Ursodeoxycholic acid reduces increased circulating endothelin 2 in primary biliary cirrhosis P. DIMOULIOS, G. KOLIOS, G. NOTAS, E. MATRELLA, C. XIDAKIS, M. KOULENTAKI, N. TSAGARAKIS, A. KOUROUMALIS & E. KOUROUMALIS Department of Gastroenterology, University Hospital Heraklion and Liver Research Laboratory of University of Heraklion, Crete, Greece Accepted for publication 13 October 2004 SUMMARY Background: Endothelins and nitric oxide regulate sin- usoidal blood flow and the perfusion of the peribiliary vascular plexus. Aims: To study the serum and hepatic vein concentra- tion of ET-1, ET-2, ET-3 and nitric oxide in patients with primary biliary cirrhosis and the effect of ursodeoxy- cholic acid treatment. Methods: Endothelins and nitrites/nitrates were meas- ured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. Endothelins were measured with commercial enzyme- linked immunosorbent assays and nitrites/nitrates with a modification of Griess reaction. Results: The ET-1 and ET-3 levels were similar in patients and controls. Primary biliary cirrhosis patients had the highest serum ET-2 (P < 0.001) compared with other groups. Nitrites/nitrates was increased in primary biliary cirrhosis (P < 0.05) compared with normal. ET-2 and nitric oxide were similar in all primary biliary cirrhosis stages. Ursodeoxycholic acid significantly decreased ET-2 in all stages (I and II: P < 0.05 and III and IV: P < 0.01) and increased nitric oxide (P < 0.05) in early primary biliary cirrhosis. Hepatic vein ET-1 and ET-3 were higher in viral cirrhosis patients, but only in primary biliary cirrhosis a significant difference for ET-1 and ET-3 between hepatic and peripheral veins was found. Conclusions: Increased ET-2 is an early defect in primary biliary cirrhosis that is significantly reduced by the ursodeoxycholic acid treatment. The possibility of a more generalized endothelial cell dysfunction in primary biliary cirrhosis requires further investiga- tion. INTRODUCTION The endothelins (ETs) consist of a family of three 21 amino acid peptides termed ET-1, ET-2 and ET-3. They are the most potent vasoconstrictor agents so far discovered and their principal role seems to be the regulation of the vascular tone. ET-1 and ET-2 have equal vasoconstrictor effect, while ET-3 has a reduced vasoconstrictor action. 1 Apart from vasoregulation, ETs exert multiple other biological actions, being involved in salt and water homeostasis, 2 cellular growth 3 and differentiation, 4 inflammation, 5 angio- genesis, 6 neural crest development, 7 neural function regulation 7 and wound healing. 8 ETs bind to two different receptors termed ET-A and ET-B. ET-A receptors, found on vascular smooth muscle cells, mediate vasoconstriction, while ET-B receptors, found predominantly on vascular endothelium, medi- ate vasodilation through nitric oxide (NO) release. 9 Production of ETs was initially attributed to endot- Correspondence to: Dr E. Kouroumalis, Faculty of Medicine, University of Crete, PO Box 2208, Heraklion, GR-71003, Greece. E-mail: kouroum@med.uoc.gr Aliment Pharmacol Ther 2005; 21: 227–234. doi: 10.1111/j.1365-2036.2005.02307.x Ó 2005 Blackwell Publishing Ltd 227