Effect of protoporphyrin IX on ursodeoxycholate-induced hypercholeresis in the rat

1988 ◽  
Vol 75 (6) ◽  
pp. 593-599
Author(s):  
J. J. Garcia-Marin ◽  
J. G. Redondo-Torres ◽  
F. Perez-Barriocanal ◽  
M. M. Berenson
Keyword(s):  
Body Weight ◽  
Bile Acid ◽  
Bile Flow ◽  
Sodium Taurocholate ◽  
Protoporphyrin Ix ◽  
Inhibitory Effect ◽  
Bicarbonate Secretion ◽  
Bile Formation ◽  
Dose Dependent ◽  
Bile Acid Secretion

1. It is known that the perfusion of rat livers with solutions containing protoporphyrin IX induces a decrease in bile flow which is not due to inhibition of bile acid secretion but rather to decreased electrolyte transport into bile. By contrast, ursodeoxycholate induces hypercholeresis, partly due to a marked stimulation of biliary bicarbonate secretion. The aim of the present work was to investigate the effect of protoporphyrin IX on ursodeoxycholate-induced choleresis in anaesthetized male Wistar rats. 2. Protoporphyrin IX infusion at rates of 10, 20 and 40 μg min−1 100 g−1 body weight into the jugular vein induced a dose-dependent inhibitory effect on bile flow as well as on bile acid and electrolyte secretion. The lowest infused rate only induced slight and non-significant changes in spontaneous bile formation and functional variables such as glycaemia, packed cell volume, blood pH, Pco2, Po2 and bicarbonate concentration, and in hepatic carbonic anhydrase activity. It was thus considered as a subtoxic dose. 3. Sodium taurocholate was infused (0.5 μmol min−1 100 g−1 body weight) over the second hour of the lowest dose of protoporphyrin IX infusion. In these rats, no significant changes in bile flow or bile acid and electrolyte secretion were observed as compared with animals receiving sodium taurocholate plus saline solution. 4. Bile acid secretion induced by ursodeoxycholate infusion (1 μmol min−1 100 g−1 body weight) was similar both in rats receiving ursodeoxycholate plus saline solution and in animals infused with this bile acid over the second hour of the lowest dose of protoporphyrin IX infusion. However, bile flow and biliary bicarbonate secretion induced by ursodeoxycholate were markedly impaired (− 43% and − 56%, respectively) by protoporphyrin IX. 5. These results indicate that in the rat, in vivo, protoporphyrin IX impairs bile formation in a dose-dependent manner. They suggest that the mechanism(s) involved in ursodeoxycholate-induced bicarbonate secretion, and hence hypercholeresis, are particularly sensitive to the inhibitory effect of protoporphyrin IX.

Taurolithochoiic acid and chlorpromazine cholestasis in the rhesus monkey

1979 ◽  
Vol 57 (10) ◽  
pp. 1138-1147 ◽  
Author(s):  
S. M. Strasberg ◽  
R. M. Kay ◽  
R. G. Ilson ◽  
C. N. Petrunka ◽  
J. E. Paloheimo
Keyword(s):  
Bile Acid ◽  
Acid Secretion ◽  
Bile Flow ◽  
Recovery Period ◽  
Secretion Rate ◽  
Bicarbonate Secretion ◽  
Bicarbonate Concentration ◽  
Bile Acid Concentration ◽  
Dose Dependent ◽  
Bile Acid Secretion

