Regulation Of Bile Secretion Research Articles

The effect of histamine in E2 nucleus of hypothalamus on the regulation of bile secretion and lipid metabolism in the rat

Bile formation is regulated by hormones, regulatory peptides, and neurotransmitters. Histamine is a biogenic amine that is mainly produced in mast cell, basophile, and neuron. The histaminergic neurons are located in the tuberal region of the posterior hypothalamus in the tuberomammillary nucleus which contains five nucleuses. The E2 nucleus is larger, its activity is more than the other nucleuses, and it also has 50 % of all histaminergic neurons. The aim of the present work was to establish the role of histamine injected into the E2 nucleus in the central regulation of bile secretion, serum lipids level, and hepatic enzymes in the rat. Rats were cannulated in the E2 nucleus for the administration of 1 μl histamine. After 1 week, the common bile duct was cannulated and bile samples were collected every 15 min for 60 min after the administration of histamine, and biochemical analyses were done on blood samples. Centrally applied histamine increased bile secretion at all studied periods, indirect bilirubin, total bilirubin, and low-density lipoprotein cholesterol levels. The results showed that histamine participates in the central regulation of bile secretion in the rat, and the E2 nucleus can be a special site for the regulation of bile secretion and lipid levels. These findings give further insight into the complexity of brain–liver interaction.

Effects of Centrally Applied Serotonin in Ventromedial Hypothalamic Nucleus on Regulation of Bile Secretion and Lipid Metabolism in the Rat

Ventromedial hypothalamic nucleus (VMH) is one of the brain regions responsible for regulating gastrointestinal activities and lipid metabolism. Hepatic enzymes and serum lipids are controlled by the central nervous system and VMH is involved in the regulation of lipid metabolism. In the present study we sought to establish the role of serotonin to regulation of bile secretion, serum lipids level and hepatic enzymes in the rat. Rats were cannulated in the VMH for the administration of serotonin. After 1 week the common bile duct was cannulated and bile samples were collected after the administration of 5-HT, and biochemical analyses occurred on blood samples. Centrally applied 5-HT increased bile secretion at all studied periods and also decreased LDL-cholesterol (LDL-c) level. Present findings show that 5-HT participates in the central regulation of bile secretion in the rat, and VMH can be a special site for regulation of bile secretion and lipid levels.

Effects of Centrally Applied Serotonin in Ventromedial Hypothalamic Nucleus on Regulation of Bile Secretion and Lipid Metabolism in the Rat

Effects of Centrally Applied Serotonin in Ventromedial Hypothalamic Nucleus on Regulation of Bile Secretion and Lipid Metabolism in the Rat

Cloning, purification, and identification of the liver canalicular ecto-ATPase as NTPDase8

Extracellular nucleotides regulate critical liver functions via the activation of specific transmembrane receptors. The hepatic levels of extracellular nucleotides, and therefore the related downstream signaling cascades, are modulated by cell-surface enzymes called ectonucleotidases, including nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39), NTPDase2/CD39L1, and ecto-5'-nucleotidase/CD73. The goal of this study was to determine the molecular identity of the canalicular ecto-ATPase/ATPDase that we hypothesized to correspond to the recently cloned NTPDase8. Human and rat NTPDase8 cDNAs were cloned, and the genes were located on chromosome loci 9q34 and 3p13, respectively. The recombinant proteins, expressed in COS-7 and HEK293T cells, were biochemically characterized. NTPDase8 was also purified from rat liver by Triton X-100 solubilization, followed by DEAE, Affigel Blue, and concanavalin A chromatographies. Importantly, NTPDase8 was responsible for the major ectonucleotidase activity in liver. The ion requirement, apparent K(m) values, nucleotide hydrolysis profile, and preference as well as the resistance to azide were similar for recombinant NTPDase8s and both purified rat NTPDase8 and porcine canalicular ecto-ATPase/ATPDase. The partial NH(2)-terminal amino acid sequences of all NTPDase8s share high identity with the purified liver canalicular ecto-ATPase/ATPDase. Histochemical analysis showed high ectonucleotidase activities in bile canaliculi and large blood vessels of rat liver, in agreement with the immunolocalization of NTPDase1, 2, and 8 with antibodies developed for this study. No NTPDase3 expression could be detected in liver. In conclusion, NTPDase8 is the canalicular ecto-ATPase/ATPDase and is responsible for the main hepatic NTPDase activity. The canalicular localization of this enzyme suggests its involvement in the regulation of bile secretion and/or nucleoside salvage.

