title: Effects of novel vasopressin receptor antagonists on renal function and cardiac hypertrophy in rats with experimental congestive heart failure.
abstract: 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 V(2) receptor subtype (V(2)) 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 V(2) 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 microl/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 microl/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 V(2) 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.
authors.affiliation: General Surgery, Rambam Medical Center, Haifa, Israel.
authors.forename: Bishara
authors.initials: B
authors.lastname: Bishara
authors.forename: Hiba
authors.initials: H
authors.lastname: Shiekh
authors.forename: Tony
authors.initials: T
authors.lastname: Karram
authors.forename: Irit
authors.initials: I
authors.lastname: Rubinstein
authors.forename: Zaher S
authors.initials: ZS
authors.lastname: Azzam
authors.forename: Niroz
authors.initials: N
authors.lastname: Abu-Saleh
authors.forename: Samy
authors.initials: S
authors.lastname: Nitecki
authors.forename: Joseph
authors.initials: J
authors.lastname: Winaver
authors.forename: Aaron
authors.initials: A
authors.lastname: Hoffman
authors.forename: Zaid A
authors.initials: ZA
authors.lastname: Abassi
mesh_terms: D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001835:Body Weight / Q000187:drug effects; D006332:Cardiomegaly / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004231:Diuresis / Q000187:drug effects*; D004334:Drug Administration Schedule; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007677:Kidney Function Tests; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D009994:Osmolar Concentration; D011759:Pyrrolidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000652:urine; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D065092:Antidiuretic Hormone Receptor Antagonists; D007211:Indoles; D009025:Morpholines; D011759:Pyrrolidines; D013141:Spiro Compounds; D012964:Sodium; C103281:satavaptan; C082134:relcovaptan