Effects of the V(2)-receptor antagonist OPC-41061 and the loop diuretic furosemide alone and in combination in rats.
This study was conducted to characterize the diuretic effect of OPC-41061, a nonpeptide vasopressin V(2)-receptor antagonist, and furosemide by administering 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) markedly elevated electrolyte-free water clearance (E-CH(2)o) to a positive value. In contrast to OPC-41061, furosemide elevated only electrolyte clearance but not E-CH(2)o. The differences in diuretic profile reflected the changes in serum sodium and hormone levels. OPC-41061 dose-dependently elevated serum sodium concentration, but furosemide tended to decrease it. The high dose 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 did not affect these parameters. When OPC-41061 was administered concomitantly with furosemide, OPC-41061 significantly increased urine volume and E-CH(2)o, and decreased urinary osmolality compared with furosemide alone. OPC-41061 dose-dependently elevated serum osmolality and sodium concentration even when administered in combination with the high dose of furosemide. These results suggest that OPC-41061 produces aquaresis leading to increased serum sodium without affecting the RAA-system. On the other hand, furosemide produced natriuresis, leading to decreased serum sodium level and activation of the RAA-system. It was also demonstrated that OPC-41061 produced an additive diuretic effect and elevated serum sodium level in the presence of furosemide.
Hirano
T
T
Second Tokushima Institute of New Drug Research, Otsuka Pharmaceutical Co. Ltd., Kawauchi-cho, Tokushima, Japan. t_hirano@research.otsuka.co.jp
Yamamura
Y
Y
Nakamura
S
S
Onogawa
T
T
Mori
T
T
D000450:Aldosterone / Q000652:urine; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines / Q000494:pharmacology*; D004231:Diuresis / Q000187:drug effects*; D004232:Diuretics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004573:Electrolytes / Q000652:urine; D005665:Furosemide / Q000494:pharmacology*; D006728:Hormones / Q000097:blood; D008297:Male; D009994:Osmolar Concentration; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000652:urine; D012964:Sodium / Q000097:blood; D000077602:Tolvaptan; D014867:Water / Q000378:metabolism
D065092:Antidiuretic Hormone Receptor Antagonists; D001552:Benzazepines; D004232:Diuretics; D004573:Electrolytes; D006728:Hormones; D014867:Water; D000077602:Tolvaptan; D000450:Aldosterone; D005665:Furosemide; D012964:Sodium; D012083:Renin