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A416 AGA ABSTRACTS GASTROENTEROLOGY, VOI. 108, NO. 4 DOSE DEPENDENT EFFECT OF ACUTE HYPERGLYCEMIA ON POSTPRANDIAL GALLBLADDER CONTRACTION AND HORMONE SECRETION. H.A.J. Gielken% A.A.M Masclee, E.S.M Muller, J. van Ostayen 1, C.B.H.W. Lamers. Depts of Gastroenterology and Hepatology and "Radiology, University Hospital Leiden, The Netherlands. Previously we have shown that during acute hyperglycemia at 15 mmol/I, CCK and meal stimulated gallbladder contraction are significantly reduced. Aim of this study was to investigate whether the inhibitory effect of acute hyperglycemia on gallbladder motility is dose-dependent, i.e. different at several levels of hyperglycemic clamping. Seven healthy volunteers (4M, 3F; age 19-26 yr) were studied after an overnight fast on 4 separate occasions in random order with blood glucose concentrations stabilized at 4, 8, 12 and 16 mmoVI using a modified clamp technique. Gallbladder volumes, measured with ultrasonography, and plasma cholecystokinin (CCK), pancreatic polypeptide (PP), and glucose levels were determined at regular intervals for 180 rain. At time 0 rain gallbladder contraction was induced by ingestion of a meal (480 kCal). Results: Basal gallbladder volumes were not significantly different between the 4 experiments. Meal stimulated gallbladder emptying was significantly (p<O,O5) and dose-dependently reduced during hyperglycemic clamping at 16 mmol/I (26:t:7%), 12 mmol/I (43:1:5%), 8 mmol/I (55-/-6%) compared to normoglycemia (68:t6%). Endogenous CCK secretion was significantly (p<0.O5) reduced compared to normoglycemia only at a glucose level of 16 mmol/I (116+98 vs 159+13 pM.120 min) and not during clamping at 12 and 8 mmoVI (136+92 and 164+39 pM.120 min respectively). PP secretion, as an indirect measure of vagal cholinergic tone, was significantly (p<0.05) and dose-dependently reduced with values of 10+_.2, 6+1, 5:t0.9 and 3!-0.9 nmol.120 min respectively during clamping at 4, 8, 12 and 16 mmol/l. Conclusions: Acute hyperglycemia at different glucose levels 1) dose- dependently inhibits meal stimulated gallbladder emptying and 2) dose- dependently inhibits vagal cholinergic tone as measured indirectly by PP secretion, 3) endogenous CCK secretion is reduced only at high p!asma glucose levels. • Procollagen IH peptide in bile - higher concentrations in primary biliary cirrhosis and primary sclerosing cholangitis. A. Gillessen, E. Foerster, W. Domschke. Department of ~ Medicine B, University ofMuenster, Muenster, Germany. In primary ,biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fibrosis is found next to the bile ducts. Consequently, it was tempting to investigate concentrations of procollagen III peptide (P-III-P) in the bile. We analyzed bile samples from 5 patients With PBC and 5 patients suffering from PSC ~nd 10 controls. The bile was obtained free of contrast medium during ERC examination. P-III-P concentrations were measured with a commercially available radioimmuno ~assay (Behring, Marburg, Germany). P-III-P concentration measured in the bile fluid of cor~trols was 0.17 I.E./ml (±2s = 0.11). All l0 patients suffering from PBC orPSC had significantly (p _<0,05) higher concentrations of P-III-P averaging 0.48 I.E,hnl (±2s =0.26). In the bile of patienis with primary biliary cirrhosis or primary sclerosing cholangiti s procollagen-III-peptide is found in significantly higher concentrations than in normal controls indicating the possible role of this marker for the assessment Of the fibrotic activity in these diseases. PROSTAGLANDINS ARE POTENT PROKINETICS FOR HUMAN GALLBLADDER IN VITRO RRSH Greaves, LJD O'Donnell, MJG Farthing. Digestive Diseases Research Centre, Medical College of St.Bartholomew's Hospital, London EC1M 6BQ Prostaglandins (PGs) have been identified in gallbladder smooth muscle and the cyclo-oxygenase inhibitor indomethacin is known to affect gallbladder motility in vivo and