The role of opioid peptides in regulation of bile secretion in intact and isolated liver

Influence of dalargin (non-selective mand d-аgonist), DADLE (selective) and DAGO (selective magonist) on the bile secretion frequency and cholates secretion was studied in acute experiments on isolated perfused liver of the white rats. Opioid peptides effects on isolated liver were revealed to mask by the higher levels of hierarchic regulation in intact liver.

The role of inositol 1,4,5-trisphosphate receptors in the regulation of bile secretion in health and disease

Ca 2+ signaling via the inositol 1,4,5-trisphosphate receptor (InsP3R) is a ubiquitous mechanism for regulation of cell function, yet very little is known about the role of the InsP3R in specific disease states. Converging lines of evidence suggest that the liver may provide a model for the role of the InsP3R in health and disease. Ca 2+ signaling is mediated entirely by the InsP3R in hepatocytes and cholangiocytes, the two types of epithelia in the liver. Here we review the role of specific InsP3R isoforms and the physiological effects of InsP3R-mediated Ca 2+ signals in both of these types of epithelia. In addition, we review evidence that the InsP3R is lost from cholangiocytes in cholestatic forms of liver disease, and discuss this as a possible final common pathway for cholestasis.

NPR-C receptors are involved in C-type natriuretic peptide response on bile secretion

C-type natriuretic peptide (CNP) is a member of the natriuretic peptide family. Previous studies reported the presence of natriuretic peptide receptors and mRNA CNP in the liver. In the present work, we sought to establish the role of CNP in the regulation of bile secretion in the rat and the possible pathways involved. CNP diminished basal as well as bile salt-evoked bile flow and bile acid output in a dose-dependent manner. It also reduced the excretion of sodium, chloride, and potassium but did not modify bile pH or the excretion of phospholipids, total proteins, and glutathione. Neither parasympathetic nor sympathetic blockade abolished CNP inhibitory response on bile secretion. The selective NPR-C agonist, C-ANP-(4-23) amide, diminished bile flow and the co-administration of both peptides did not further decrease it. CNP did not alter mean arterial pressure or portal venous pressure at any given doses. CNP decreased bile acid-dependent flow without affecting bile acid-independent flow. The inhibitory effect of CNP did not involve the participation of the autonomic nervous system or hemodynamic changes. The participation of NPR-C receptors in CNP response is strongly supported by present findings. The present study shows that CNP modulates bile secretion in the rat, suggesting that CNP may be part of the large family of peptides involved in the regulation of gastrointestinal physiology.

Bile secretion is centrally regulated by C-type natriuretic peptide.

1. Current evidence supports that C-type natriuretic peptide (CNP) is the brain natriuretic peptide. Natriuretic peptide receptors and mRNA CNP have been reported in the liver and in discrete areas and nucleus of the central nervous system involved in the regulation of gastrointestinal physiology. In the present work, we sought to establish the role of CNP in the central regulation of bile secretion in the rat and to delineate the possible pathways and mechanisms involved. 2. To examine the role of CNP on bile secretion, the peptide was applied in the brain lateral ventricle (1, 10, and 100 ng/microL) and bile samples were collected every 15 min for 60 min. The role of the autonomic nervous system in CNP response was assessed by atropine or combined phentolamine and propranolol administration. 3. Centrally applied CNP diminished basal as well as bile salt-evoked bile flow in a dose-dependent manner. CNP reduced bile acid output as well as sodium and potassium excretion, supporting CNP effect on bile acid-dependent flow. CNP also decreased chloride excretion and increased bile pH. The excretion of total glutathione was not affected by centrally applied CNP suggesting that this peptide does not alter bile acid-independent flow. Neither parasympathetic nor sympathetic blockade abolished CNP inhibitory response on bile secretion. Mean arterial pressure and portal venous pressure were not modified by CNP. 4. Present findings show that centrally applied CNP modulates bile secretion in a dose-dependent fashion. CNP alkalinized bile and reduced bile acid-dependent flow without affecting bile acid-independent flow. The inhibitory response of CNP on bile secretion was not mediated by the autonomic nervous system. Present findings give further support to the role of CNP as the brain natriuretic peptide.

