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Intrahepatic versus extrahepatic cholestasis — Improved scintigraphic discrimination with the hepatic extraction fraction
2062
ABSTRACTS
OF PAPERS
LUMINAL SFCRETIN: ARTEFACT,DIRECT SECRETION OR BASAL SECRBTICN WiTH PARACELLULAR TRANSPORT ? G. Lake-Bakaar*, Joan Preece.Acad Dept of Med,
Royal Free Hesp, London.*Presentaddress: DMCSDNY, Brooklyn,NY A numberof studieshave demohsteatedrecovery of significantamounts'ofGI hormonesincludingsecretin, in intestinalperfusate.. .Thiscould result from mucosal damage,direct transapical seccetionor basal secretion with paracellular transportinto the gut lumen. We have studiadthe originof in vivo luminalsecretin in our previouslydescribedrabbit intestinalperfusion model. Duodenalperfusionwith HCl in molar concentrations above 0.05N and at perfusionrates over 2ml/minresulted in significantmucosaldamagedemonstratedby both scanningand transmission electronmicroscopy. Perfusionwith O.OlN,O.O125N and 0.025NHCl at 2ml/minresultedin a dosedependentreleaseof secretin into the perfusate. Vinblastinea microfilament inhibitor (lmg/kgbolus followedby O.lmg/kg/hriv), had no effecton recovery. However, colchicinea microtubular inhibitor(Smg/kgfollowedby lq/kg/hr) significantly decreasedsecretinrecovery. Pretreatment with iv secretinantibodyalso significantly reduced recovery.
CONTROL n=6 VINBLASTINE n=2 COLCHICINE n=2 ANTI-SECRN n=6
O.OlNHCL 1.08~2.0 0.60~1.0 1.321.5 0.110.3
O.OlNHCL 0.025NHCL 4.97+9.1 15.4~13.8 ng/nlh (M+SD) 4.66+2.9 15,32+11.0. N.S. 0.71tO.4 0.34+0.2 P 0.025 2.90+3.0 2.29e2.8 P 0.025
GASTROENTEROLOGY
Vol. 92. No. 6
INDUCTION OF CHOLESTEROL HALABSORPTION BY A NEWPOLYOLEYL CELLULOSE (POC). W.G. Linscheer, N. Hiroae, K.L. Raheja. Section of Gaatroenterology, VA Nedical Center and SUNYHealth Science Center, Syracuse, NY. Lowering of blood cholesterol by drug tberapy ia “ot satisfactory becauae of side effect8 and tost factors. We have teated, in an experimental rat model, a compound consisting of two nonnal dietary ingredients, namely oleic acid and cellulose. The oleic acid polymerized to a backbone of cellulose (synthesized by A.S. Hoffman and J. Nightingale, U. of Washington, WA) has lipid properties and is not absorbed from the inteatinal tract. The effect on the inteatinal absorption of cholesterol was evaluated by means of perfusion studies of proximal rat smal1 bowel in vivo as described previously (Am. J. Physiol., 246, G492-499, 1984). Experimental design: Rates of absorption of cholesterol from a control solution containing oleic acid (20 mM), cholesterol (1 mll) and Na taurocholate (30 ~II) in lactate Ringer, wdre compared with rates of absorption from a test solution of similar composition but containing also 3.75 lJHof POC. Resul ts: Rates of cholesterol absorption from tbe control perfusate was 14.54 + 0.54 (SE) nM/min/an smal1 bowel va 8.77 + 0.22 nM/min/cm (p
These resultssuggestthat at lovrates of ducdenal perfusion,luminalsecretinprobablyresults from basal seccetionwith paracellular diffusion.
IWTRAHEPATIC VERSUSEXTNAHgPATIC CHOLESTASIS- IHPROVED
SCINTIGRAPHIC DISCRIIIIUATIONWITH THE HBPATICEXTRACTIOU FKACTIOU.D.Lieberman,P.Brown,G.Krishnamurthy,J.Juni; Portland VAHC,Portland,OR and Univ.Hichigan,Ann Arbor, HI.