Taurolithocholic acid (TLC) and chlorpromazine (CPZ) cholestasis were studied in reversible primate models in order to determine the level of injury, changes in canalicular permeability, and the effects of taurocholic acid (TC) on the production of cholestasis. TLC produced dose-dependent cholestasis. Reductions in bile acid secretion rate and concentration, larger decreases in [14C]erythritol clearance than in total bile flow, and increased bicarbonate concentration in bile indicated that the cholestasis was canalicular in origin. TC prevented cholestasis; it also caused an increased secretion of TLC in bile, but the TLC:TC concentration ratio was unchanged, providing evidence that TC is beneficial because it hastens excretion of TLC from the liver cell in micelles. Permeability to [3H]inulin was increased during the recovery period. CPZ caused reductions in bile flow, bile acid secretion rate, and [14C]erythritol clearance, and almost completely eliminated biliary bicarbonate secretion, suggesting a mixed canalicular and ductular form of cholestasis. When TC was given with CPZ, no reductions in bile acid secretion rate or [14C]erythritol clearance were found but bicarbonate secretion was markedly reduced, bicarbonate concentration diminished, and bile acid concentration increased, i.e., TC protected against the canalicular component of CPZ cholestasis and unmasked the ductular component. Permeability to inulin was increased in three of four animals. TLC cholestasis occurs predominately at the canalicular level, whereas CPZ probably affects bile flow at the ductular level as well. TC protects the hepatocyte against the effects of both agents.

Effect of choleretics on canalicular transport of protoporphyrin in the rat liver

1982 ◽  
Vol 242 (4) ◽  
pp. G347-G353
Author(s):  
D. L. Avner ◽  
M. M. Berenson
Keyword(s):  
Bile Acid ◽  
Acid Secretion ◽  
Transport Process ◽  
Bile Flow ◽  
Ethacrynic Acid ◽  
Sodium Taurocholate ◽  
Secretory Process ◽  
Sodium Dehydrocholate ◽  
Major Route ◽  
Bile Acid Secretion

The major route of protoporphyrin elimination is biliary secretion. To clarify the nature of the secretory process, maximal canalicular secretion of protoporphyrin was determined under basal conditions and after treatment with various choleretics. The maximal secretion of protoporphyrin under basal conditions was 0.07 +/- 0.01 micrograms.min-1.100 g body wt-1. Infusion of physiological amounts of sodium taurocholate increased protoporphyrin secretion 13-fold (0.90 +/- 0.02), primarily by increasing the biliary protoporphyrin concentration. Biliary protoporphyrin secretion tended to plateau in spite of a continued rise in both biliary bile acid secretion and concentration. Infusion of sodium dehydrocholate increased protoporphyrin secretion, but to only 35% of that achieved by sodium taurocholate. Ethacrynic acid and phenobarbital increased bile flow over controls but failed to enhance protoporphyrin transport. Thus, canalicular secretion of protoporphyrin was maximally enhanced by micelle-forming bile acids and unaffected by nonbile acid choleretics. The observed limitation of protoporphyrin secretion may be related to achievement of a canalicular transport maximum or to a toxic effect of protoporphyrin on the transport process.

Effects of Na+ replacement and amiloride on ursodeoxycholic acid-stimulated choleresis and biliary bicarbonate secretion

1987 ◽  
Vol 252 (2) ◽  
pp. G163-G169 ◽  
Author(s):  
J. R. Lake ◽  
R. W. Van Dyke ◽  
B. F. Scharschmidt
Keyword(s):  
Bile Acid ◽  
Ursodeoxycholic Acid ◽  
Bile Flow ◽  
Acid Output ◽  
Fold Increase ◽  
Isolated Perfused Rat Liver ◽  
Bicarbonate Secretion ◽  
Bile Formation ◽  
Li Substitution ◽  
Stimulation Of

