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 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.