In pteviousstudies,biliaryscintigraphy with Tc-IDA compounds providedexcellentdiscrimination between intrahepatic and extrahepatic cholestasis, exceptin patients with profound cholestasis who had poor visualization of the biliary tree. We have now used deconvolution analysis to determine what we term the hepatic extraction fraction (HEF) of a hypothetical single circulatory pass of radionuclide. Dur hypothesis was that the HEF would be normal in patients with extrahepatic obstruction alone. but would be impaired in patients with severe cirrhosis. The puroose of this study was to compare the HEF in patients with profound cholestasis (bilirubin > 3 mg/dl) due to either cirrhosis or common bile duet obstruction (CBDO). The diagnosis of cirrhosis was based on histology and/or the presence of Subjects were fasted overnightand esophageal varices.
received2-5 mCi of Tc-99m-DISIDA.The liver t 112 excretion was determined.A Fourier technique was used
to deconvolute a truc liver curve which was fit with an exponential least squares to detanalne the HEF. The results are suunnarized on the following table: Grouo u0nna1 CBW Cirrhosis
Bili (a&dl) HEF (X1 1: 0.4 100 89.4 (67-100) 6.8 8 9 14.1 33.7 (13-44)* *different from other groups, p < .Ol The t 1/2 excretion of radionuclide was delayed in both groups. However, the HEF wes abnormalin the cirrhotics comparedto patientswith severecholestasis due to CBDO. Conclusion: In petients with cholestasis due to severe cirrhosis, the HEF is abnormal, which may reflect impaired In contrast, when cholestasis is due hepatocyte function. to CBDD, the HEF is usually normal, although excretion of The addition of deconvolution radionuclide is deleyed. analysis to biliary scintigraphy augments the discrimination between intrahepatic and extrahepatic cholestasis.
CDRRELATION BETWEEN ULCEROGENIC AND NEUROTOXICEFFECTS OF 1-~.~THYL-4-PAEEIYL-1,2,3,6-TETRAHYDROPYRIDINE(HPTP) AIID ITS Depts. REDUCED DERIVATIVEIN HATS. E. Marshall, ,$. &&Q. of Patbology, Brighae and Womeo’s Aosp., Harvard lied. Sch., Boston, MA 02115. Duodenal ulcers develop In rats givon IIPTP, a dopaslinerHeurotoxicity csr! be causinG parkinsonisn. neurotoxin GIC I,lodulated by dopamine uptake blockade and monoar..ine oxidase Since it is unlikely that the reduced (HAO) inhibition. farm l-methyl-4-phenyl-piperídine (MPPP) is oxidized, we tested for correlation between GI and extrapyramidal toxiciwith ty in rats given elther MPTP or MPPP and pretreated specific inhibitors of catecholamine uptake or HAD. Female SpraCue-Dawley rats (150-18Og) received the dopamine ubtake the norepinephrine uptake inhibitor GDR-12909 (l.Ory/lOOg), inhibitor maprotiline (l.Omg/lOOg), or the MAO-A inhibitor clorgyline (O.lmg/lOOg) lntragastrically lig), 30 min prior to MPTP (Z.Om&/lOOg) SC x3/d for 4 days. Additional rats ig CBR-12909 or maprotiline (3.Omg/lOOg), or clorreceived HPPP (30.0mg/lOOg) SC cyline (0.3mg/lOOg), 30 min before A group of NPPP rats receivedthe HAOxl/d for 4 days. inhibitor 1-deprenyl (0.3q/lOOg) ig xl/d to match IIPTP rats receiving 1-deprenyl (O.lm&/lOO&) i.g x3/d in a previous exblotility was rated semiquantitatively every hour; periment. duodenal ulcer severity and size were quantitated at autopsy on day 5. Motility disruption correlated with duodcnal ulcer severity (r.0.553, p