In these studies, we have tested the hypothesis that bile acid-dependent bile formation is attributable, in part, to the stimulation of active bicarbonate secretion and have further explored the cellular mechanism(s) possibly involved in this process using the isolated perfused rat liver. Under control conditions, ursodeoxycholic acid (UDCA) infusion (3 mumol/min X 20 min) produced a 3.7-fold increase in bile flow and a 7.4-fold increase in HCO3- output. Amiloride (an inhibitor of Na+-H+ exchange) decreased UDCA-stimulated bile flow by 20.6% and decreased biliary HCO3- output by 24.9% but increased biliary UDCA output by 42.9%. Thus amiloride decreased UDCA choleretic efficiency (microliter UDCA-stimulated bile/mumol UDCA output) by 45% and UDCA-stimulated increase in HCO3- output per unit UDCA secreted by 48%. Substitution of Li+ for Na+ in perfusate virtually abolished (greater than 95% decrease) both the UDCA choleresis and increase in biliary HCO3- output but modestly decreased (39.6%) biliary bile acid output. Li+ substitution thus decreased UDCA choleretic efficiency by 98% and the UDCA-stimulated increase in HCO3- output by 96%. Amiloride had no effect and Li+ substitution produced a modest decrease in basal bile flow (26.0%) and HCO-3 output (33.5%). Neither amiloride nor Li+ substitution significantly affected UDCA uptake by cultured hepatocytes or by perfused liver. Amiloride (1 mM) also decreased taurocholate (TC)-stimulated choleresis by 48.5%, biliary TC output by 7.2%, and the choleretic efficiency of TC by 45%.(ABSTRACT TRUNCATED AT 250 WORDS)

Protoporphyrin IX-Induced Impairment of Biliary Lipid Secretion in the Rat

1989 ◽  
Vol 77 (5) ◽  
pp. 473-478 ◽  
Author(s):  
F. Perez-Barriocanal ◽  
J. G. Redondo-Torres ◽  
G. R. Villanueva ◽  
E. Arteche ◽  
M. M. Berenson ◽  
...  
Keyword(s):  
Body Weight ◽  
Bile Acid ◽  
Bile Flow ◽  
Acid Output ◽  
Total Phospholipid ◽  
Protoporphyrin Ix ◽  
Biliary Secretion ◽  
Canalicular Membrane ◽  
Anaesthetized Rats ◽  
Phospholipid Species

1. In order to gain information on the effect of protoporphyrin IX on changes in the properties of the canalicular plasma membrane, we studied the release of canalicular membrane constituents, namely phospholipids, cholesterol and 5′-nucleotidase, into bile in anaesthetized rats receiving saline or taurocholate (0.5 μmol min−1 100 g−1 body weight) with or without protoporphyrin IX infusion (10 or 20 μg min−1 100 g−1 body weight). 2. Protoporphyrin IX induced an impairment of spontaneous bile flow and of biliary secretion of cholesterol, phospholipids and bile acids. The taurocholate-induced increase in bile acid output was not significantly reduced by protoporphyrin IX at either of the doses used. However, when a cholestatic dose of protoporphyrin IX was infused, the taurocholate-induced bile flow and secretion of lecithin and cholesterol were significantly reduced. 3. Biliary output of phospholipid species other than lecithin did not counterbalance the protoporphyrin IX-induced reduction in biliary lecithin secretion. Biliary outputs of both total phospholipid and lecithin were inhibited by protoporphyrin IX to similar extents. 4. Protoporphyrin IX alone had no effect on the biliary release of 5′-nucleotidase, whereas when it was given with taurocholate, it increased the bile acid-induced biliary output of this enzyme markedly. 5. In summary, these results indicate that protoporphyrin IX impairs the biliary secretion of phospholipids and cholesterol but not that of bile acid. The release of canalicular membrane constituents other than lipids was also modified by protoporphyrin IX.

[14C]erythritol clearance and canalicular bile acid-independent flow in the baboon

1982 ◽  
Vol 242 (5) ◽  
pp. G475-G480
Author(s):  
S. M. Strasberg ◽  
R. G. Ilson ◽  
C. N. Petrunka
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Bile Flow ◽  
Quantitative Assessment ◽  
Sodium Taurocholate ◽  
Hepatic Bile ◽  
Bile Formation ◽  
Canalicular Bile

The use of [14C]erythritol for the quantitative assessment of hepatic bile formation has been studied in baboons using sodium taurocholate to generate canalicular bile flow. It has been found that increments in [14C]erythritol clearance are equal to taurocholate-induced increments in bile flow, but there was no change in [14C]erythritol clearance when bile flow was increased by secretin. No evidence was found to support the view that bile acids affect bile acid-independent bile flow.

