Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats

Vasopressin 1a receptor partial agonism increases sodium excretion and reduces portal hypertension and ascites in cirrhotic rats

Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assesse...

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Published in:Hepatology (Baltimore, Md.) Vol. 63; no. 1; pp. 207 - 216
Main Authors: Fernández‐Varo, Guillermo, Oró, Denise, Cable, Edward Earl, Reichenbach, Vedrana, Carvajal, Silvia, de la Presa, Bernardino González, Wiśniewski, Kazimierz, Ginés, Pere, Harris, Geoffrey, Jiménez, Wladimiro
Format: Journal Article
Language:English
Published: United States Wiley Subscription Services, Inc 01-01-2016
Subjects:
Animals
Aorta
Argipressin
Argipressin receptors
Ascites
Ascites - drug therapy
Ascites - etiology
Ascites - metabolism
Blood pressure
Cirrhosis
Coronary vessels
Creatinine
Drug therapy
Excretion
Heart
Heart diseases
Hepatology
Hypertension
Hypertension, Portal - drug therapy
Hypertension, Portal - etiology
Hypertension, Portal - metabolism
Intravenous administration
Liver cirrhosis
Liver Cirrhosis - complications
Liver Cirrhosis - metabolism
Male
Rats
Rats, Wistar
Receptors, Vasopressin - agonists
Rodents
Sodium
Sodium - metabolism
Thorax
Urine
Vasoactive agents
Vasoconstriction
Vasopressin
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Summary:Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1a‐AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30‐minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice‐daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose‐dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a‐AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a‐AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta. Conclusion: FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a‐AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis. (Hepatology 2016;63:207–216)
Bibliography:Potential conflict of interest: Dr. Gines consults and received grants from Ferring and Sequana. He consults for Ikaria. Dr. Harris is employed by Ferring. Dr. Cable is employed by Ferring. Dr. Wisniewski is employed by Ferring.
Supported by grants from Dirección General de Investigación Científica y Técnica (SAF12‐35979) and Ferring Research Institute (to W.J.). CIBERehd is funded by the Instituto de Salud Carlos III.
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SourceType-Scholarly Journals-1
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ISSN:0270-9139
1527-3350
DOI:10.1002/hep.28250