Chronic blockade of endothelin receptors in cirrhotic rats: hepatic and hemodynamic effects.
OBJECTIVE
Because controversial roles have been attributed to activation of the hepatic paracrine endothelin (ET) system in cirrhosis, this study assessed whether chronic ET receptor blockade modifies the development of portal hypertension in cirrhotic rats.


METHODS
Cirrhotic and control rats received the mixed ET receptor antagonist RO 48-5695 or vehicle daily for 10 weeks. At the end of the treatment period, portal pressure, systemic hemodynamics, standard renal and liver function tests, hepatic concentration of hydroxyproline, and liver messenger RNA (mRNA) expression of procollagen type I were measured.


RESULTS
Cirrhotic rats had portal hypertension and hyperdynamic circulation with no differences between animals treated or not treated with the ET-receptor antagonist. However, cirrhotic rats receiving ET-receptor blockade long-term showed a higher hepatic hydroxyproline content and procollagen type I mRNA expression than cirrhotic animals receiving vehicle.


CONCLUSIONS
The results indicate that the liver paracrine ET system does not play a major role in the pathogenesis of portal hypertension and support the concept that this system takes part in an autocrine loop that counteracts the development of liver fibrogenesis.
Poo
J L
JL
Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), and Hospital Clínic Universitari, University of Barcelona, Barcelona, Spain.
Jiménez
W
W
María Muñoz
R
R
Bosch-Marcé
M
M
Bordas
N
N
Morales-Ruiz
M
M
Pérez
M
M
Deulofeu
R
R
Solé
M
M
Arroyo
V
V
Rodés
J
J
D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects*; D006909:Hydroxyproline / Q000378:metabolism; D006975:Hypertension, Portal / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D007677:Kidney Function Tests; D008099:Liver / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000150:complications / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D017082:Portal Pressure / Q000187:drug effects; D011347:Procollagen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D011347:Procollagen; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D006909:Hydroxyproline