Bile Flow In Dogs Research Articles

The effect of prostanoids on hepatic bile flow in dogs with normal liver and bile duct cell hyperplasia

Bile flow rates and composition are subject to a wide variety of neural, endocrine and paracrine influences. The effects of these multiple factors may be different in the diseased liver compared to the response produced in the normal liver. As prostanoids may have a therapeutic role in liver disease it was intended to evaluate the effects of two principal therapeutic prostanoids, prostaglandin E 2 and prostacyclin, on bile flow in dogs with a normal liver and in dogs with hepatotoxin-induced liver injury. Initially, in awake animals with chronic biliary and gastric fistulas the bile flow response to prostaglandin E 2 and prostacyclin was evaluated and compared to the response produced by bile salt infusion alone and to that produced by the standard choleretic hormones, secretin and glucagon. The animals were then fed α-naphthylisothiocyanate (ANIT) and the studies repeated. ANIT is a hepatotoxin that produces bile duct cell hyperplasia which was confirmed in dogs by demonstrating that ANIT increased [ 3H]thymidine incorporation by isolated canine bile duct cells. In normal dogs, the prostanoids, secretin, and glucagon increased hepatic bile flow. 10 days of ANIT feeding produced a hypercholeresis. While secretin was able to stimulate the hyperplastic biliary epithelium and increase bile flow over values produced by the hyperplastic biliary epithelium alone, neither prostaglandin E 2, prostacyclin, or glucagon appeared to stimulate the hyperplastic biliary epithelium. As ANIT produced evidence of cholestasis and hepatocellular damage, only secretin would seem to have a potential therapeutic role in increasing bile flow in cholestatic liver disorders associated with bile duct cell hyperplasia.

Effect of cyclosporine and steroids on canine bile flow

Cyclosporine and hydrocortisone are the main immunosuppressants used in transplant surgery. The purpose of this study was to determine the effect of intravenous administration of cyclosporine and hydrocortisone on bile flow in dogs. Cyclosporine in doses of 0.5, 1.0 and 1.5 mg.kg-1.hr-1 were administered along with 18 mumol/min intravenous sodium taurocholate to dogs with chronic biliary and gastric fistulas. Bile volume and bile chloride concentration and output were increased by cyclosporine in a dose-related manner, whereas bile salt concentration decreased and bile salt output was unchanged. Hydrocortisone produced small but significant increases in bile flow only at the highest dose of hydrocortisone administered. Subsequently, experiments were performed when sodium taurocholate was administered in progressively increasing doses (9, 18 and 36 mumol/min), with the dose changed every hour. Bile volume, [14C]erythritol clearance in bile and bile salt concentrations were measured with and without cyclosporine and hydrocortisone administration. Cyclosporine increased the bile salt-independent fraction of canalicular bile flow and ductular bile flow. Experiments evaluating the role of the cyclosporine carrier polyoxyethylated castor oil (Cremophor EL) demonstrated that this substance had no independent choleretic activity, whereas cyclosporine dissolved in ethanol and administered without Cremophor EL significantly increased bile flow. The results of this study indicate that cyclosporine stimulates chloride-rich choleresis independent of bile salt secretion.

Effect of cyclosporine and steroids on canine bile flow

Cyclosporine and hydrocortisone are the main immunosuppressants used in transplant surgery. The purpose of this study was to determine the effect of intravenous administration of cyclosporine and hydrocortisone on bile flow in dogs. Cyclosporine in doses of 0.5, 1.0 and 1.5 mg · kg−1 · hr−1 and hydrocortisone in doses of 1.25, 2.5 and 5 mg · kg−1 · hr−1 were administered along with 18 μmol/min intravenous sodium taurocholate to dogs with chronic biliary and gastric fistulas. Bile volume and bile chloride concentration and output were increased by cyclosporine in a dose-related manner, whereas bile salt concentration decreased and bile salt output was unchanged. Hydrocortisone produced small but significant increases in bile flow only at the highest dose of hydrocortisone administered. Subsequently, experiments were performed when sodium taurocholate was administered in progressively increasing doses (9, 18 and 36 μmol/min), with the dose changed every hour. Bile volume, [14C]erythritol clearance in bile and bile salt concentrations were measured with and without cyclosporine and hydrocortisone administration. Cyclosporine increased the bile salt-independent fraction of canalicular bile flow and ductular bile flow. Experiments evaluating the role of the cyclosporine carrier polyoxyethylated castor oil (Cremophor EL) demonstrated that this substance had no independent choleretic activity, whereas cyclosporine dissolved in ethanol and administered without Cremophor EL significantly increased bile flow. The results of this study indicate that cyclosporine stimulates chloride-rich choleresis independent of bile salt secretion.

