Secretin Choleresis Research Articles

Insulin modulates secretin choleresis through a PKC-a-mediated inhibition of cAMP and PKA

Insulin modulates secretin choleresis through a PKC-a-mediated inhibition of cAMP and PKA

The function of alkaline phosphatase in the liver: Regulation of intrahepatic biliary epithelium secretory activities in the rat

We studied the effects of alkaline phosphatase (AP) on the secretory processes of the rat intrahepatic biliary epithelium as well as the role of the intrahepatic biliary epithelium in the uptake and biliary secretion of exogenous AP. The effects of acute and chronic administration of AP on bile secretory parameters were investigated in vivo in normal and bile duct ligated (BDL) rats and in vitro in isolated rat bile duct units (IBDU).In vivo, acute AP administration decreased bile flow and biliary bicarbonate excretion and abolished secretin choleresis in BDL rats but not in normal rats. On the contrary, the AP inhibitor, levamisole, increased in BDL rat bile flow and biliary bicarbonate excretion. In vitro, basal and secretin-stimulated Cl−/HCO3− exchanger activity in IBDU was immediately inhibited by AP intraluminal microinjection (apical exposure) but only after a prolonged exposure to the basolateral pole. Levamisole increased the Cl−/HCO3− exchanger activity of IBDU. A significant basolateral uptake of AP occurs in IBDU with a progressive transport to the apical domain. AP chronic treatment increased AP and γ-glutamyltranspeptidase (γ-GT) activities in the intrahepatic bile ducts and hepatocyte canalicular pole, promoted enlargement of bile canaliculi, and decreased bile flow and biliary bicarbonate excretion. In conclusion, the intrahepatic biliary epithelium plays a role in the uptake and biliary secretion of serum AP. AP inhibits the secretory processes of the intrahepatic biliary epithelium and induces features of intrahepatic cholestasis after chronic administration. These findings indicate that AP plays an active role in down-regulating the secretory activities of the intrahepatic biliary epithelium. (Hepatology 2000;32:174-184.)

Bile acid-independent bile flow is differently regulated by glucagon and secretin in humans after orthotopic liver transplantation.

The present study characterizes recovery of bile secretion after orthotopic liver transplantation (OLT) in humans with special regard to hormonal regulation of bile acid-independent bile flow by glucagon and secretin. Sixty-seven patients with an uncomplicated postoperative course were studied during the first 3 weeks after OLT to determine normalization of bile flow. A group of 7 and 10 patients, respectively, underwent a biliary stimulation test by either glucagon at days 7, 14, and 21 after OLT or by secretin at days 2, 10, and 21 after OLT. Secretin tests were similarly performed in patients with acute severe rejection during the first 10 days after OLT, while glucagon tests were performed in patients with acute allograft rejection occurring 2 weeks after OLT. Furthermore, hormone effects were studied in nontransplanted patients after cholecystectomy with indwelling biliary T tube. After OLT, bile secretory function recovered and stabilized within 14 days after surgery by reconstitution of both bile acid-dependent and -independent bile flow. Two weeks after OLT, bile secretion was comparable with nontransplanted patients after cholecystectomy. Glucagon and secretin stimulated bile acid-independent bile flow in transplanted and nontransplanted patients significantly, yet secretin choleresis, unlike glucagon choleresis, had already occurred during the first days after OLT and was unaffected by acute allograft rejection. These results allow the speculation that, in humans, glucagon and secretin exert their choleretic activity by different mechanisms and/or at different anatomical sites in the liver. Assuming that secretin acts at the bile duct cells, its secretory capacity was not altered by the transplantation procedure and during moderate or severe rejection episodes, as opposed to glucagon choleresis, which most likely originates in the hepatocytes and requires an entirely reconstituted canalicular transport system after OLT.

Bile acid-independent bile flow is differently regulated by glucagon and secretin in humans after orthotopic liver transplantation.

