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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on May 8, 2008; DOI: 10.1124/jpet.108.137745

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Received for publication February 11, 2008.
Revised May 7, 2008.
Accepted for publication May 7, 2008.

Effects of novel vasopressin receptor antagonists on renal function and cardiac hypertrophy in rats with experimental congestive heart failure

Bishara Bishara 1, Hiba Shiekh 2, Tony Karram 3, Irit Rubinstein 4, Zaher Azzam 5, Niroz Abu-Saleh 4, Samy Nitecki 3, Joseph Winaver 4, Aaron Hoffman 3, Zaid Abassi 4*

1 General Surgery A, Rambam medical center 2 Technion, Faculty of medicine 3 Vascular Surgery, Rambam Medical Center 4 Department of Physiology and Biophysics, Faculty of Medicine, Technion 5 Internal Medicine B, Rambam Medical Center

* Address correspondence to: E-mail: abassi{at}tx.technion.ac.il

Abstract

Objective: 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 V1a and V2 antagonists on renal function and cardiac hypertrophy in rats with CHF. Methods: The effects of acute administration of SR49059 (0.1mg/kg) and SR 121463B (0.3mg/kg), V1a and V2 antagonists, respectively on renal function, and of chronic treatment (3.0mg/kg/day for 7 or 28 days, via osmotic minipumps or P.O), on water excretion and cardiac hypertrophy were studied in rats with aorto-caval fistula and control rats. Results: CHF induction increased plasma AVP (12.8±2.5 vs. 32.2±8.3 pg/ml, P<0.05). Intravenous bolus injection of SR121463B 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 SR49059 did not affect urine flow. Similarly, administration of SR121463B, but not SR49059, to rats with CHF significantly increased V from 20.8±6.4 to 91.6±26.5 µl/min (p<0.01). The diuretic effects of SR 121463B were associated with significant decline in urinary osmolality and insignificant change of Na+ excretion. In line with its acute effects, chronic administration of SR121463B to CHF rats increased daily urinary volume 2-5 fold throughout the treatment period. Both SR121463B and SR49059 significantly reduced heart weight in CHF rats when administered for 4, but not 1 week. Conclusions: 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.


Key words: Aorto-caval fistula, Congestive heart failure, Kidney, Rat, Renal hemodynamics, V1 & V2 antagonists




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