Quantitative hepatobiliary scintigraphy as a measure of bile flow in dogs with cholestatic disease

SUMMARY In 25 dogs with spontaneous cholestatic disease, the hepatobiliary dynamics were evaluated by use of scintigraphy and a 99mTc-labeled iminodiacetate (ida) derivative. Hyperbilirubinemia existed in all dogs, with serum total bilirubin concentration ranging from 6 to 262 (μmol/L. An appropriate compartmental model was used to characterize the liver time-activity curves. Model-dependent variables for hepatic uptake and biliary excretion of radiolabeled IDA were found to reliably represent the underlying physiologic processes. Measurements directly derived from the liver time-activity curves of IDA, representing the moments of accumulation of 50 and 95% of the maximal hepatic activity did not accurately represent the hepatic uptake by being significantly influenced by biliary excretion and by competition of renal excretion. The time-interval between 95% and 50% of the maximal activity in the excretory phase proved to be a quantitative characteristic of bile flow in all instances. Compartmental analysis of 99mTc-ida excretory scintigraphy characterized bile flow quantitatively in clinically normal dogs and in dogs with cholestasis. The method permitted the clinical evaluation of cholestasis based on quantitative, instead of the usual qualitative, and on functional, instead of phenomenologic, criteria.

Role of glucagon in cholecystokinin-stimulated bile flow in dogs.

Although many choleretic agents are known, their physiological roles and interrelationships in increasing bile flow remain largely undetermined. Exogenous cholecystokinin (CCK), glucagon, and insulin are stimulants of hepatic bile flow in animals and humans. Of possible importance in the choleresis produced by CCK is the stimulation by exogenous CCK of glucagon and insulin release from the pancreas. This research evaluates the role of glucagon and insulin in the choleresis produced by CCK. Dogs with chronic biliary and gastric fistulas were used. The synthetic octapeptide of CCK (CCK-8) administered in increasing doses produced progressive increases in bile volume, bile bicarbonate secretion, and bile chloride concentration and output. The choleresis produced by CCK-8 was qualitatively similar to that produced by intravenous glucagon. CCK-8 administration in increasing doses produced progressive increases in plasma glucagon. When bile flow changes during CCK-8 administration were correlated with changes in plasma glucagon, significant correlation existed. CCK-8 significantly increased serum insulin concentration only at the highest dose of CCK-8 administered. Somatostatin is an inhibitor of hormone release. Administration of somatostatin, along with CCK-8, inhibited the choleresis and the increased plasma glucagon produced by CCK-8 administration alone. During acute experiments in anesthetized dogs, the pancreas and stomach were removed to eliminate endogenous glucagon and insulin release. (ABSTRACT TRUNCATED AT 250 WORDS)

Effect of theophylline on glucagon and secretin stimulated bile flow.

This experiment was performed to determine the effect of theophylline on glucagon and secretin stimulated bile flow. We intended to determine the effect of theophylline, a proposed stimulant of canalicular bile flow, on the bile flow response produced by well-recognized stimulants of canalicular (glucagon) and ductular (secretin) bile flow. Dogs with chronic bile fistulas were used. Dose-response curves for glucagon and secretin were produced by administration of a wide range of glucagon and secretin doses. The effect of 20 mg/kg/hr theophylline on the dose-response curves was determined. Theophylline significantly increased the bile flow and bile electrolyte changes produced by glucagon at low doses but not at maximal doses of glucagon for stimulation of bile flow. Theophylline significantly increased bile volume and bile electrolyte changes at all doses of secretin, including maximal doses. These results suggest that theophylline and glucagon, both purported to be stimulants of canalicular bile flow in dogs, utilize the same receptor mechanism to stimulate bile flow. The effects of secretin, a proposed ductular stimulant, are potentiated by theophylline. On a functional basis, it is possible that there are separate canalicular and ductular loci of hormone action in stimulation of bile secretion.

Effect of Somatostatin and Bombesin on Secretin-Stimulated Ductular Bile Flow in Dogs

The effects of somatostatin and bombesin on the choleresis produced by intraduodenal acid infusion were evaluated in dogs. Because of the documented effect of these agents on hormone release, serum gastrin and plasma secretin levels were monitored. Intraduodenal acid (12 mmol/h) increased bile flow and bile bicarbonate secretion and nearly doubled systemic plasma secretin levels. Bombesin significantly increased the bicarbonate-rich choleresis produced by intraduodenal acid and increased secretin release. Somatostatin inhibited completely the choleresis produced by 12 mmol/h of intraduodenal acid but did not significantly change systemic plasma secretin levels. Subsequent studies evaluated the effects of somatostatin (10 micrograms/kg . h) on bile flow and on systemic and portal plasma secretin concentrations stimulated by exogenous secretin administration and intraduodenal acid infusion. These studies demonstrated that somatostatin did not significantly change the choleretic response or the increases in plasma secretin produced by exogenous secretin. During duodenal acid infusion, somatostatin inhibited the choleresis and significantly decreased portal plasma secretin release. Evaluation of the relationship of the increase in bile flow to the increase in portal vein secretin concentrations, as well as comparison of the degree of inhibition of bile flow with the inhibition of secretin release produced by somatostatin, indicates that secretin produces approximately 80% of the choleresis produced by acid in the duodenum. Bombesin augments bile flow stimulated by infusion of acid into the duodenum by increasing secretin release, while somatostatin decreases bile flow produced by acid in the duodenum by directly inhibiting the release of secretin from the duodenal mucosa.