The present study characterizes recovery of bile secretion after orthotopic liver transplantation (OLT) in humans with special regard to hormonal regulation of bile acid-independent bile flow by glucagon and secretin. Sixty-seven patients with an uncomplicated postoperative course were studied during the first 3 weeks after OLT to determine normalization of bile flow. A group of 7 and 10 patients, respectively, underwent a biliary stimulation test by either glucagon at days 7, 14, and 21 after OLT or by secretin at days 2, 10, and 21 after OLT. Secretin tests were similarly performed in patients with acute severe rejection during the first 10 days after OLT, while glucagon tests were performed in patients with acute allograft rejection occurring 2 weeks after OLT. Furthermore, hormone effects were studied in nontransplanted patients after cholecystectomy with indwelling biliary T tube. After OLT, bile secretory function recovered and stabilized within 14 days after surgery by reconstitution of both bile acid-dependent and -independent bile flow. Two weeks after OLT, bile secretion was comparable with nontransplanted patients after cholecystectomy. Glucagon and secretin stimulated bile acid-independent bile flow in transplanted and nontransplanted patients significantly, yet secretin choleresis, unlike glucagon choleresis, had already occurred during the first days after OLT and was unaffected by acute allograft rejection. These results allow the speculation that, in humans, glucagon and secretin exert their choleretic activity by different mechanisms and/or at different anatomical sites in the liver. Assuming that secretin acts at the bile duct cells, its secretory capacity was not altered by the transplantation procedure and during moderate or severe rejection episodes, as opposed to glucagon choleresis, which most likely originates in the hepatocytes and requires an entirely reconstituted canalicular transport system after OLT. (Hepatology 1997 Nov;26(5):1272-81)

Nitric oxide stimulates bile flow and glutathione excretion independent of cyclic GMP-induced HCO 3- excretion : [formula omitted] Dept. Medicine and Liver Center, Yale University School of Medicine, New Haven, CT and ∗Dept. Gastroenterology, Edith Wolfson Medical Center, Holon, Israel

Based on studies in the pig, secretin choleresis has been proposed to be initiated by colchicine-inhibitable, exocytic insertion into the basolateral cholangiocyte membrane of intracytoplasmatic vesicles containing a H+ ATPase. Formal prof of this hypothesis in the intact liver of other species, however, is lacking. The effect of the microtubule inhibitor colchicine on the ductular bile formation and HCO−3 secretion induced by secretin was, therefore, explored in a secretin-responsive rat model characterized by marked hyperplasia of bile ductules.While colchicine pretreatment significantly decreased basal bile flow from 142.1±8.8 to 83.4±8.2 μl· min−1·kg−1 (p<0.001) and basal biliary erythritol clearance from 112.7±6.3 to 69.9±7.0 μl·min−1. kg−1 (pš0.05), it did not significantly affect basal biliary [HCO−3], nor basal biliary bile acid output. Moreover, colchicine did not alter the effects of secretin. Thus, the secretin-induced increments in bile flow, biliary [HCO−3] and biliary HCO−3 output averaged 58.2±13.6 μl·min−1·kg−1, 16.6±3.1 mM and 5.3±1.4 μmol·min−1·kg−1 in vehicle-pretreated controls and 78.4±12.0 μl·min−1·kg−1, 16.1±2.7 mM and 5.1±0.5 μmol·min−1·kg−1 in colchicine-pretreated animals (all p values=n.s), respectively. This suggests that, at least in the rat model used, microtubule-dependent mechanisms are involved in basal, bile acid independent canalicular, but not in secretin-induced ductular, bile formation. Inasmuch as microtubule-dependent mechanisms are required for vesicle movement, this argues strongly against an absolute requirement for exocytic vesicle insertion in the ductular choleresis induced by secretin.

Colchicine does not inhibit secretin-induced choleresis in rats exhibiting hyperplasia of bile ductules: evidence against a pivotal role of exocytic vesicle insertion

Based on studies in the pig, secretin choleresis has been proposed to be initiated by colchicine-inhibitable, exocytic insertion into the basolateral cholangiocyte membrane of intracytoplasmatic vesicles containing a H+ ATPase. Formal prof of this hypothesis in the intact liver of other species, however, is lacking. The effect of the microtubule inhibitor colchicine on the ductular bile formation and HCO−3 secretion induced by secretin was, therefore, explored in a secretin-responsive rat model characterized by marked hyperplasia of bile ductules.While colchicine pretreatment significantly decreased basal bile flow from 142.1±8.8 to 83.4±8.2 μl· min−1·kg−1 (p<0.001) and basal biliary erythritol clearance from 112.7±6.3 to 69.9±7.0 μl·min−1. kg−1 (pš0.05), it did not significantly affect basal biliary [HCO−3], nor basal biliary bile acid output. Moreover, colchicine did not alter the effects of secretin. Thus, the secretin-induced increments in bile flow, biliary [HCO−3] and biliary HCO−3 output averaged 58.2±13.6 μl·min−1·kg−1, 16.6±3.1 mM and 5.3±1.4 μmol·min−1·kg−1 in vehicle-pretreated controls and 78.4±12.0 μl·min−1·kg−1, 16.1±2.7 mM and 5.1±0.5 μmol·min−1·kg−1 in colchicine-pretreated animals (all p values=n.s), respectively. This suggests that, at least in the rat model used, microtubule-dependent mechanisms are involved in basal, bile acid independent canalicular, but not in secretin-induced ductular, bile formation. Inasmuch as microtubule-dependent mechanisms are required for vesicle movement, this argues strongly against an absolute requirement for exocytic vesicle insertion in the ductular choleresis induced by secretin.

