Increase In Bicarbonate Output Research Articles

Heat-stable enterotoxin ofEscherichia colistimulates a non-CFTR-mediated duodenal bicarbonate secretory pathway

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is an important pathway for duodenal mucosal bicarbonate secretion. Duodenal biopsies from CF patients secrete bicarbonate in response to heat-stable enterotoxin from Escherichia coli (STa) but not cAMP. To explore the mechanism of STa-induced bicarbonate secretion in CF more fully, we examined the role of CFTR in STa-stimulated duodenal bicarbonate secretion in mice. In vivo, the duodenum of CFTR (-/-) or control mice was perfused with forskolin (10(-4) M), STa (10(-7) M), uroguanylin (10(-7) M), 8-bromoguanosine 3',5'-cGMP (8-Br-cGMP) (10(-3) M), genistein (10(-6) M) plus STa, or herbimycin A (10(-6) M) plus STa. In vitro, duodenal mucosae were voltage-clamped in Ussing chambers, and bicarbonate secretion was measured by pH-stat. The effect of genistein, DIDS (10(-4) M), and chloride removal was also studied in vitro. Control, but not CF, mice produced a significant increase in duodenal bicarbonate secretion after perfusion with forskolin, uroguanylin, or 8-Br-cGMP. However, both control and CF animals responded to STa with significant increases in bicarbonate output. Genistein and herbimycin A abolished this response in CF mice but not in controls. In vitro, STa-stimulated bicarbonate secretion in CF tissues was inhibited by genistein, DIDS, and chloride-free conditions, whereas bicarbonate secretion persisted in control mice. In the CF duodenum, STa can stimulate bicarbonate secretion via tyrosine kinase activity resulting in apical Cl(-)/HCO(3)(-) exchange. Further studies elucidating the intracellular mechanisms responsible for such non-CFTR mediated bicarbonate secretion may lead to important therapies for CF.

Long-term bile diversion enhances basal and duodenal oleate-stimulated pancreatic exocrine secretion in dogs.

There have been no previous reports whether long-term bile diversion enhances pancreatic exocrine secretion. The aim of this study was to elucidate the effect of long-term bile diversion on pancreatic exocrine secretion. Four mongrel dogs were prepared for chronic gastric and pancreatic fistulas and received intraduodenal sodium oleate infusion (controls). These dogs, then underwent diversion of bile from the intestines by ligating the common bile duct and interposing a segment of jejunum between the gallbladder and the urinary bladder (total biliary diversion [TBD]). After three weeks, the dogs received an identical sodium oleate infusion. TBD augmented basal pancreatic exocrine secretion compared with controls (4.4-fold increase in basal flow volume; 9.0-fold increase in bicarbonate output; and 3.3-fold increase in protein output). Likewise, TBD augmented oleate-stimulated exocrine secretion (2.0-fold increase in cumulative flow volume; 2.6-fold increase in bicarbonate output; and 1.4-fold increase in protein output). TBD also augmented basal and oleate-stimulated plasma cholecystokinin levels. Administration of a Cholecystokinin-A receptor antagonist (loxiglumide) after TBD reduced the flow volume and bicarbonate output to the control levels, and the protein output to less than a half of the control level. Long-term bile diversion enhances basal and oleate-stimulated pancreatic exocrine secretion, at least partly via increased cholecystokinin secretion.

Intracerebroventricular secretin enhances pancreatic volume and bicarbonate response in rats

Although secretin has been found within the brain, its central role in pancreatic exocrine function has not been previously addressed. The hypothesis that intracerebroventricular secretin enhances pancreatic volume and bicarbonate output at doses that have no effect when given intravenously was tested. Sprague-Dawley rats had a cannula stereotactically placed into the left lateral cerebral ventricle 24 hours before study. At laparotomy the bile and pancreatic ducts were separately cannulated and excluded for tared collections and bicarbonate assay. Increasing doses of intracerebroventricular secretin (0.005, 0.05, and 0.5 microgram/1.0 microliter) induced a significant dose-related increase in bicarbonate output (2.95, 3.32, and 4.02 microEq/30 min, respectively) above basal (2.62 microEq/30 min) compared with control or intracerebroventricular saline treated animals. Pancreatic volume increased to 59.7 microliters at the lowest intracerebroventricular dose and increased (p < 0.025) to 65.8 microliters at the 0.05 intracerebroventricular secretin dose when compared with basal (59.4 microliters). To show that this was not a systemic effect of secretin, intravenous infusion of secretin at 0.005 and 0.05 microgram/kg/hr failed to stimulate either volume or bicarbonate output compared with that observed with intracerebroventricular secretin over the same dose range. These observations indicate that intracerebroventricular secretin stimulates pancreatic volume and bicarbonate output and suggest that central secretin may play a role in the regulation of exocrine pancreatic secretion.

