Diabetes enhances the intrahepatic vascular response to endothelin-1 in cirrhotic rats: association with the ETA receptor and pERK up-regulation.

Abstract

BACKGROUND & AIMS:

Cirrhosis is characterized by increased intrahepatic vascular resistance and enhanced vasocontractile responsiveness that impedes portal inflow and elevates portal pressure, in which endothelin-1 (ET-1) plays a role. Diabetes and glucose influence vasoresponsiveness but their impact on the intrahepatic vascular bed in cirrhosis is unknown. To investigate intrahepatic ET-1 vasoresponsiveness in cirrhotic rats with and without diabetes and to explore the underlying mechanisms.

METHODS:

Spraque-Dawley rats received common bile-duct ligation (BDL) to induce cirrhosis. Streptozotocin was injected to induce diabetes in the BDL rats (BDL/STZ). In situ liver perfusion was performed to obtain the ET-1 concentration-response curves. The basic hemodynamics and hepatic protein expressions of ET-1 receptors, pERK, ERK, pAkt, Akt, iNOS, eNOS, peNOS and calmodulin were evaluated. The circulating concentrations of N-terminal pro-brain natriuretic peptide (NT-ProBNP), blood urea nitrogen (BUN) and creatinine were also determined.

RESULTS:

Body weight, mean arterial pressure, heart rate and survival rate were significantly decreased in the BDL/STZ rats. The perfusion pressure changes in response to ET-1 were higher in the BDL/STZ group for all perfusates. ETA receptor and pERK expressions were enhanced in the BDL/STZ group. The circulating concentrations of NT-ProBNP, BUN and creatinine, as well as SMA flow, were not significantly different between the BDL and BDL/STZ groups.

CONCLUSION:

Cirrhotic rats with diabetes showed higher intrahepatic ET-1 vasoresponsiveness than normoglycemic cirrhotic rats. This effect is not affected by changes in perfused glucose concentration and may be related, at least in part, to intrahepatic ETA R receptor and pERK over-expression.

• Authors: Jing-Yi Lee, Fa-Yauh Lee, Teh-Ia Huo, Sun-Sang Wang, Hui-Chun Huang, Han-Chieh Lin, Chiao-Lin Chuang, Shou-Dong Lee
• Journal: Liver international : official journal of the International Association for the Study of the Liver (Liver Int) Vol. 35 Issue 3 Pg. 704-12 (Mar 2015) ISSN: 1478-3231 [Electronic] United States
• PMID: 24636620 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Endothelin-1
• Peptide Fragments
• Receptor, Endothelin A
• pro-brain natriuretic peptide (1-76)
• Natriuretic Peptide, Brain
• Creatinine
• PERK kinase
• eIF-2 Kinase

Topics

• Animals
• Blood Urea Nitrogen
• Creatinine (blood)
• Diabetes Mellitus, Experimental (chemically induced, complications, physiopathology)
• Disease Models, Animal
• Endothelin-1 (pharmacology)
• Hemodynamics (drug effects)
• Hypertension, Portal (complications)
• Liver Cirrhosis, Experimental (complications, physiopathology)
• Male
• Natriuretic Peptide, Brain (blood)
• Peptide Fragments (blood)
• Perfusion
• Portal Pressure (drug effects)
• Rats
• Rats, Sprague-Dawley
• Receptor, Endothelin A (metabolism)
• Up-Regulation (drug effects)
• Vasoconstriction (drug effects)
• eIF-2 Kinase (metabolism)