Centrally applied atrial natriuretic factor diminishes bile secretion in the rat

Little is known about the role of centrally applied peptides in the regulation of bile secretion. We previously reported that the intravenous injection of atrial natriuretic factor (ANF) reduces bile acid dependent flow without affecting portal venous pressure in the rat. In the present work, we studied the effects of centrally applied ANF on bile secretion and the possible pathways involved. Rats were cannulated in the brain lateral ventricle for the administration of 1, 10 and 100 ng/μl ANF. After 1 week, the common bile duct was cannulated and bile samples were collected every 15 min for 60 min after the administration of ANF. The excretion rate of various biliary components was assessed. Bile secretion experiments were also performed after bilateral truncal vagotomy or atropine administration to evaluate the participation of a vagal pathway. In addition, the role of the sympathetic system was addressed by combined administration of propranolol and phentolamine. Centrally applied ANF did not modify blood pressure but diminished bile flow and bile acid output. It also reduced sodium and potassium secretion but did not modify protein or phospholipid excretion. Neither bilateral truncal vagotomy nor atropine administration abolished ANF response. Furthermore, combined administration of adrenergic antagonists did not alter ANF inhibitory effect on bile flow. In conclusion, centrally applied ANF reduced bile acid dependent flow not through a vagal or adrenergic pathway in the rat, suggesting the involvement of a peptidergic pathway.

Cholestatic Properties and Hepatic Transport of Steroid Glucuronides

In summary, the data suggest that E217G is transported by both MOAT and P-glycoprotein into bile, but that P-glycoprotein serves as the target site for cholestasis. We postulate that this target site may be accessed from either the intracellular compartment or the canaliculus, and that MOAT serves as the major delivery route for E217G to the canaliculus. At low, physiologic concentrations of E217G, MOAT-mediated excretion into bile is a detoxification mechanism, serving to prevent intracellular accumulation of a toxic metabolite. However, following administration of high, cholestatic doses, MOAT-mediated excretion into bile results in very high concentrations in bile, on the other of 2-3 mM (see Fig. 4). It is likely that the hydrophobic nature of E217G allows it to partition from bile into the canalicular membrane, from which it can access P-glycoprotein and thus induce cholestasis. Much work is still needed to validate this model of E217G cholestasis. Definitive evidence of P-glycoprotein-mediated transport of E217G must be obtained in cell lines transfected with P-glycoprotein where MRP is absent. More importantly, the mechanism by which interaction of E217G with P-glycoprotein influences bile flow is unknown. Higgins and colleagues have provided evidence that P-glycoprotein regulates a Cl- channel in a manner analogous to that of CFTR, the cystic fibrosis transmembrane conductance regulator. While Cl- channels have been shown to be important in the regulation of the volume of the hepatocyte in the presence of altered osmotic conditions, a role for this channel in bile flow has not been demonstrated. Nevertheless, these studies implicate a role of P-glycoprotein in the regulation of bile secretion by the liver.

A new way to obtain contrast-free bile during ERCP

Experiments with human bile have relied on samples obtained from the gallbladder during cholecystectomy or from various biliary drainage tubes such as nasobiliary drains, T-tubes, or percutaneous biliary catheters. 1 McAllister EW Carey LC Brady PG Heller R Kovacs SG The role of polymeric surface smoothness of biliary stents in bacterial adherence, biofilm deposition, and stent occlusion. Gastrointest Endosc. 1993; 39: 422-425 Abstract Full Text PDF PubMed Scopus (89) Google Scholar , 2 Leung JWC Ling TKW Kung JLS Vallance-Owen J The role of bacteria in the blockage of biliary stents. Gastrointest Endosc. 1988; 34: 19-22 Abstract Full Text PDF PubMed Scopus (160) Google Scholar Although these approaches provide large quantities of bile, they have limitations. Bile obtained from the gallbladder of patients undergoing cholecystectomy cannot be considered normal, since most gallbladders removed surgically are diseased, and gallbladder bile is quite different qualitatively from fresh “hepatic bile” obtained from the bile ducts. 3 Nathanson MH Boyer JL Mechanisms and regulation of bile secretion. Hepatology. 1991; 14: 551-566 Crossref PubMed Scopus (372) Google Scholar In addition, subjects with external drainage devices usually have obstructed biliary systems, which can lead to important changes in bile composition.