prevent gallstones. However the effect of naturally occurring prostaglandins on human gallbladder motility is unclear. We therefore examined the effects of PGE2, PGF2~, prostacyclin (PGI2), the thromboxane A2 mimetic U46619, and cholecystokiniu-oetapeptide (CCK-8) on in vitro contractility of human gallbladders obtained from patients undergoing elective cholecystectomy for gallstones. Gallbladder muscle strips were mounted in or.gran baths .containing gassed Krebs Solution at 37°C in the presence of 3 x 10" M indomethacin to prevent endogenous prostaglandin synthesis. An initial tension of lg was applied and changes m isometric tension were measured using a force- displacement transducer. Relaxant properties of PGI 2 were tested using muscl e strips pre-contraeted with U46619 (3x10"TM). ECs0 (the concentration of agonist which produced 50% of the maximum contraction) was calculated for each agonist All the prostaglandins produced slow sustained contractions (onset 3-5 minutes, plateau 8-15 min) apart from PGI2 which had a negligible effect on basal tone. CCK-8 was the most effective agonist~n=9). Maximal response of the PGs as a percentage of maximal response to 10" M CCK-8 was 5cJ + 11% for U46619 (mean *_ SEM, n=9), 54 + 0% for PGF2Q(n=2), and 31 + 5% for PGE2 (n=6). PGI2 produced a mean z SEM maximum relaxation of tissue pre- contracted with 3x10"7 M U46619 of 67_+ 10% (n=4). Although CCK-8 produced the highest maximal response, prostaglandins were active at lower concentrations. The rank order of potency was PGEa > U46619 > PGF2,~ > CCK-8 with ECs0 values + SEM of 8 8 7 7 2.47_+1.16x10- M, 1.57+1.14x10" M, 2.6+0.6xl0- M. and 2.63+0.43x10" M. Prostaglandins are potent contractors of human gallbladder smooth muscle and are active al lower concentrations than CCK-8. Although prostacyelin does not affect basal gallbladder tone of chronic cholecystitis gallbladders, it is a potent relaxant of contracted tissue. CHOLESTASIS IN IUXTA- AND PERIAMPULLARY DUODENAL DIVERTICULA? B. GroB, G. Richter, A. Beyer, H. Kastner, M. Wienbeck. Department of Medicine III, Zentralklinikum Augsburg, Germany. Controversy exists with respect to morbidity associated to iuxta- and periampullary duodenal diverticula. Therefore we prospectively evaluated in our Gastroenterology Unit between June 1993 and March 1994 i0 men and 8 women, mean age 72.5 years (range: 56 to 89). The diagnosis of iuxta- and periampullary duodenal diverticula was made by duodenoscopy and endoscopic retrograde cholangio- pancreaticography (ERCP). The diagnosis of chole- stasis was based on typical clinical (pain in the right upper abdomen and jaundice) and biochemical (bilirubin > I.I mg/dl; alkaline phosphatase > 190 U/l) symptoms as well as abnormalities in ultra- sonography and ERCP (dilated bile ducts, bile duct stones). 6 (33.3%) of the patients had perl- ampullary and 12 (66.6%) iuxtaampullary diver- ticula. 16 patients had only one diverticulum. In two cases 3 diverticula were seen. The mean size of the diverticul& was 1.71 cm in diameter (range: 0.5 to 3 cm). 14 (77~8%) patients complained of pain in the right upper abdomen, but only 6 (33.3%) patients showed jaundice. Increased bilirubin was found in i0 (55.5%) patients, increased alkaline phosphatase in 7 (38.8%). In 13 (72.2%) patients dilated bile ducts were demonstrated by ERCP and ultrasonography. 8 (44%) of them showed bile duct stones in ERCP. There was a significant correlation between pain in the right upper abdomen and iuxta- ampullary duodenal diverticula (p=0.017, xZ-test). Alkaline phosphatase and bilirubin tended to be elevated in iuxtaampullary diverticula (NIS.). The very strong association of iuxtaampullary diverticula with right upper abdominal pain and dilated bile ducts supports the hypothesis that the diverticula cause clinical symptoms, although overt cholestasis occurred only in a minority. The association of periampullary diverticula with these symptoms is less strong.

