The doctoral dissertations of the former Helsinki University of Technology (TKK) and Aalto University Schools of Technology (CHEM, ELEC, ENG, SCI) published in electronic format are available in the electronic publications archive of Aalto University - Aaltodoc.
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Measurement of Epithelial Electrical Passive Parameters and its Application to Study Gastric Defence against Acid and Ulcerogenic Agents

Harri Mustonen

Dissertation for the degree of Doctor of Science in Technology to be presented with due permission of the Department of Electrical and Communications Engineering for public examination and debate in Auditorium S5 at Helsinki University of Technology (Espoo, Finland) on the 28th of November, 2003, at 12 o'clock noon.

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Dissertation is also available in print (ISBN 951-22-6798-5)

Abstract

The aim of this study was to develop a reliable method for measuring epithelial membrane and shunt resistances. This was accomplished by improving the intraepithelial two dimensional cable analysis by using multiple electrodes simultaneously and by sequentially applying the intraepithelial current through different electrodes thus taking advantage of their spatial relationship. The improvement achieved with this novel method is its excellent temporal resolution; changes in the membrane and shunt pathway resistances can be typically measured in 9-20 seconds. The actual measurement time depends on the target tissue, number of electrodes, electrode noise and distance configuration.

This technique was applied to investigate the effects of luminal acid on membrane resistances of Necturus gastric (antral) mucosa. The main finding was that luminal acid closes sodium selective, amiloride blockable channels on the apical cell membrane probably by protonating 1-2 amino acid residues of the channel molecule itself. These findings suggest that the epithelium can generate a protective barrier against the luminal acidic offence by closing its apical cell membrane channels. Besides direct protection against H+ influx, another possible advantage gained by closure of the Na+-selective channels in the apical cell membrane is the maintenance of a sufficient transmembrane Na+ gradient for Na+-dependent acid equivalent transport processes across the basolateral cell membrane.

The method was also used to elucidate the effects of luminal ethanol on the epithelial membrane resistances of Necturus gastric mucosa. Surprisingly, the first effects were seen on the basolateral cell membrane, not on the apical cell membrane or on the shunt pathway, as would have been expected. With ion substitution and channel blocker experiments, it was deduced that potassium selective channels on the basolateral cell membrane were opened by luminal ethanol exposure. This opening of potassium channels decreased cell volume. The present data indicate that opening of basolateral K+ channels with resultant epithelial cell shrinkage are among the earliest functional perturbations that might precede and underlie ethanol induced gastric mucosal injury. The subsequent opening of apical Na+ selective channels with consequent increase in intracellular Na+ load after more prolonged ethanol exposure suggests further functional deterioration of the epithelium. On the other hand, the profound changes in intraepithelial resistances provoked by stronger ethanol insult (i.e. collapse of Ra, decrease in Rs and closing of the gap-junctions as judged from the increased Rx) are more compatible with a structural damage of the epithelium and probably reflect emerging disruption of the surface epithelium.

This thesis consists of an overview and of the following 4 publications:

  1. Kiviluoto T., Mustonen H. and Kivilaakso E., 1989. Effect of barrier-breaking agents on intracellular pH and epithelial membrane resistances: studies in isolated Necturus antral mucosa exposed to luminal acid. Gastroenterology 96, No. 6, pages 1410-1418.
  2. Mustonen H., 1998. Improved intraepithelial two-dimensional cable analysis with application to Necturus gastric antral mucosa. Pflügers Archiv – European Journal of Physiology 436, No. 5, pages 646-652.
  3. Mustonen H. and Kivilaakso E., 1997. Luminal acid increases apical cell membrane resistance in isolated Necturus antral mucosa. Gastroenterology 113, No. 3, pages 875-883.
  4. Mustonen H. and Kivilaakso E., 2003. Effect of luminal ethanol on epithelial resistances and cell volume in isolated Necturus gastric mucosa. Digestive Diseases and Sciences 48, No. 10, pages 2037-2044.

Keywords: gastric defence, gastric epithelia, gastric antrum, stomach, duodenal epithelia, acids, ulcerogenic agents, membrane resistance, cell membranes, luminal ethanol, shunt resistance, Necturus gastric mucosa, two-dimensional cable analysis, electrical modelling

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© 2003 Helsinki University of Technology

Last update 2011-05-26