Regulation of bile secretion by prostaglandins: Role of hemodynamic parameters and nitric oxide (NO)

Regulation of bile secretion by prostaglandins: Role of hemodynamic parameters and nitric oxide (NO)

Effects of Ca2+ agonists on cytosolic Ca2+ in isolated hepatocytes and on bile secretion in the isolated perfused rat liver

The effects of increases in cytosolic Ca2+ on hepatocyte bile secretion are unknown. A number of agents that alter levels of cytosolic Ca2+ in the hepatocyte also produce hepatic vasoconstriction and activate protein kinase C, which complicates interpretations of their effects on bile secretion. To better understand the role of cytosolic Ca2+ in bile secretion, we examined the effect of the Ca2+ ionophore A23187 (0.1 mumol/L), the Ca2+ agonist vasopressin (10 nmol/L) and the Ca(2+)-mobilizing agent, 2,5-di(tert-butyl)-1,4-benzohydroquinone (25 mumol/L) on cytosolic Ca2+ in isolated hepatocytes and on bile flow in the isolated perfused rat liver, using vasodilators and inhibitors of protein kinase C and Ca2+ influx. Single-pass perfused livers were used, and cytosolic Ca2+ was measured by luminescent photometry in isolated hepatocytes loaded with the Ca(2+)-sensitive photoprotein aequorin. After A23187 perfusion, a sustained 74% +/- 10% (mean +/- S.D.) decrease in bile flow and a sustained 271% +/- 50% increase in perfusion pressure was observed. Simultaneous pretreatment with the vasodilator papaverine (25 mumol/L) and the protein kinase C inhibitor H-7 (50 mumol/L) abolished the pressure increase but not the decrease in bile flow, whereas pretreatment with Ni2+ (25 mumol/L) to block the influx of extracellular Ca2+ markedly reduced both the pressure increase and the decrease in bile flow. Vasopressin produced a transient (mean = 6 min) 75% +/- 4% decrease in bile flow and a sustained 7% +/- 4% increase in perfusion pressure. Pretreatment with H-7 alone corrected the vasopressin-induced pressure increase but also failed to eliminate the decrease in bile flow, whereas pretreatment with Ni2+ decreased the magnitude of the decrease by two-thirds without affecting the increase in perfusion pressure, 2,5'-di(tert-butyl)-1,4-benzohydroquinone produced a transient 65% +/- 20% decrease in bile flow and a transient 56% +/- 15% increase in perfusion pressure. In isolated hepatocytes, bromo-A23187, the nonfluorescent form of the ionophore, produced a sustained 56% +/- 32% increase in the cytosolic Ca2+ signal, whereas vasopressin resulted in a transient 241% +/- 75% increase and 2,5-di(tert-butyl)-1,4-benzohydroquinone resulted in a sustained 149% +/- 66% increase. The ionophore-induced increase in Ca2+ was abolished completely by pretreatment of the hepatocytes with Ni2+, whereas the vasopressin-induced increase was reduced by 38%.(ABSTRACT TRUNCATED AT 400 WORDS)

Regulation of bile secretion by sympathetic nerves in perfused rat liver.

Although the biliary system is innervated by the autonomic nervous system, little is known about the regulation of bile secretion by hepatic nerves. In rat liver perfused in situ with constant pressure and erythrocyte-free medium, hepatic nerves were electrically stimulated (20 V, 20 Hz, 2 ms) by a platinum electrode placed around the hepatic artery and portal vein. Nerve stimulation caused a decrease in bile flow, bile acid secretion, and portal flow. The nerve effects on bile secretion were mediated via alpha 1-receptors. In this system, artificial reduction of perfusion flow by 30% led to a similar decrease of bile flow. In perfusion systems with constant flow and erythrocyte-free medium or with constant pressure and erythrocyte-containing medium, the nerve effects were reproduced despite the altered hemodynamics and the increased oxygen supply. In addition, partial inhibition by sodium nitroprusside of the nerve-induced reduction of portal flow had little effect on the reduction in bile secretion. In conclusion, a direct effect on bile formation was suggested. Yet an additional role of a vascular-mediated effect could not definitively be excluded. With the use of inhibitors of prostanoid synthesis the nerve effects on bile secretion were markedly reduced, suggesting a mediating or modulating role of prostanoids.

Mechanisms and regulation of bile secretion

Mechanisms and regulation of bile secretion

Mechanisms and regulation of bile secretion

Mechanisms and regulation of bile secretion

Protein kinase C agonists inhibit bile secretion independently of effects on the microcirculation in the isolated perfused rat liver.

