/kg) mar
kedly elevated electrolyte-free water clearance (E-CH2O) to a positive valu
e. In contrast to OPC-41061, furosemide elevated only electrolyte clearance
but not E-CH2O. The differences in diuretic profile reflected the changes
in serum sodium and hormone levels. OPC-41061 dose-dependently elevated ser
um sodium concentration, but furosemide tended to decrease it. The high dos
e of furosemide (100 mg/kg) significantly elevated serum renin activity and
aldosterone concentration, indicating that furosemide activated the renin-
angiotensin-aldosterone system (RAA-system). On the other hand, OPC-41061 d
id not affect these parameters. When OPC-41061 was administered concomitant
ly with furosemide, OPC-41061 significantly increased urine volume and E-CH
2O, and decreased urinary osmolality compared with furosemide alone. OPC-41
061 dose-dependently elevated serum osmolality and sodium concentration eve
n when administered in combination with the high dose of furosemide. These
results suggest that OPC-41061 produces aquaresis leading to increased seru
m sodium without affecting the RAA-system. On the other hand, furosemide pr
oduced natriuresis, leading to decreased serum sodium level and activation
of the RAA-system. It was also demonstrated that OPC-41061 produced an addi
tive diuretic effect and elevated serum sodium level in the presence of fur
osemide.