Secretin stimulates bile ductular secretory activity through the cAMP system.

Although convincing evidence has been obtained to support a ductular origin of secretin choleresis, the precise mechanism of the choleretic effect of the hormone is poorly understood. The present studies were carried out to 1) further clarify the anatomic site at which secretin stimulates bile flow and 2) establish the signal transduction system underlying this effect. To this end, parenchymal and nonparenchymal liver cells, the latter enriched in bile duct cells, were isolated from rats with ductular cell hyperplasia, and the effect of secretin on intracellular formation of both adenosine 3',5'-cyclic monophosphate (cAMP) and inositol phosphates (IPs) was compared with that observed with glucagon and [Tyr10,13,Phe22,Trp25]secretin (SG-secretin). In the pancreas, secretin stimulates both messenger systems, while SG-secretin activates only the cAMP cascade. In isolated hepatocytes, both secretin and SG-secretin failed to increase formation of cAMP and IPs, which were instead activated by glucagon. In isolated bile duct cells, secretin induced formation of both cAMP and IPs, while SG-secretin stimulated solely the cAMP system, as in the pancreas. Glucagon did not stimulate either messenger system in this cell preparation. In vivo, both secretin and SG-secretin stimulated a bicarbonate-rich fluid in rats with bile ductular cell hyperplasia and in normal guinea pigs, which was demonstrated to originate at the distal biliary epithelium. These findings support the existing view that glucagon stimulates canalicular bile flow, while secretin increases secretory activity at the bile ductules and/or ducts. More importantly, they indicate that stimulation of ductular secretory activity by secretin is mediated by the cAMP system and does not involve the IP signal transduction pathway.

Biliary physiology in rats with bile ductular cell hyperplasia. Evidence for a secretory function of proliferated bile ductules.

To establish the role of the biliary epithelium in bile formation, we studied several aspects of biliary physiology in control rats and in rats with ductular cell hyperplasia induced by a 14-d extrahepatic biliary obstruction. Under steady-state conditions, spontaneous bile flow was far greater in obstructed rats (266.6 +/- 51.9 microliters/min per kg) than in controls (85.6 +/- 10.6 microliters/min per kg), while excretion of 3-hydroxy bile acids was the same in the two groups. Infusion of 10 clinical units (CU)/kg per h secretin produced a minimal choleretic effect in controls (+3.8 +/- 1.9 microliters/min per kg) but a massive increase in bile flow in the obstructed animals (+127.8 +/- 34.9 microliters/min per kg). Secretin choleresis was associated with an increase in bicarbonate biliary concentration and with a decline in [14C]mannitol bile-to-plasma ratio, although solute biliary clearance significantly increased. Conversely, administration of taurocholate (5 mumol/min per kg) produced the same biliary effects in control rats and in rats with proliferated biliary ductules. In the obstructed animals, the biliary tree volume measured during taurocholate choleresis (67.4 +/- 15.8 microliters/g liver) was significantly greater than that determined during the increase in bile flow induced by secretin (39.5 +/- 10.4 microliters/g liver). These studies indicate that, in the rat, the proliferated bile ductules/ducts spontaneously secrete bile and are the site of secretin choleresis. Furthermore, because the proliferated cells expressed phenotypic traits of bile ductular cells, our results suggest that whereas under normal conditions the biliary ductules/ducts in the rat seem to contribute little to bile formation, secretion of water and electrolytes is a property of biliary epithelial cells.