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.

Secretin enhances [14C]erythritol clearance in unanesthetized dogs.

To determine the effect of secretin infusion on clearance of inert markers into bile, unanesthetized dogs fitted with Thomas cannulas received continuous infusions of [14C]erythritol and [3H]inulin throughout study. Taurocholic acid administered sequentially at 9.0, 20.0, and 40.0 mumol/min enhanced [14C]erythritol clearance, and GIH secretin (3 units/min) administered along with TCA (40.0 mumol/min) increased [14C]erythritol clearance from 4.9 +/- 1.2 ml/10 min to 6.8 +/- 1.3 ml/10 min (P less than 0.001), but simultaneously measured [3H]inulin clearance was unaltered. Secretin alone also increased [14C]erythritol clearance but did not alter [3H]inulin clearance. The increase in [14C]erythritol clearance per unit increase in bile flow was less during secretin infusion than TCA. Thus, secretin increases [14C]erythritol transport through restricted channels, probably distal to the canaliculi. [14C]Erythritol may not be an accurate marker for canalicular bile flow in dogs during secretin infusion.

The role of cyclic AMP in canine secretin-stimulated bile flow

Cyclic nucleotide secretion rates in bile during the physiologic stimulation of ductular bile flow in dogs was evaluated by measurement of bile cyclic AMP concentration during the stimulation of secretin release by infusion of acid into the duodenum of dogs with chronic bile fistulas. The effects of PGA 1 and theophylline on secretin-stimulated bile flow and cyclic AMP secretin rates were also evaluated. Endogenous secretin stimulated bicarbonate-rich bile flow and decreased bile cyclic AMP concentration. PGA 1 significantly decreased secretin-stimulated bile flow but not bile cyclic AMP secretion. Theophylline did not alter secretin-stimulated bile flow or cyclic AMP secretion rates. These data indicate that based on cyclic AMP content in bile, secretin-stimulated ductular bile flow is unrelated to cyclic AMP metabolism.

Biliary spasmolytic action of 3-(2,4,5-triethoxybenzoyl)propionic acid (AA-149) in dogs

The spasmolytic action of 3-(2,4,5-triethoxybenzoyl)propionic acid (AA-149) on the biliary tract was investigated i in anesthetized dogs. Intravenous administration of AA-149 at 2 mg/kg and higher doses produced a dose- dependent reduction in passage resistance through the choledochoduodenal junction and in gallbladder pressure, and a dose-dependent increase in bile flow. AA-149, like cholecystokinin, decreased biliary ductal pressure in spite of increasing the bile flow in dogs with ligation of the cystic duct of the gallbladder, whereas taurocholate increased the pressure as well as the bile flow. Moreover, the spasmic response of the choledochoduodenal junction to morphine was depressed strongly by AA-149, but not consistently by atropine. The effects of AA-149 were not influenced by pretreatment with atropine, phentolamine or propranolol. These findings strongly suggest that AA-149 releaxed the biliary tract and depressed the morphine-induced spasm by a mechanism different from those of anticholinergic and sympathomimetic agents.

Effect of the histamine (H2) inhibitor metiamide on histamine-stimulated bile flow in dogs.

The effects of the histamine H2-receptor inhibitor metiamide on histamine-stimulated canine bile flow and gastric hydrogen ion output were evaluated. Histamine was found to stimulate bile volume in doses comparable to those that stimulated gastric hydrogen ion output; both responses appeared to have the same maximal response dose, 150 mug/kg per h. Metiamide alone did not alter hepatic bile flow. Administration of metiamide, 2 mg/kg per h, along with various doses of histamine demonstrated that the H2-receptor antagonist decreased bile volume and gastric hydrogen ion output from values obtained with histamine administration alone. The D50 of histamine for bile flow was 16.3 mug/kg per h and the D50 for hydrogen ion output was 44.2 mug/kg per h, Kinetic analysis suggests that the decrease in histamine-stimulated hydrogen ion output produced by metiamide is the result of competitive inhibition; the decrease in histamine-stimulated bile volume by metiamide which is different from the hydrogen ion inhibition, suggests noncompetitive inhibition. These data indicate that the mechanism of histamine choleresis is different from the mechanism of histamine-stimulated gastric acid output and that histamine-stimulated bile flow may not be the result of direct hormone-receptor interaction.