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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Long-Term Aquaretic Efficacy of a Selective Nonpeptide V2-Vasopressin Receptor Antagonist, SR121463, in Cirrhotic Rats

Wladimiro Jiménez, Claudine Serradeil-Le Gal, Josefa Ros, Carmen Cano, Pilar Cejudo, Manuel Morales-Ruiz, Vicente Arroyo, Marc Pascal, Francisca Rivera, Jean-Pierre Maffrand and Juan Rodés
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 83-90;
Wladimiro Jiménez
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Claudine Serradeil-Le Gal
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Josefa Ros
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Carmen Cano
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Pilar Cejudo
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Manuel Morales-Ruiz
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Vicente Arroyo
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Marc Pascal
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Francisca Rivera
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Jean-Pierre Maffrand
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Juan Rodés
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Abstract

Water retention in experimental cirrhosis can be reversed by blocking V2-vasopressin (AVP) receptors with the nonpeptide antagonist OPC-31260 or by using the κ-opioid receptor agonist niravoline, a compound inhibiting central AVP release. However, reluctance to use these drugs in human beings has emerged because the former loses aquaretic efficacy in rats after 2 days of treatment and the latter may have adverse effects in humans. Recently, a new potent and selective nonpeptide V2-AVP receptor antagonist, SR121463, has been developed that could be useful for the treatment of dilutional hyponatremia in human cirrhosis. The current study assessed the aquaretic efficacy of 10-day chronic oral administration of SR121463 (0.5 mg/kg/day) in cirrhotic rats with ascites and impaired water excretion after a water load (minimum urinary osmolality >160 mOsm/kg and percentage of water load excreted <60%). Urine volume (UV), osmolality (UOsmV), and sodium excretion (UNaV) were measured daily. At the end of the 10-day treatment, mean arterial pressure also was measured. In basal conditions cirrhotic rats showed ascites, sodium retention, and impaired water excretion. UV, UOsmV, and UNaV did not change throughout the study in cirrhotic rats receiving the vehicle. In contrast, SR121463 increased UV and reduced UOsmV during the 10-day treatment. This resulted in a greater renal ability to excrete a water load and normalization in serum sodium and osmolality. During the first 6 days of treatment, SR121463 also increased UNaV without affecting mean arterial pressure. These data suggest that SR121463 could be of therapeutical value for chronic management of human cirrhosis.

Footnotes

  • Send reprint requests to: Dr. Wladimiro Jiménez, Laboratorio Hormonal, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain. E-mail:wjimenez{at}medicina.ub.es

  • ↵1 This work was supported by grants from Sanofi Recherche and Dirección General de Investigación Cientı́fica y Técnica (SAF99-0016). P.C. received a grant from Institut d'Investigacions Biomèdiques August Pi i Sunyer. Portions of this investigation were presented at the 50th Annual Meeting of the American Association for the Study of the Liver Diseases, Dallas, November 5–9, 1999.

  • Abbreviations:
    AVP
    vasopressin
    mUOsm
    minimum urinary osmolality
    UAVPV
    urinary excretion of AVP
    ALD
    aldosterone
    UALDV
    urinary excretion of aldosterone
    UcAMPV
    urinary excretion of cAMP
    UOsm
    urine osmolality
    UNaV
    urine sodium
    UKV
    urine potassium
    MAP
    mean arterial pressure
    • Received March 30, 2000.
    • Accepted May 25, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Long-Term Aquaretic Efficacy of a Selective Nonpeptide V2-Vasopressin Receptor Antagonist, SR121463, in Cirrhotic Rats

Wladimiro Jiménez, Claudine Serradeil-Le Gal, Josefa Ros, Carmen Cano, Pilar Cejudo, Manuel Morales-Ruiz, Vicente Arroyo, Marc Pascal, Francisca Rivera, Jean-Pierre Maffrand and Juan Rodés
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 83-90;

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Long-Term Aquaretic Efficacy of a Selective Nonpeptide V2-Vasopressin Receptor Antagonist, SR121463, in Cirrhotic Rats

Wladimiro Jiménez, Claudine Serradeil-Le Gal, Josefa Ros, Carmen Cano, Pilar Cejudo, Manuel Morales-Ruiz, Vicente Arroyo, Marc Pascal, Francisca Rivera, Jean-Pierre Maffrand and Juan Rodés
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 83-90;
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