Prostaglandins are potent prokinetics for human gallbladder in vitro

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A416 AGA ABSTRACTS GASTROENTEROLOGY, VOI. 108, NO. 4

• DOSE DEPENDENT EFFECT OF ACUTE HYPERGLYCEMIA ON POSTPRANDIAL GALLBLADDER CONTRACTION AND HORMONE SECRETION. H.A.J. Gielken% A.A.M Masclee, E.S.M Muller, J. van Ostayen 1, C.B.H.W. Lamers. Depts of Gastroenterology and Hepatology and "Radiology, University Hospital Leiden, The Netherlands.

Previously we have shown that during acute hyperglycemia at 15 mmol/I, CCK and meal stimulated gallbladder contraction are significantly reduced. Aim of this study was to investigate whether the inhibitory effect of acute hyperglycemia on gallbladder motility is dose-dependent, i.e. different at several levels of hyperglycemic clamping. Seven healthy volunteers (4M, 3F; age 19-26 yr) were studied after an overnight fast on 4 separate occasions in random order with blood glucose concentrations stabilized at 4, 8, 12 and 16 mmoVI using a modified clamp technique. Gallbladder volumes, measured with ultrasonography, and plasma cholecystokinin (CCK), pancreatic polypeptide (PP), and glucose levels were determined at regular intervals for 180 rain. At time 0 rain gallbladder contraction was induced by ingestion of a meal (480 kCal). Results: Basal gallbladder volumes were not significantly different between the 4 experiments. Meal stimulated gallbladder emptying was significantly (p<O,O5) and dose-dependently reduced during hyperglycemic clamping at 16 mmol/I (26:t:7%), 12 mmol/I (43:1:5%), 8 mmol/I (55-/-6%) compared to normoglycemia (68:t6%). Endogenous CCK secretion was significantly (p<0.O5) reduced compared to normoglycemia only at a glucose level of 16 mmol/I (116+98 vs 159+13 pM.120 min) and not during clamping at 12 and 8 mmoVI (136+92 and 164+39 pM.120 min respectively). PP secretion, as an indirect measure of vagal cholinergic tone, was significantly (p<0.05) and dose-dependently reduced with values of 10+_.2, 6+1, 5:t0.9 and 3!-0.9 nmol.120 min respectively during clamping at 4, 8, 12 and 16 mmol/l. Conclusions: Acute hyperglycemia at different glucose levels 1) dose- dependently inhibits meal stimulated gallbladder emptying and 2) dose- dependently inhibits vagal cholinergic tone as measured indirectly by PP secretion, 3) endogenous CCK secretion is reduced only at high p!asma glucose levels.

• Procol lagen IH pept ide in bile - h igher concent ra t ions in p r i m a r y b i l ia ry c i r rhos is and p r i m a r y sclerosing cholangit is . A. Gillessen, E . Foerster, W. Domschke. Department of ~ Medicine B, University ofMuenster, Muenster, Germany.

In primary ,biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) fibrosis is found next to the bile ducts. Consequently, it was tempting to investigate concentrations of procollagen III peptide (P-III-P) in the bile.

We analyzed bile samples from 5 patients With PBC and 5 patients suffering from PSC ~nd 10 controls. The bile was obtained free of contrast medium during ERC examination. P-III-P concentrations were measured with a commercially available radioimmuno ~assay (Behring, Marburg, Germany).

P-III-P concentration measured in the bile fluid of cor~trols was 0.17 I.E./ml (±2s = 0.11). All l0 patients suffering from PBC o rPSC had significantly (p _<0,05) higher concentrations of P-III-P averaging 0.48 I.E,hnl (±2s =0.26).

In the bile of patienis with primary biliary cirrhosis or primary sclerosing cholangiti s procollagen-III-peptide is found in significantly higher concentrations than in normal controls indicating the possible role of this marker for the assessment Of the fibrotic activity in these diseases.

• PROSTAGLANDINS ARE POTENT PROKINETICS FOR HUMAN GALLBLADDER I N VITRO RRSH Greaves, LJD O'Donnell, MJG Farthing. Digestive Diseases Research Centre, Medical College of St.Bartholomew's Hospital, London EC1M 6BQ

Prostaglandins (PGs) have been identified in gallbladder smooth muscle and the cyclo-oxygenase inhibitor indomethacin is known to affect gallbladder motility in vivo and prevent gallstones. However the effect of naturally occurring prostaglandins on human gallbladder motility is unclear. We therefore examined the effects of PGE2, PGF2~, prostacyclin (PGI2), the thromboxane A 2 mimetic U46619, and cholecystokiniu-oetapeptide (CCK-8) on in vitro contractility of human gallbladders obtained from patients undergoing elective cholecystectomy for gallstones.