The role of hormones in the regulation of bile secretion is not known; however vasoactive agents, which act via the phosphoinositide signal transduction pathway, may mediate changes in bile flow by altering the hepatic microvasculature. We therefore examined the effects of phorbol esters and diacylglycerol, agonists of the protein kinase C branch of the phosphoinositide cascade, on perfusion pressure and bile flow in a single-pass, hemoglobin-free, isolated perfused rat liver system with constant perfusate flow. The active phorbol ester, 12,13-phorbol dibutyrate, produced a dose-dependent (maximal effect at 10(-6) M), sustained and reversible decrease in bile flow from 1.09 +/- 0.18 to 0.61 +/- 0.09 microliters per min per gm liver (37.2 +/- 5.9%) while simultaneously increasing perfusion pressure from 12.3 +/- 0.7 to 21.5 +/- 2.5 cm H2O (74.0 +/- 4.3%). Both effects were inhibited by the synthetic protein kinase C antagonist H-7. 1,2-Dioctanoyl-sn-glycerol, a diacylglycerol, produced changes in bile flow and perfusion pressure that were similar to, but more marked than, those caused by 12,13-phorbol dibutyrate, whereas the inactive phorbol ester 4 alpha-phorbol didecanoate and the vehicle dimethyl sulfoxide had no effects on either parameter. 12,13-Phorbol dibutyrate infusion resulted in reversible decreases in oxygen consumption (23.3%) and a reversible vascular redistribution of trypan blue dye but did not alter hepatic venous effluent concentrations of K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological and physiological doses of insulin and determinants of bile flow in dogs.

The role of insulin in control of bile secretion is uncertain. To study the mechanism of choleresis produced by large doses of insulin, bile was collected through modified Thomas cannulas from dogs anesthetized with pentobarbital. Animals received pipenzolate methylbromide, sodium taurocholate, and [14C]erythritol. After bile flow had stabilized three animals received infusions of insulin at 2, 4, 13, 26, 35, and 70 mU . kg-1 . min-1 for 40 min each. Bile and [14C]erythritol clearance increased (P less than 0.005), but bile salt output remained constant, suggesting that the choleresis was mainly due to enhanced bile salt-independent canalicular flow. Plasma insulin and glucagon levels also rose when insulin was infused. To exclude the possible effects of glucagon three additional animals received somatostatin (800 ng . kg-1 . min-1) along with infusions of insulin. Bile flow and [14C]erythritol clearance again increased significantly, but glucagon levels remained low, suggesting that the effects on bile flow were due to insulin alone. To determine whether physiological doses of insulin altered bile flow dogs were anesthetized with pentobarbital and received pipenzolate methylbromide, taurocholate, [14C]erythritol, and somatostatin (800 ng . kg-1 . min-1). Insulin (0.2 and 0.8 mU . kg-1 . min-1) was infused through the portal vein for 1 h each. Bile flow and [14C]erythritol clearance increased with insulin (0.8 mU . kg-1 . min-1; P less than 0.02), suggesting that the choleresis may have been due to bile salt-independent canalicular flow. Plasma insulin rose to physiological postprandial levels. These studies demonstrate that pharmacological and physiological levels of insulin administered to dogs produce a significant choleresis. Thus insulin may play an important role in the regulation of bile secretion.

Is glucagon a choleretic hormone at physiologic blood levels?

The mechanism of action and possible physiologic implications of glucagon-induced choleresis were investigated in two groups of dogs. Group I demonstrated, in chronic animal models, that glucagoninduced choleresis was not associated with increased bile acid output and was not blocked by somatostatin or Piptal, suggesting a direct stimulatory effect on bile acid-independent canalicular flow. In acute animal models (group II), glucagon infusion at rates which produced postprandial levels in the portal vein induced significant choleresis, implying that glucagon may have a physiologic role in the regulation of bile secretion. No consistent relation between bile secretion and portal venous blood flow could be demonstrated.

SPONTANEOUS AND BILE SALT STIMULATED BILE SECRETION IN THE ADELIE PENGUIN (PYGOSCELIS ADELIAE)

The flow rate and ionic composition of bile during spontaneous secretion were measured in anaesthetized penguins in which the enterohepatic circulation had been interrupted and with i.v. injection of saline to replace secretory loss. During the first two hours the rate of flow increased, and then remained relatively constant for a further two and a half hours. During this time the concentration of bile salt fell, but the concentrations of other ions showed small fluctuations only. Sodium taurocholate increased the rate of bile flow and the excretion of ions, except that of bicarbonate. Sodium taurolithocholate initially produced cholestasis but later apparently increased bile flow and had an overall choleretic effect. It is suggested that the active excretion of bicarbonate ions by the bile ducts is the predominant regulator of bile secretion in the penguin.