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CARDIOVASCULAR

Effects of Novel Vasopressin Receptor Antagonists on Renal Function and Cardiac Hypertrophy in Rats with Experimental Congestive Heart Failure

General Surgery (B.B.), Vascular Surgery (T.K., S.N., A.H.), and Internal Medicine (Z.S.A.), Rambam Medical Center, Haifa, Israel; and Department of Physiology and Biophysics, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel (H.S., I.R., N.A.-S., J.W., Z.A.A.)

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 V_1a receptor subtype (V_1a) 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), V_1a 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 V_1a antagonists improve water balance and cardiac hypertrophy in CHF and might be beneficial for the treatment of water retention and cardiac remodeling in CHF.

Address correspondence to: Dr. Zaid A. Abassi, Department of Physiology and Biophysics, Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Haifa 31096, Israel. E-mail: abassi{at}tx.technion.ac.il