History of hepatic bile formation: old problems, new approaches

2014 ◽  
Vol 38 (4) ◽  
pp. 279-285 ◽  
Author(s):  
Norman B. Javitt
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Water Flow ◽  
Bile Flow ◽  
Water Movement ◽  
Sodium Taurocholate ◽  
Biliary System ◽  
Hepatic Bile ◽  
Bile Formation ◽  
Osmotic Effect

Studies of hepatic bile formation reported in 1958 established that it was an osmotically generated water flow. Intravenous infusion of sodium taurocholate established a high correlation between hepatic bile flow and bile acid excretion. Secretin, a hormone that stimulates bicarbonate secretion, was also found to increase hepatic bile flow. The sources of the water entering the biliary system with these two stimuli were differentiated by the use of mannitol. An increase in its excretion parallels the increase in bile flow in response to bile acids but not secretin, which led to a quantitative distinction between canalicular and ductular water flow. The finding of aquaglyceroporin-9 in the basolateral surface of the hepatocyte accounted for the rapid entry of mannitol into hepatocytes and its exclusion from water movement in the ductules where aquaporin-1 is present. Electron microscopy demonstrated that bile acids generate the formation of vesicles that contain lecithin and cholesterol after their receptor-mediated canalicular transport. Biophysical studies established that the osmotic effect of bile acids varies with their concentration and also with the proportion of mono-, di-, and trihydroxy bile acids and provides a basis for understanding their physiological effects. Because of the varying osmotic effect of bile acids, it is difficult to quantify bile acid independent flow generated by other solutes, such as glutathione, which enters the biliary system. Monohydroxy bile acids, by markedly increasing aggregation number, severely reduce water flow. Developing biomarkers for the noninvasive assessment of normal hepatic bile flow remains an elusive goal that merits further study.

Differing effects of norcholate and cholate on bile flow and biliary lipid secretion in the rat

1984 ◽  
Vol 246 (1) ◽  
pp. G67-G71
Author(s):  
E. R. O'Maille ◽  
S. V. Kozmary ◽  
A. F. Hofmann ◽  
D. Gurantz
Keyword(s):  
Bile Acid ◽  
Acid Secretion ◽  
Bile Acids ◽  
Bile Flow ◽  
Critical Micellar Concentration ◽  
Biliary Lipid ◽  
Lipid Secretion ◽  
Unit Increase ◽  
Cholesterol Secretion ◽  
Bile Acid Secretion

The effects of norcholate (a C23 bile acid that differs from cholate in having a side chain containing four rather than five carbon atoms) on bile flow and biliary lipid secretion were compared with those of cholate, using the anesthetized rat with a bile fistula. Norcholate and cholate were infused intravenously over the range of 0.6-6.0 mumol X min-1 X kg-1. Both bile acids were quantitatively secreted into bile; norcholate was secreted predominantly in unconjugated form in contrast to cholate, which was secreted predominantly as its taurine or glycine conjugates. The increase in bile flow per unit increase in bile acid secretion induced by norcholate infusion [17 +/- 3.2 (SD) microliters/mumol, n = 8] was much greater than that induced by cholate infusion (8.6 +/- 0.9 microliters/mumol, n = 9) (P less than 0.001). Both bile acids induced phospholipid and cholesterol secretion. For an increase in bile acid secretion (above control values) of 1 mumol X min-1 X kg-1, the increases in phospholipid secretion [0.052 +/- 0.024 (SD) mumol X min-1 X kg-1, n = 9] and cholesterol secretion (0.0071 +/- 0.0033 mumol X min-1 X kg-1, n = 9) induced by norcholate infusion were much less than those induced by cholate infusion (0.197 +/- 0.05 mumol X min-1 X kg-1, n = 9, and 0.024 +/- 0.011 mumol X min-1 X kg-1, n = 9, respectively; P less than 0.001 for both phospholipid and cholesterol). The strikingly different effects of norcholate on bile flow and biliary lipid secretion were attributed mainly to its possessing a considerably higher critical micellar concentration than cholate.