ABSTRACTS
OF PAPERS
LUMINAL SFCRETIN: ARTEFACT,DIRECT SECRETION OR BASAL SECRBTICN WiTH PARACELLULAR TRANSPORT ? G. Lake-Bakaar*, Joan Preece.Acad Dept of Med,
Royal Free Hesp, London.*Presentaddress: DMCSDNY, Brooklyn,NY A numberof studieshave demohsteatedrecovery of significantamounts'ofGI hormonesincludingsecretin, in intestinalperfusate.. .Thiscould result from mucosal damage,direct transapical seccetionor basal secretion with paracellular transportinto the gut lumen. We have studiadthe originof in vivo luminalsecretin in our previouslydescribedrabbit intestinalperfusion model. Duodenalperfusionwith HCl in molar concentrations above 0.05N and at perfusionrates over 2ml/minresulted in significantmucosaldamagedemonstratedby both scanningand transmission electronmicroscopy. Perfusionwith O.OlN,O.O125N and 0.025NHCl at 2ml/minresultedin a dosedependentreleaseof secretin into the perfusate. Vinblastinea microfilament inhibitor (lmg/kgbolus followedby O.lmg/kg/hriv), had no effecton recovery. However, colchicinea microtubular inhibitor(Smg/kgfollowedby lq/kg/hr) significantly decreasedsecretinrecovery. Pretreatment with iv secretinantibodyalso significantly reduced recovery.
CONTROL n=6 VINBLASTINE n=2 COLCHICINE n=2 ANTI-SECRN n=6
O.OlNHCL 1.08~2.0 0.60~1.0 1.321.5 0.110.3
O.OlNHCL 0.025NHCL 4.97+9.1 15.4~13.8 ng/nlh (M+SD) 4.66+2.9 15,32+11.0. N.S. 0.71tO.4 0.34+0.2 P 0.025 2.90+3.0 2.29e2.8 P 0.025
GASTROENTEROLOGY
Vol. 92. No. 6
INDUCTION OF CHOLESTEROL HALABSORPTION BY A NEWPOLYOLEYL CELLULOSE (POC). W.G. Linscheer, N. Hiroae, K.L. Raheja. Section of Gaatroenterology, VA Nedical Center and SUNYHealth Science Center, Syracuse, NY. Lowering of blood cholesterol by drug tberapy ia “ot satisfactory becauae of side effect8 and tost factors. We have teated, in an experimental rat model, a compound consisting of two nonnal dietary ingredients, namely oleic acid and cellulose. The oleic acid polymerized to a backbone of cellulose (synthesized by A.S. Hoffman and J. Nightingale, U. of Washington, WA) has lipid properties and is not absorbed from the inteatinal tract. The effect on the inteatinal absorption of cholesterol was evaluated by means of perfusion studies of proximal rat smal1 bowel in vivo as described previously (Am. J. Physiol., 246, G492-499, 1984). Experimental design: Rates of absorption of cholesterol from a control solution containing oleic acid (20 mM), cholesterol (1 mll) and Na taurocholate (30 ~II) in lactate Ringer, wdre compared with rates of absorption from a test solution of similar composition but containing also 3.75 lJHof POC. Resul ts: Rates of cholesterol absorption from tbe control perfusate was 14.54 + 0.54 (SE) nM/min/an smal1 bowel va 8.77 + 0.22 nM/min/cm (p
These resultssuggestthat at lovrates of ducdenal perfusion,luminalsecretinprobablyresults from basal seccetionwith paracellular diffusion.
IWTRAHEPATIC VERSUSEXTNAHgPATIC CHOLESTASIS- IHPROVED
SCINTIGRAPHIC DISCRIIIIUATIONWITH THE HBPATICEXTRACTIOU FKACTIOU.D.Lieberman,P.Brown,G.Krishnamurthy,J.Juni; Portland VAHC,Portland,OR and Univ.Hichigan,Ann Arbor, HI.