The effect of secretin on bile flow and bile acid and bilirubin excretion following relief of prolonged bile duct obstruction in the rat

Bile flow was re-established in rats whose bile ducts had been obstructed for 5, 10, 15 and 28 days (Groups I, II, III and IV, n = 5). The effect of i.v. secretin on bile flow in control rats, whose bile ducts had been cannulated, was minimal, but in cholestatic rats there was an immediate response which was related to the duration of the obstruction and the degree of bile duct proliferation. In 40 min the mean excess bile flow production amounted to 76, 258, 320 and 432 microliters/100 g body wt. in Groups I, II, III and IV, respectively. Choleresis was prolonged in the Group IV rats that had developed cirrhosis. Synthetic secretin had a minimal effect on bile acid and bilirubin excretion. It is postulated that the proliferating bile ductules are the site of secretin choleresis, although the possibility that reduced inactivation of the hormone plays a role cannot be excluded.

Biliary Mannitol Clearance and Bile Salt Output Before and During Secretin Choleresis in the Dog

The clearance of 14C-mannitol in the bile before and during intravenous secretin was measured in anesthetized dogs receiving a constant infusion of taurocholate. During secretin, bile flow (+80%) and bicarbonate output (+140%) both rose while bile salt output was unchanged (+2.4%). Mannitol clearance increased significantly by 20 +/- 8% (P less than 0.05). The ratio of bile salt output to mannitol clearance fell significantly after secretin by 14 +/- 7% (P less than 0.01). Secretin caused, therefore, a significant rise in mannitol clearance in this canine preparation. This may be due either to a rise in the bile salt independent fraction of canalicular bile or to tubular entry of mannitol.

The effect of truncal vagotomy on taurocholate choleresis and secretin choleresis

Mongrel dogs were prepared for cholecystectomy, chronic bile and gastric fistulas, and pyloroplasty. Taurocholate choleresis and secretin choleresis were observed before and after truncal vagotomy. Vagotomy caused minor decreases in bicarbonate output and an increase in chloride output but had no influence on bile flow, bile salt concentration, or bile salt output. Vagotomy had no influence on secretin choleresis. The findings indicate that previously observed reductions in bile salt secretion after vagotomy are due to some mechanism other than the influence of vagotomy on hepatic bile secretion.

Cyclic Amp in Secretin Choleresis

Cyclic AMP output in the bile in response to intravenous secretin was measured in 11 patients, 12 baboons, and 15 dogs. Secretin was given to patients with bile drainage tubes as an intravenous bolus (1 U per kg). In baboons and dogs both secretin infusion (4 U per kg per hr) and bolus injection (1 U per kg) were used. In baboons cyclic AMP was also determined in liver, extrahepatic duct tissue, and in perfusate from isolated segments of extrahepatic bile ducts. Secretin induced a marked choleresis in all three species. In humans, biliary cyclic AMP concentration increased an average (+/- 1 SE) of 68% +/- 12% and in baboons 4-fold, but no increase occurred in dogs. In baboons, cyclic AMP concentration increased in both bile duct tissue and perfusate from isolated bile ducts concomitant with secretin choleresis, but not in liver. In humans the choleretic effects of sodium dehydrocholate, aminophylline, and glucagon were compared to dibutyryl cyclic AMP (DBcyclic AMP). All agents increased bile flow 2- to 3-fold. Cyclic AMP concentration in bile markedly increased after glucagon and DBcyclic AMP but not after sodium dehydrocholate and aminophylline. We conclude that cyclic AMP is implicated in secretin choleresis in both humans and baboons, but not in dogs. The bile duct appears to be the site of cyclic AMP elaboration induced by secretin in baboons and probably is also in man.

The effect of secretin on the hepatic excretion of telepaque.

The effect of secretin choleresis on hepatic excretion of Telepaque was studied in dogs. Results show that unlike the effects of bile salts, secretin has no influence on the amount of Telepaque excreted per unit time but significantly reduces the concentration of Telepaque in bile. Bile production by the liver and its modification by secretin are discussed. The dilutional effect of secretin on contrast material in bile may explain the variability in the degree of visualization and the occasional nonvisualization noted in normal patients on cholecystography. Thus, inhibition of secretin production during radiographic examination may improve visualization in a number of circumstances.

Effects of secretin and bile salt infusions on canine bile composition and flow.