Mechanisms behind changes in gastric acid and bicarbonate outputs during the human interdigestive motility cycle.

Human gastric interdigestive acid and bicarbonate outputs vary cyclically in association with the migrating motor complex (MMC). These phenomena were studied in 26 healthy volunteers by constant-flow gastric perfusion, with continuous recording of pH and Pco2 in mixed gastric effluent and concomitant open-tip manometry of gastroduodenal motility. Stable acid and bicarbonate outputs were registered during less than 50% of the MMC cycle. Acid secretion started to increase 71 +/- 3% into the cycle, with maximum output during antral phase III. Bicarbonate output increased biphasically 1) 40 +/- 5% into the cycle, coinciding with reflux of bile, and 2) at the end of duodenal phase III when the aspirate was devoid of bile. The bicarbonate peak associated with phase III was abolished by atropine (0.01 mg/kg iv, n = 8) and by pyloric occlusion (n = 9) but remained unchanged after omeprazole (n = 10). The acid peak was abolished by both atropine and omeprazole. It is concluded that the MMC-related changes in acid and alkaline outputs represent two different and independent phenomena. Acid secretion cyclicity is due to periodical variations in cholinergic stimulation of the parietal cells. In contrast, the phase III-associated increase in bicarbonate output is due to duodenogastric reflux.

Effect of pancreatic denervation and atropine on the pancreatic response to secretin.

To study the influence of extrapancreatic nerves and intrapancreatic cholinergic activity on the pancreatic response to secretin, six dogs underwent extrapancreatic denervation and creation of pancreatic fistulae. A second group of six dogs had pancreatic fistulae created without pancreatic denervation. The pancreatic exocrine response to graded doses of secretin (16-500 ng/kg/h) was determined, both alone and during a background infusion of cholecystokinin-octapeptide (CCK8, 50 ng/kg/h). All studies were replicated during administration of atropine (10 micrograms/kg/h). Secretin-induced bicarbonate output was significantly inhibited by atropine in both the innervated and denervated groups. Combined secretin and CCK8 elicited a dose-dependent increase in bicarbonate output and a sustained increase in protein output in both groups, regardless of atropine. In addition, potentiation of secretin-induced bicarbonate output by CCK8 was observed despite both extrinsic pancreatic denervation and administration of atropine. We conclude that endogenous intrapancreatic cholinergic activity influences the pancreatic response to secretin. Potentiation of secretin-induced bicarbonate output by CCK, however, is not dependent on neural mediation.

Motility-related cyclic fluctuations of interdigestive gastric acid and bicarbonate secretion in man. A source of substantial variability in gastric secretion studies.

The relationship between interdigestive gastric motility and secretion was studied in eight healthy volunteers. Acid and bicarbonate output rates were measured with a high time resolution, using a perfusion system based on continuous registration of pH and PCO2 of gastric effluent. Antral pressure was measured by manometry. The total duration of the interdigestive motility cycle (time between two phase-III complexes) was 96 +/- 12 min (mean +/- SE). In late migrating motor complex phase II, acid output, bicarbonate output, and bile reflux increased significantly. Acid secretion reached a peak in association with motor phase III. The gastric lumen was then rapidly alkalinized; this phenomenon was due to a simultaneous decrease in acid secretion and a short-lasting (15 +/- 2 min, mean +/- SE) phasic increase in bicarbonate output, which was not associated with bile reflux (bilirubin). After these phase-III-related events both acid and bicarbonate output rates reached a relatively stable level during phase I and early phase II. This period of stability constituted 47 +/- 3% (acid) and 41 +/- 6% (bicarbonate, means +/- SE), respectively, of the cycle. The peak to base line output ratio was 6.6 +/- 1.2 (p < 0.001) for acid and 2.8 +/- 0.3 (p < 0.001) for bicarbonate (means +/- SE). The results show a marked variability in acid and bicarbonate output rates during the interdigestive motility cycle. The magnitude of this variability has previously been underestimated owing to poor time resolution of the secretion measurements. If not taken into account, these 'spontaneous' secretory variations may constitute a considerable source of error in gastric secretion studies.

