Enhancement of endothelial nitric oxide production by chenodeoxycholic acids in patients with hepatobiliary diseases.

The purpose of this study was to clarify whether physiological concentrations of bile acids could affect endothelial nitric oxide production. We investigated the relationships between clinical concentrations of individual bile acids observed in patients with hepatobiliary diseases and endothelial nitric oxide production induced by each bile acid. Fifteen serum bile acids were measured using high-performance liquid chromatography combined with enzymatic fluorometry in 8 patients with liver cirrhosis, obstructive jaundice, and 8 healthy subjects. The effects of individual bile acids on nitric oxide production were examined in human umbilical endothelial cells by measuring the concentration of NO2- in the cultured medium. NO release in the blood was also determined by measuring the NO2-/NO3- concentration in these patients. In patients with hepatobiliary diseases, the plasma concentrations of chenodeoxycholic acid, ursodeoxycholic acid and cholic acid (free acid, taurine and glycine conjugates) were markedly elevated. Incubation of cells with chenodeoxycholic acid and deoxycholic acid (free acid, taurine and glycine conjugates) enhanced NO2- production in a concentration-dependent manner, while cholic acid (free and its conjugates) did not. The effects of individual bile acids on nitric oxide production were additive. Patients with liver cirrhosis and obstructive jaundice had higher plasma levels of NO2-/NO3- levels than the control subjects. These results suggest that increased plasma concentrations of chenodeoxycholic acid (free, taurine and glycine conjugates) in patients with hepatobiliary diseases may induce endothelial nitric oxide production. Thus, nitric oxide production induced by bile acids may be involved in the pathogenesis of circulatory abnormalities in patients with liver diseases.

[1]  W. Shin,et al.  Bile acids increase intracellular Ca2+ concentration and nitric oxide production in vascular endothelial cells , 2000, British journal of pharmacology.

[2]  T. Nakajima.  Bile Acids Increase Intracellular Ca2+ and Nitric Oxide Production in Vascular Endothelial Cells , 2000 .

[3]  M. Omata,et al.  Increased excretion of nitric oxide in exhaled air of patients with chronic renal failure. , 1999, Clinical science.

[4]  R. Schrier,et al.  Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. , 1998, The New England journal of medicine.

[5]  F. Trevisani,et al.  Systemic and regional hemodynamics in pre-ascitic cirrhosis. , 1997, Journal of hepatology.

[6]  E. Christensen,et al.  Continuous blood pressure monitoring in cirrhosis. Relations to splanchnic and systemic haemodynamics. , 1997, Journal of hepatology.

[7]  Y. Okuda,et al.  Eicosapentaenoic acid enhances nitric oxide production by cultured human endothelial cells. , 1997, Biochemical and biophysical research communications.

[8]  G. Mengozzi,et al.  Hyperdynamic circulation in patients with cirrhosis: direct measurement of nitric oxide levels in hepatic and portal veins. , 1997, Journal of hepatology.

[9]  R. Schrier,et al.  Endothelium‐dependent vascular hyporesponsiveness without detection of nitric oxide synthase induction in aortas of cirrhotic rats , 1995, Hepatology.

[10]  R. Schrier,et al.  Normalization of nitric oxide production corrects arterial vasodilation and hyperdynamic circulation in cirrhotic rats. , 1995, Gastroenterology.

[11]  M. Niederberger.  Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis*1 , 1995 .

[12]  R. Schrier,et al.  Increased aortic cyclic guanosine monophosphate concentration in experimental cirrhosis in rats: Evidence for a role of nitric oxide in the pathogenesis of arterial vasodilation in cirrhosis , 1995, Hepatology.

[13]  A. Gasbarrini,et al.  Hyperdynamic circulation of advanced cirrhosis: a re-appraisal based on posture-induced changes in hemodynamics. , 1995, Journal of hepatology.

[14]  W. Jiménez,et al.  Nitric oxide production in arterial vessels of cirrhotic rats , 1995, Hepatology.

[15]  R. Groszmann.  Hyperdynamic circulation of liver disease 40 years later: Pathophysiology and clinical consequences , 1994, Hepatology.

[16]  R. Moreau,et al.  Vascular hyporesponsiveness to endothelin 1 in rats with cirrhosis. , 1994, Gastroenterology.

[17]  O. Bulbena,et al.  Increased serum nitrite and nitrate levels in patients with cirrhosis: Relationship to endotoxemia , 1993, Hepatology.

[18]  S. S. Lee,et al.  Vasoactive effects of bile salts in cirrhotic rats: In vivo and In vitro studies , 1993, Hepatology.

[19]  W. Jiménez,et al.  Impaired responsiveness to angiotensin II in experimental cirrhosis: Role of nitric oxide , 1993, Hepatology.

[20]  P. Pizcueta,et al.  Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition. , 1992, Gastroenterology.

[21]  W. Jiménez,et al.  Pathogenesis of arterial hypotension in cirrhotic rats with ascites: Role of endogenous nitric oxide , 1992, Hepatology.

[22]  J. Reid,et al.  Impaired pressor reactivity in cirrhosis: Evidence for a peripheral vascular defect , 1991, Hepatology.

[23]  S. Moncada,et al.  Hyperdynamic circulation in cirrhosis: a role for nitric oxide? , 1991, The Lancet.

[24]  J. Neuberger,et al.  The effect of bile salts on human vascular endothelial cells. , 1991, Biochimica et biophysica acta.

[25]  L. Ignarro,et al.  Vascular smooth muscle-derived relaxing factor (MDRF) and its close similarity to nitric oxide. , 1990, Biochemical and biophysical research communications.

[26]  Vicente Arroyo,et al.  Peripheral arterial vasodilation hypothesis: A proposal for the initiation of renal sodium and water retention in cirrhosis , 1988, Hepatology.

[27]  S. Moncada,et al.  Vascular endothelial cells synthesize nitric oxide from L-arginine , 1988, Nature.

[28]  J. Finberg,et al.  Bile salts, hypotension and obstructive jaundice. , 1984, Clinical science.

[29]  Y. Seyama,et al.  Serum concentrations of bile acid glucuronides in hepatobiliary diseases. , 1983, Digestion.

[30]  J. Finberg,et al.  CARDIOVASCULAR RESPONSIVENESS TO VASOACTIVE AGENTS IN RATS WITH OBSTRUCTIVE JAUNDICE , 1982, Clinical and experimental pharmacology & physiology.

[31]  M. Berant,et al.  Effect of isolated cholaemia on systemic haemodynamics and kidney function in conscious dogs. , 1982, Clinical science.

[32]  J. Finberg,et al.  Blunted pressor response to angiotensin and sympathomimetic amines in bile-duct ligated dogs. , 1981, Clinical science.

[33]  R. Uenoyama,et al.  A measurement of individual bile acids in serum by high-performance liquid chromatography for clinical diagnostic information of hepatobiliary diseases. , 1980, The Kobe journal of medical sciences.

[34]  S. Okuyama,et al.  A NEW ANALYTICAL METHOD OF INDIVIDUAL BILE ACIDS USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY AND IMMOBILIZED 3α-HYDROXYSTEROID DEHYDROGENASE IN COLUMN FORM , 1979 .

[35]  P. Ross,et al.  Serum bile acids in the diagnosis of hepatobiliary disease. , 1977, Gut.

[36]  I. Makino,et al.  Sulfated and nonsulfated bile acids in urine, serum, and bile of patients with hepatobiliary diseases. , 1975, Gastroenterology.

[37]  K. Mashimo,et al.  Conjugated and unconjugated serum bile acid levels n patients with hepatobiliary diseases. , 1969, Gastroenterology.