ARTICLESEffects of secretin and bile salt infusions on canine bile composition and flowRD Soloway, ML Clark, KM Powell, Senior JR, and FP BrooksRD Soloway, ML Clark, KM Powell, Senior JR, and FP BrooksPublished Online:01 Mar 1972https://doi.org/10.1152/ajplegacy.1972.222.3.681MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformationCited ByAnimal Farm: Considerations in Animal Gastrointestinal Physiology and Relevance to Drug Delivery in HumansJournal of Pharmaceutical Sciences, Vol. 104, No. 9Postpyloric Gastrointestinal PeptidesAnatomy and Physiology of the Biliary EpitheliumPostpyloric Gastrointestinal PeptidesChanges in biliary excretory mechanisms in bile duct-ligated ratDigestive Diseases and Sciences, Vol. 41, No. 2Secretin prevents taurocholate-induced intrahepatic cholestasis in the ratJournal of Hepatology, Vol. 20, No. 6Effects of secretin on bile production in two kinds of cholestatic models by choledocho-caval fistula and bile duct ligation in ratsGastroenterologia Japonica, Vol. 27, No. 3Secretin1 January 2011Effect of secretin on bile formation in rats with cirrhosis of the liver: Structure-function relationshipGastroenterology, Vol. 97, No. 4Hypersecretion of biliary fatty acids in patients with exocrine pancreatic diseaseInternational journal of pancreatology, Vol. 1, No. 5-6Effects of Furosemide on Biliary Secretion, Pancreatic Blood Flow, and Pancreatic Exocrine Secretion8 March 2013 | The Journal of Clinical Pharmacology, Vol. 23, No. 10Biliary Mannitol Clearance and Bile Salt Output Before and During Secretin Choleresis in the DogGastroenterology, Vol. 76, No. 5The effect of secretin on bile production, splanchnohepatic hemodynamics and liver function in catsActa Physiologica Scandinavica, Vol. 102, No. 4Erythritol and mannitol clearances with taurocholate and secretin-induced cholereses.J L Barnhart, and B Combes1 February 1978 | American Journal of Physiology-Endocrinology and Metabolism, Vol. 234, No. 2The effects of acute and chronic ethanol administration on canine bile secretionThe American Journal of Digestive Diseases, Vol. 21, No. 12A Comparison Between the Bile Acid Concentration and the Inorganic Cation-Anion Difference in Dog BileGastroenterology, Vol. 67, No. 1Gastro-Intestinal Hormones and Bile Secretion in the Perfused Pig Liver: The Effects of Secretin, Cholecystokinin and PentagastrinANZ Journal of Surgery, Vol. 44, No. 2Interrelationship of Bile Salts, Phospholipids, and Cholesterol in Bile During Manipulation of the Enterohepatic Circulation in the Conscious DogGastroenterology, Vol. 64, No. 6 More from this issue > Volume 222Issue 3March 1972Pages 681-686 Copyright & PermissionsCopyright © 1972 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1972.222.3.681PubMed5022680History Published online 1 March 1972 Published in print 1 March 1972 Metrics

Canalicular bile formation in the isolated perfused rat liver.

Canalicular bile formation in the isolated perfused rat liver.

Characteristics of inhibition of gastric secretion by secretin.

Characteristics of inhibition of gastric secretion by secretin.

Electrical potential differences in the biliary tree.

Abstract 1. 1. Electrical potential differences (p.d.'s) have been measured between the major bile ducts and blood (or vascular perfusion fluid) in perfused guinea pig livers and in livers of unanesthetized dogs. The bile duct lumen was always electrically negative by 2 to 23 mV. 2. 2. In the absence of the hormone secretin larger p.d.'s were correlated with higher bile concentrations of Na + , K + , and bile acid anions and with lower concentrations of Cl − and HCO 3 − . In taurocholate choleresis the p.d. either increased, decreased, or remained unchanged, mirroring changes in bile composition. 3. 3. Secretin choleresis was associated with an increased duct-negative p.d. in the dog. 4. 4. Calculation from the Nernst equation that K + in bile is at equilibrium but that Na + and Cl − concentrations are lower than equilibrium values. 5. 5. These results suggest that distal reabsorption in the biliary tree involved active absorption of both Na + and Cl − , possibly by a coupled, electrically neutral pump; that the hormone secretin activates an active anion secretory mechanism; and that the p.d. in the absence of secretin is simply an NaCl (or NaCl-NaHCO 3 ) diffusion potential.

Canalicular bile production in dogs.

Canalicular bile production in dogs.

Role of bile ducts during secretin choleresis in dogs.

Role of bile ducts during secretin choleresis in dogs.