Effect of sucralfate on human gastric bicarbonate secretion and local prostaglandin E 2 metabolism

The protective and ulcer-healing properties of sucralfate on gastroduodenal mucosa are well established. In this study, the possible mode of action of sucralfate in humans has been explored by examining its effect on gastric bicarbonate secretion and luminal prostaglandin E 2 (PGE 2) output from the intact stomach. The gastric output of bicarbonate and PGE 2 has been calculated using a perfusion technique before, during, and after perfusion with sucralfate (8 mg/ml) in eight healthy volunteers. A significant increase in bicarbonate output occurred during the period of sucralfate perfusion returning to basal values during the post-sucralfate period. Pretreatment with indomethacin (25 mg/hour) failed to influence this secretory response. Luminal PGE 2 output was significantly increased in the post-sucralfate perfusion period only. These changes were caused mainly by an increase in gastric secretory volume with insignificant increases in concentrations of bicarbonate and PGE 2. These results suggest that stimulation of gastric bicarbonate secretion and PGE 2 output by sucralfate may play a role in its protective actions.

Effect of luminal pH on the output of bicarbonate and PGE2 by the normal human stomach.

The gastric output of bicarbonate and prostaglandin E2 has been calculated using a perfusion technique before and after instillation of 100 mM hydrochloric acid into the stomach of seven healthy volunteers. A significant increase in bicarbonate output occurred from 258 +/- 38 mumol/30 min during the basal period to 531 +/- 86 mumol/30 min after return of the intragastric pH to neutral (p less than 0.05). Prostaglandin E2 output also increased significantly from 410 +/- 136 pmol/30 min to 1002 +/- 194 pmol/30 min (p less than 0.05). The changes were caused mainly by an increase in gastric secretory volume with only non-significant increases in concentrations of bicarbonate and prostaglandin E2. The results suggest that mechanisms exist to adjust the rate of gastric bicarbonate secretion to the prevailing intraluminal pH and that this may occur through the release of prostaglandin E2.

The effect of neurotensin on pure pancreatic secretion in man.

The effect of neurotensin on human pancreatic secretion and its role in the control of pancreatic function are not well defined. In the present investigation I have studied the effect of low doses of neurotensin on pure pancreatic secretion in six subjects with external transduodenal drainage of the main pancreatic duct performed after biliary tract surgery. Intravenous infusion of neurotensin at doses of 0.5 and 2.5 pmol X kg-1 X min-1, administered during submaximal pancreatic stimulation with secretin and cerulein, caused a significant and dose-dependent stimulation of pancreatic secretion (volume, bicarbonate, and protein). The effect of neurotensin was rapid, persisted for the duration of neurotensin infusions, and ceased immediately when the administration of the peptide was discontinued. Compared with control values, the increase in bicarbonate output averaged 24.8% and 44.8% and the increase in protein output 29.2% and 54% for the two different doses of neurotensin used, respectively. The clear effectiveness of the small doses of neurotensin used in the present study strongly suggests that the stimulatory effect of the peptide on pancreatic secretion may be of physiologic significance.

Effect of side-chain shortening on the physiologic properties of bile acids: Hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents

To define whether side-chain length influences the physiologic properties of bile acids, nor-ursodeoxycholate (nor-UDC), the C23-nor derivative of ursodeoxycholate (UDC), was synthesized in both nonradioactive and radioactive forms (23-14C). Its hepatic translocation, hepatic biotransformation, and effect on bile flow, biliary bicarbonate, and biliary lipid secretion were compared with that of UDC and those of their respective glycine and taurine conjugates in anesthetized biliary fistula hamsters, rats, and guinea pigs, as well as the isolated perfused hamster liver. Hepatic uptake and biliary output of nor-UDC was slower than that of UDC or cholyltaurine in the isolated perfused hamster liver. In biliary fistula animals, nor-UDC was secreted only in bile. Biliary recovery of nor-UDC as compared to that of UDC was prolonged in the rat and hamster, although not in the guinea pig. Hepatic biotransformation, assessed by chromatography of bile, showed that conjugation of nor-UDC was inefficient, as unconjugated nor-UDC was present in bile; there was little amidation with glycine or taurine in any species, but sulfates and glucuronides, as well as other metabolites, were formed, with the pattern of biotransformation varying among species. When infused over a dosage range of 0.2–30 μmol/kg · min, nor-UDC induced a striking choleresis of canalicular origin. The bile acid-dependent flow was increased threefold in hamsters, ninefold in rats, and nearly twofold in guinea pigs when compared to that induced by UDC. The choleresis was associated with a linear increase in bicarbonate output and concentration in bile, and little phospholipid or cholesterol secretion was induced. A competition experiment in the bile fistula hamster indicated that nor-UDC or its metabolites, or both, appeared to compete for canalicular transport of ursocholyltaurine (a cholyltaurine epimer) when the latter was secreted under its Vmax conditions. Conjugates of nor-UDC and UDC were promptly and almost completely recovered in bile without appreciable hepatic biotransformation; the conjugates did not induce a hypercholeresis or increase biliary bicarbonate concentration. It is proposed that a fraction of nor-UDC is secreted into canalicular bile in the unconjugated form and is protonated by a hydrogen ion derived from carbonic acid that was generated by the hydration of luminal CO2 by carbonic anhydrase present in biliary ductular cells.

