PT - JOURNAL ARTICLE AU - Takahiro Hirano AU - Yoshitaka Yamamura AU - Shigeki Nakamura AU - Toshiyuki Onogawa AU - Toyoki Mori TI - Effects of the V<sub>2</sub>-Receptor Antagonist OPC-41061 and the Loop Diuretic Furosemide Alone and in Combination in Rats DP - 2000 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 288--294 VI - 292 IP - 1 4099 - http://jpet.aspetjournals.org/content/292/1/288.short 4100 - http://jpet.aspetjournals.org/content/292/1/288.full SO - J Pharmacol Exp Ther2000 Jan 01; 292 AB - This study was conducted to characterize the diuretic effect of OPC-41061, a nonpeptide vasopressin V2-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-Ch2 o) to a positive value. In contrast to OPC-41061, furosemide elevated only electrolyte clearance but not E-Ch2 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-Ch2 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. The American Society for Pharmacology and Experimental Therapeutics