Biliary Inter-Relationship between Phospholipid, Bilirubin and Taurocholate in the Anaesthetized Rat

1984 ◽  
Vol 67 (5) ◽  
pp. 499-504 ◽  
Author(s):  
J. J. García-Marín ◽  
A. Esteller
Keyword(s):  
Body Weight ◽  
Bile Flow ◽  
Bile Salts ◽  
Mixed Micelle ◽  
Enterohepatic Circulation ◽  
Important Determinant ◽  
Sodium Taurocholate ◽  
Micelle Formation ◽  
Mixed Micelle Formation ◽  
Anaesthetized Rat

1. The interference between biliary phospholipid and bilirubin secretion was investigated in rats with bile fistulae, under conditions of normal and maximal bilirubin secretion. The enterohepatic circulation of bile salts was interrupted and the animals received infusions of sodium taurocholate, a micelle-forming physiological bile salt. 2. Sodium taurocholate infusion (0.19 μmol min−1 100 g−1 body weight) induced an increase in bile flow and phospholipid secretion, while basal bilirubin secretion was not increased. 3. Bilirubin infusion (0.26 μmol min−1 100 g−1 body weight) induced a decrease in basal and taurocholate-stimulated phospholipid secretion. Biliary mixed micelle formation was presumably altered during bilirubin infusion, although bile taurocholate concentration, taurocholate secretion rate and bile flow were not modified. 4. When sodium taurocholate was infused during bilirubin-decreased phospholipid secretion, this secretion was restored but maximal biliary bilirubin secretion was not increased. 5. These results provide circumstantial evidence for the hypothesis that mixed micelle formation is not an important determinant of maximal bilirubin transport into bile.

The contribution of the extrahepatic bile ducts to bile formation

1976 ◽  
Vol 54 (5) ◽  
pp. 757-763 ◽  
Author(s):  
S. M. Strasberg ◽  
C. N. Petrunka ◽  
R. G. Ilson
Keyword(s):  
Bile Acid ◽  
Bile Flow ◽  
Bile Ducts ◽  
Bilirubin Concentration ◽  
Bile Formation ◽  
Fed State ◽  
Extrahepatic Bile Ducts ◽  
Bile Flow Rate ◽  
Two Sides ◽  
Bile Samples

This study was performed to determine the contribution of the extrahepatic bile ducts to bile flow in the rhesus monkey. Bile flow from the two sides of the liver was divided. The major extrahepatic bile ducts remained connected to one side of the liver only. Bile flow, and the concentrations of [14C]erythritol, bicarbonate, bile acid, and bilirubin in bile samples from the two sides of the liver, in the fed state were measured and compared. An estimate of the net flow from the extrahepatic ducts was obtained from the [14C]erythritol concentrations on the two sides of the liver and the bile flow rate on the side with the extrahepatic ducts. The [14C]erythritol bile–plasma ratio was significantly lower in bile collected from the side with the extrahepatic bile ducts, than in bile from the other side of the liver. About 10% of total hepatic bile flow originated in the extrahepatic bile ducts, in the fed state. The bicarbonate-[14C]erythritol concentration ratio was significantly higher in bile from the side with the extrahepatic bile ducts. Bicarbonate – bile acid, and bicarbonate–bilirubin concentration ratios were also significantly higher in bile from the side of the liver with the extrahepatic ducts. The extrahepatic bile ducts have a physiologically significant role in the secretion of bile water. Bicarbonate is secreted in association with water in the extrahepatic ducts.

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