In pteviousstudies,biliaryscintigraphy with Tc-IDA compounds providedexcellentdiscrimination between intrahepatic and extrahepatic cholestasis, exceptin patients with profound cholestasis who had poor visualization of the biliary tree. We have now used deconvolution analysis to determine what we term the hepatic extraction fraction (HEF) of a hypothetical single circulatory pass of radionuclide. Dur hypothesis was that the HEF would be normal in patients with extrahepatic obstruction alone. but would be impaired in patients with severe cirrhosis. The puroose of this study was to compare the HEF in patients with profound cholestasis (bilirubin > 3 mg/dl) due to either cirrhosis or common bile duet obstruction (CBDO). The diagnosis of cirrhosis was based on histology and/or the presence of Subjects were fasted overnightand esophageal varices.
received2-5 mCi of Tc-99m-DISIDA.The liver t 112 excretion was determined.A Fourier technique was used
to deconvolute a truc liver curve which was fit with an exponential least squares to detanalne the HEF. The results are suunnarized on the following table: Grouo u0nna1 CBW Cirrhosis
Bili (a&dl) HEF (X1 1: 0.4 100 89.4 (67-100) 6.8 8 9 14.1 33.7 (13-44)* *different from other groups, p < .Ol The t 1/2 excretion of radionuclide was delayed in both groups. However, the HEF wes abnormalin the cirrhotics comparedto patientswith severecholestasis due to CBDO. Conclusion: In petients with cholestasis due to severe cirrhosis, the HEF is abnormal, which may reflect impaired In contrast, when cholestasis is due hepatocyte function. to CBDD, the HEF is usually normal, although excretion of The addition of deconvolution radionuclide is deleyed. analysis to biliary scintigraphy augments the discrimination between intrahepatic and extrahepatic cholestasis.
CDRRELATION BETWEEN ULCEROGENIC AND NEUROTOXICEFFECTS OF 1-~.~THYL-4-PAEEIYL-1,2,3,6-TETRAHYDROPYRIDINE(HPTP) AIID ITS Depts. REDUCED DERIVATIVEIN HATS. E. Marshall, ,$. &&Q. of Patbology, Brighae and Womeo’s Aosp., Harvard lied. Sch., Boston, MA 02115. Duodenal ulcers develop In rats givon IIPTP, a dopaslinerHeurotoxicity csr! be causinG parkinsonisn. neurotoxin GIC I,lodulated by dopamine uptake blockade and monoar..ine oxidase Since it is unlikely that the reduced (HAO) inhibition. farm l-methyl-4-phenyl-piperídine (MPPP) is oxidized, we tested for correlation between GI and extrapyramidal toxiciwith ty in rats given elther MPTP or MPPP and pretreated specific inhibitors of catecholamine uptake or HAD. Female SpraCue-Dawley rats (150-18Og) received the dopamine ubtake the norepinephrine uptake inhibitor GDR-12909 (l.Ory/lOOg), inhibitor maprotiline (l.Omg/lOOg), or the MAO-A inhibitor clorgyline (O.lmg/lOOg) lntragastrically lig), 30 min prior to MPTP (Z.Om&/lOOg) SC x3/d for 4 days. Additional rats ig CBR-12909 or maprotiline (3.Omg/lOOg), or clorreceived HPPP (30.0mg/lOOg) SC cyline (0.3mg/lOOg), 30 min before A group of NPPP rats receivedthe HAOxl/d for 4 days. inhibitor 1-deprenyl (0.3q/lOOg) ig xl/d to match IIPTP rats receiving 1-deprenyl (O.lm&/lOO&) i.g x3/d in a previous exblotility was rated semiquantitatively every hour; periment. duodenal ulcer severity and size were quantitated at autopsy on day 5. Motility disruption correlated with duodcnal ulcer severity (r.0.553, p