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3 Table1 Clinical features and laboratory data of the patients studied

4 Fig.1 The plasma levels of endothelin-1 in the venous blood (ETv) of variceal patients with liver cirrhosis(lc+), idiopathic portal hypertension (IPH+) and primary biliary cirrhosis(pbc+) along with those of non variceal patients with PBC (PBC-) and healthy subjects. Fig.2 The plasma levels of endothelin-1 in the portal blood (ETp) of variceal patients with liver cirrhosis(lc+), idiopathic portal hypertension (IPH+) and primary biliary cirrhosis(pbc+) along with those of non variceal patients with PBC(PBC-). ;p<0.01

5 Fig.3 a, b, c&d Correlation between plasma levels of endothelin-1 in venous blood (ETv) (a&b) or those in portal blood (ETp) (c&d) and serum total bilirubin (TB) levels (a&c) or values of indocyanine green dye retention rate at 15 min (ICG R15) (b&d) in variceal patients with liver cirrhosis. N.S.; not significant

6 Fig.4 a, b, c&d Correlation between plasma levels of endothelin-1 in venous blood (ETv) (a&b) or those in portal blood (ETp) (c&d) and serum total bilirubin(tb) levels (a&c) or values of indocyanine green dye retention rate at 15 min(icg R15) (b&d) in variceal patients with primary biliary cirrhosis. N.S.; not significant Fig.5 Change in endothelin-1 levels in the portal blood (ETp) before and after endoscopic injection sclerotherapy(eis) in variceal patients with liver cirrhosis(lc+; solid line \, n=6) and primary biliary cirrhosis(pbc+; dotted line c c, n=3) classified into patients with increased (a) and decreased (b) portal vein pressure(pvp) after EIS.

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8 1) Vane J: Control of the circulation by endothelial mediators. Int Arch Allergy Immunol 101: 333 \345,1993 2) Yanagisawa M, Kurihara H, Kimura S, et al: A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332: 411 \415,1988 3) Luscher TF, Tanner FC: Endothelial regulation of vascular tone and growth. Am J Hyper- tens 6: 283 \293,1993 4) Moller S, Henriksen JH: Endothelins in chronic liver disease. Scand J Clin Lab Invest

9 56: 481 \490,1996 release endothelin-augmentation by transforming growth factor Ĉ and kupffer cellconditioned media. Klin Wochenschr 69: 387 5) Asbert M, Gines A, Gines P, et al: Circulating levels of endothelin in cirrhosis. Gastroenterology 104: 1485 \1491, ,1991 \ 6) Isobe H, Satoh M, Sakai H, et al: Increased plasma endothelin-1 levels in patients with cirrhosis and esophageal varices. J Clin Gastroenterol 17: 227 \230,1993 7) Gandhi C. R, Stephenson K, Olson M. S,: Endothelin, a potent peptide agonist in the liver. J Biol Chem 265: \17435,1990 8) Gondo K, Ueno T, Sakamoto M, et al: The endothelin-1 binding site in rat liver tissue: light-and electron-microscopic autoradiographic studies. Gastroenterology 104: 1745 \ 1749,1993 9) Sakamoto M, Ueno T, Kin M, et al: Ito cell contraction in response to endothelin-1 and substance P. Hepatology 18: 978 \983, ) Martinet JP, Legault L, Cernacek P, et al: Changes in plasma endothelin-1 and big endothelin-1 induced by transjugular intrahepatic portosystemic shunts in patients with cirrhosis 17) Pinzani M, Milani S, Defranco R, et al Endothelin-1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 110: 534 \548, ) Bluhm RE, Frazer MG, Vore M, et al Endothelin 1 and 3: Potent cholestatic agents secreted and excreted by the liver that interact with cyclosporine. Hepatology 18: 961 \968, ) Kew MC, Varma RR, Dos Santos HA, et al: Portal hypertension in primary biliary cirrhosis. Gut 12: 830 \834,1971 and refractory ascites. J Hepatol 25: 700 \ 706, ) Namiki A, Hirata Y, Ishikawa M, et al: Endothelin-1 and endothelin-3 induced vasor- elaxation via common generation of endothelium-derived nitric oxide. Life Sci 50: 677 \682, ) Veglio F, Pinna G, Melchio R, et al: Plasma endothelin levels in cirrhotic subjects. J Hepatol 15: 85 \87, ) Uchihara M, Izumi N, Sato C, et al: Clinical significance of elevated plasma endothelin concentration in patients with cirrhosis. Hepatology 16: 95 \99, ) Rieder H, Ramadori G, Meyer KH,: Sinusoidal endothelial liver cells in vitro 27) Toyonaga A, Iwao T, Sumino M, et al: Portal pressure after prophylactic sclerotherapy in patients with high-risk varices. J Hepatol 21: 515 \520,1994

10 The clinical significance of plasma endothelin-1 in venous and portal blood of patients with portal hypertension Toshihiko KOJIMA, Shunji KAISE, Katsutoshi OBARA, Hiromasa OHIRA, Masahito KURODA, Tohru TAKAGI, Reiji KASUKAWA To investigate the significance of endothelin-1(et) in the pathophysiology of portal hypertension, we measured the plasma levels of ET in venous and portal blood of 37 patients with portal hypertension by means of enzyme immunoassay. The ET levels in venous blood (ETv) in patients with liver cirrhosis (LC,n=16), idiopathic portal hypertension(iph,n=13) and primary biliary cirrhosis (PBC,n=8) were higher than those in healthy subjects. The ET levels in portal blood (ETp) in patients with IPH were significantly lower than those in patients with LC and PBC. No correlation between the levels of ETv or ETp and values of portal vein pressure (PVP) was noted in any kinds of diseases. ETp values correlated with total bilirubin values in LC patients, whereas ETv and ETp values correlated with indocyanine green dye retention rate at 15 minutes values in PBC patients. After endoscopic injection sclerotherapy (EIS) of esophagogastric varices, both ETp levels and PVP values were decreased in 4 of 6 LC patients, whereas both ETp levels and PVP values were increased in 2 of 3 PBC patients. These results suggest that ETp might play some roles in the pathophysiology of portal hypertension. Department of Internal Medicine II, Fukushima Medical University School of Medicine(Fukushima)

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