Gallbladder muscle strips were mounted in or.gran baths .containing gassed Krebs Solution at 37°C in the presence of 3 x 10" M indomethacin to prevent endogenous prostaglandin synthesis. An initial tension of lg was applied and changes m isometric tension were measured using a force- displacement transducer. Relaxant properties of PGI 2 were tested using muscl e strips pre-contraeted with U46619 (3x10"TM). ECs0 (the concentration of agonist which produced 50% of the maximum contraction) was calculated for each agonist

All the prostaglandins produced slow sustained contractions (onset 3-5 minutes, plateau 8-15 min) apart from PGI2 which had a negligible effect on basal tone. CCK-8 was the most effective agonist~n=9). Maximal response of the PGs as a percentage of maximal response to 10" M CCK-8 was 5cJ + 11% for U46619 (mean *_ SEM, n=9), 54 + 0% for PGF2Q (n=2), and 31 + 5% for PGE2 (n=6). PGI2 produced a mean z SEM maximum relaxation of tissue pre- contracted with 3x10 "7 M U46619 of 67_+ 10% (n=4).

Although CCK-8 produced the highest maximal response, prostaglandins were active at lower concentrations. The rank order of potency was PGEa > U46619 > PGF2,~ > CCK-8 with ECs0 values + SEM of

8 8 7 7 2.47_+1.16x10- M, 1.57+1.14x10" M, 2.6+0.6xl0- M. and 2.63+0.43x10" M. Prostaglandins are potent contractors of human gallbladder smooth

muscle and are active al lower concentrations than CCK-8. Although prostacyelin does not affect basal gallbladder tone of chronic cholecystitis gallbladders, it is a potent relaxant of contracted tissue.

CHOLESTASIS IN IUXTA- AND PERIAMPULLARY DUODENAL DIVERTICULA? B. GroB, G. Richter, A. Beyer, H. Kastner, M. Wienbeck. Department of Medicine III, Zentralklinikum Augsburg, Germany.

Controversy exists with respect to morbidity associated to iuxta- and periampullary duodenal diverticula. Therefore we prospectively evaluated in our Gastroenterology Unit between June 1993 and March 1994 i0 men and 8 women, mean age 72.5 years (range: 56 to 89). The diagnosis of iuxta- and periampullary duodenal diverticula was made by duodenoscopy and endoscopic retrograde cholangio- pancreaticography (ERCP). The diagnosis of chole- stasis was based on typical clinical (pain in the right upper abdomen and jaundice) and biochemical (bilirubin > I.I mg/dl; alkaline phosphatase > 190 U/l) symptoms as well as abnormalities in ultra- sonography and ERCP (dilated bile ducts, bile duct stones). 6 (33.3%) of the patients had perl- ampullary and 12 (66.6%) iuxtaampullary diver- ticula. 16 patients had only one diverticulum. In two cases 3 diverticula were seen. The mean size of the diverticul& was 1.71 cm in diameter (range: 0.5 to 3 cm). 14 (77~8%) patients complained of pain in the right upper abdomen, but only 6 (33.3%) patients showed jaundice. Increased bilirubin was found in i0 (55.5%) patients, increased alkaline phosphatase in 7 (38.8%). In 13 (72.2%) patients dilated bile ducts were demonstrated by ERCP and ultrasonography. 8 (44%) of them showed bile duct stones in ERCP. There was a significant correlation between pain in the right upper abdomen and iuxta- ampullary duodenal diverticula (p=0.017, xZ-test). Alkaline phosphatase and bilirubin tended to be elevated in iuxtaampullary diverticula (NIS.). The very strong association of iuxtaampullary diverticula with right upper abdominal pain and dilated bile ducts supports the hypothesis that the diverticula cause clinical symptoms, although overt cholestasis occurred only in a minority. The association of periampullary diverticula with these symptoms is less strong.