TY - JOUR T1 - Effects of Novel Vasopressin Receptor Antagonists on Renal Function and Cardiac Hypertrophy in Rats with Experimental Congestive Heart Failure JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 414 LP - 422 DO - 10.1124/jpet.108.137745 VL - 326 IS - 2 AU - Bishara Bishara AU - Hiba Shiekh AU - Tony Karram AU - Irit Rubinstein AU - Zaher S. Azzam AU - Niroz Abu-Saleh AU - Samy Nitecki AU - Joseph Winaver AU - Aaron Hoffman AU - Zaid A. Abassi Y1 - 2008/08/01 UR - http://jpet.aspetjournals.org/content/326/2/414.abstract N2 - Arginine vasopressin (AVP) plays an important role in renal hemodynamic alterations, water retention, and cardiac remodeling in congestive heart failure (CHF). The present study evaluated the acute and chronic effects of vasopressin V1a receptor subtype (V1a) and vasopressin V2 receptor subtype (V2) antagonists on renal function and cardiac hypertrophy in rats with CHF. The effects of acute administration of SR 49059 [(2S)1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4-dimethoxybenzene-sulfonyl)-3-hydroxy-2,3-dihydro-1H-indole-2-carbonyl]-pyrrolidine-2-carboxamide)] (0.1 mg/kg) and SR 121463B (1-[4-(N-tert-butylcarbamoyl)-2-methoxybenzenesulfonyl]-5-ethoxy-3-spiro-[4-(2-morpholinoethoxy)cyclohexane]indol-2-one, fumarate; equatorial isomer) (0.3 mg/kg), V1a and V2 antagonists, respectively, on renal function, and of chronic treatment (3.0 mg/kg/day for 7 or 28 days, via osmotic minipumps or p.o.), on water excretion and cardiac hypertrophy were studied in rats with aortocaval fistula and control rats. CHF induction increased plasma AVP (12.8 ± 2.5 versus 32.2 ± 8.3 pg/ml, p < 0.05). Intravenous bolus injection of SR 121463B to controls produced dramatic diuretic response (from 5.5 ± 0.8 to 86.3 ± 21.9 μl/min; p < 0.01). In contrast, administration of SR 49059 did not affect urine flow. Likewise, administration of SR 121463B, but not SR 49059, to rats with CHF significantly increased urinary flow rate from 20.8 ± 6.4 to 91.6 ± 26.5 μl/min (p < 0.01). The diuretic effects of SR 121463B were associated with a significant decline in urinary osmolality and insignificant change of Na+ excretion. In line with its acute effects, chronic administration of SR 121463B to CHF rats increased daily urinary volume 2 to 5-fold throughout the treatment period. Both SR 121463B and SR 49059 significantly reduced heart weight in CHF rats when administered for 4 weeks, but not 1 week. These results suggest that V2 and V1a antagonists improve water balance and cardiac hypertrophy in CHF and might be beneficial for the treatment of water retention and cardiac remodeling in CHF. The American Society for Pharmacology and Experimental Therapeutics ER -