URSODEOXYCHOLATE INCREASES CYTOSOLIC CALCIUM-CONCENTRATION AND ACTIVATES CL- CURRENTS IN A BILIARY CELL-LINE

被引:45
作者
SHIMOKURA, GH [1 ]
MCGILL, JM [1 ]
SCHLENKER, T [1 ]
FITZ, JG [1 ]
机构
[1] DUKE UNIV,MED CTR,DEPT MED,DIV GASTROENTEROL,DURHAM,NC 27710
关键词
D O I
10.1016/0016-5085(95)90407-7
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Background & Aims: Ursodeoxycholate (UDC) stimulates a bicarbonate-rich choleresis, but the cellular mechanisms involved are not fully established. Because ductular secretion also increases biliary HCO3- concentration, the purpose of this study was to evaluate whether UDC has direct effects on duct cells by measuring intracellular calcium concentration ([Ca2+](l)) and membrane Cl- permeability in Mz-ChA-1 human cholangiocarcinoma cells. Methods: Intracellular calcium levels were measured using fura-2 fluorescence, Membrane Cl- permeability was assessed in subconfluent monolayers using I-125 efflux and in individual cells using whole-cell patch clamp techniques. Results: Exposure to UDC (2.5 mmol/L) increased [Ca2+](i) from 180 +/- 25 to 639 +/- 84 nmol/L due to release of Ca2+ from intracellular stores and stimulated I-125 efflux approximately threefold above basal levels. Exposure to extracellular (1.25 mmol/L) or intracellular (100 mu mol/L) UDC activated currents carried by Cl- ions; intracellular UDC increased current density from 4.7 +/- 1.3 to 32.5 +/- 8.8 pA/pF, UDC-stimulated currents were inhibited by chelation of intracellular calcium, Conclusions: UDC in pharmacological concentrations increases [Ca2+](i) and stimulates Cl- efflux through opening of Cl- channels in biliary cells. We speculate that UDC could increase bile flow by direct stimulation of ductular secretion and may be of therapeutic benefit to patients with cystic fibrosis who have impaired adenosine 3',5'-cyclic monophosphate-dependent biliary secretion.
引用
收藏
页码:965 / 972
页数:8
相关论文
共 42 条
  • [21] CANALICULAR BILE-SALT INDEPENDENT BILE FORMATION - CONCEPTS AND CLUES FROM ELECTROLYTE TRANSPORT IN RAT-LIVER
    GRAF, J
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1983, 244 (03): : G233 - G246
  • [22] GRYNKIEWICZ G, 1985, J BIOL CHEM, V260, P3440
  • [23] IMPROVED PATCH-CLAMP TECHNIQUES FOR HIGH-RESOLUTION CURRENT RECORDING FROM CELLS AND CELL-FREE MEMBRANE PATCHES
    HAMILL, OP
    MARTY, A
    NEHER, E
    SAKMANN, B
    SIGWORTH, FJ
    [J]. PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, 1981, 391 (02): : 85 - 100
  • [24] Hofmann Alan F., 1994, P677
  • [25] BILIARY ADENOCARCINOMA - CHARACTERIZATION OF 3 NEW HUMAN-TUMOR CELL-LINES
    KNUTH, A
    GABBERT, H
    DIPPOLD, W
    KLEIN, O
    SACHSSE, W
    BITTERSUERMANN, D
    PRELLWITZ, W
    ZUMBUSCHENFELDE, KHM
    [J]. JOURNAL OF HEPATOLOGY, 1985, 1 (06) : 579 - 596
  • [26] INHIBITION OF NA+/H+ EXCHANGE IN THE RAT IS ASSOCIATED WITH DECREASED URSODEOXYCHOLATE HYPERCHOLERESIS, DECREASED SECRETION OF UNCONJUGATED URSODEOXYCHOLATE, AND INCREASED URSODEOXYCHOLATE GLUCURONIDATION
    LAKE, JR
    RENNER, EL
    SCHARSCHMIDT, BF
    CRAGOE, EJ
    HAGEY, LR
    LAMBERT, KJ
    GURANTZ, D
    HOFMANN, AF
    [J]. GASTROENTEROLOGY, 1988, 95 (02) : 454 - 463
  • [27] LENZEN R, 1992, AM J PHYSIOL, V26, pG527
  • [28] LEVINE RA, 1976, GASTROENTEROLOGY, V70, P537
  • [29] IMMUNOHISTOCHEMICAL DETECTION OF CHLORIDE/BICARBONATE ANION-EXCHANGERS IN HUMAN LIVER
    MARTINEZANSO, E
    CASTILLO, JE
    DIEZ, J
    MEDINA, JF
    PRIETO, J
    [J]. HEPATOLOGY, 1994, 19 (06) : 1400 - 1406
  • [30] ADENOSINE-TRIPHOSPHATE ACTIVATES ION PERMEABILITIES IN BILIARY EPITHELIAL-CELLS
    MCGILL, JM
    BASAVAPPA, S
    MANGEL, AW
    SHIMOKURA, GH
    MIDDLETON, JP
    FITZ, JG
    [J]. GASTROENTEROLOGY, 1994, 107 (01) : 236 - 243