Duodenal mucosal bicarbonate secretion in humans: a brief review.

The human proximal duodenum serves as the crucible for the neutralization of gastric acid. Methods have been developed and validated that permit isolation of 4-cm segments of either the proximal or distal duodenum. These isolated segments were free of contamination from gastric, pancreatic, and biliary secretions. At rest the healthy human proximal duodenum produced approximately 175 mumol cm-h: or, assuming that the duodenal bulb is approximately 4 cm in length, 700 mumol h. The distal duodenum (the third part) produced significantly less bicarbonate, approximately 25 mumol/cm-h. HCl produced a prompt and sustained increase in bicarbonate output from both duodenal segments. Bicarbonate output was less in the distal duodenum, indicating a proximal-to-distal gradient. Synthetic prostaglandin E1 caused a dose-related increase in output. Substitution of the NaCl perfusate with Na2SO4 produced a brief decrease, suggesting a chloride bicarbonate exchange mechanism. Vasoactive intestinal polypeptide significantly increased proximal duodenal bicarbonate output. Bicarbonate production by the duodenal mucosa is probably an important defensive factor in maintaining mucosal integrity.

Effect of insulin on canalicular bile formation

Mongrel dogs were prepared by cholecystectomy, ligation of the lesser pancreatic duct, and insertion of gastric and duodenal cannulas. The common bile duct was cannulated through the duodenal fistula. After bile flow had been stabilized by intravenous infusion of sodium taurocholate the dogs were given an intravenous injection of insulin or 0.9% NaCl (control). Insulin caused marked increases in bile flow, chloride output, and biliary clearance of erythritol and small increases in bicarbonate output and bile salt output. The increased erythritol clearance indicates that canalicular secretion contributes to insulin choleresis in dogs.

Effect of electrical stimulation of the vagus nerves on bile secretion in Anaesthetized sheep.

Bile was collected before and during electrical stimulation of the vagus nerves in acute experiments on sheep with ligated cystic ducts. Most stimuli caused no change in bile formation, but a 10-V, 10-Hz stimulus caused a slight increase in bicarbonate output. Neither the response to infused secretin nor the maximum rate of bile salt transport by liver cells changed during vagal stimulation. It was concluded that the vagal innervation of the liver is not likely to play a major role in the regulation of bile formation in sheep.

Effects of cigarette smoking on bicarbonate and volume of duodenal contents.

The effect of smoking on bicarbonate and volume of duodenal juice was studied. It was found that in the basal condition smoking produced significant decreases in bicarbonate content and volume of duodenal samples. On the contrary, during pancreatic stimulation with secretin at approximately 50% of maximal secretion, smoking resulted in significant increases in bicarbonate output and volume. Decrease in buffering power of duodenal juice in the basal condition can, at least partially, explain the causative relation of smoking and peptic ulcer disease.

Effect of Selective and Truncal Vagotomy on Insulin-Stimulated Bile Secretion in Dogs

Dogs were prepared by cholecystectomy, ligation of the lesser pancreatic duct, and insertion of Thomas cannulas into the stomach and duodenum. Hepatic bile was collected by cannulating the common bile duct through the duodenal fistula. Insulin, 1 U per kg, increased bile flow and chloride concentration. Neither selective hepatic nor selective extrahepatic vagotomy reduced the stimulation of bile flow produced by insulin. Selective hepatic vagotomy reduced control chloride output, but had no significant effect on insulin choleresis. Selective extrahepatic vagotomy decreased bile bicarbonate concentration and output in both control and postinsulin periods. Truncal vagotomy reduced, but did not abolish, the increase in bile flow following insulin. Control bile bicarbonate concentration was reduced after truncal vagotomy, and truncal vagotomy prevented the increase in bicarbonate output after insulin. These results indicate that an extravagal mechanism is important to insulin-induced choleresis.