Glycine minimizes reperfusion injury in a low-flow, reflow liver
perfusion model in the rat.
Zhong, Zhi, Shannon Jones, and Ronald G. Thurman.
Laboratory of Hepatobiology and Toxicology, Department of
Pharmacology, University of North Carolina at Chapel Hill, Chapel
Hill, NC 27514
APStracts 2:0154G, 1995.
This study investigated the effects of glycine on reperfusion injury
in a low-flow, reflow liver perfusion model. With this protocol,
livers were perfused at low flow rates around 1 ml/g/min for 75 min,
which caused cells in pericentral regions of the liver lobule to
become anoxic because of insufficient delivery of oxygen. When normal
flow rates (about 4 ml/g/min) were restored for 40 min, an oxygen
-dependent reperfusion injury occurred. Upon reflow, lactate
dehydrogenase (LDH), a cytosolic enzyme, and malondialdehyde (MDA),
an end product of lipid peroxidation, were released into the effluent
perfusate. LDH increased from basal levels of about 1 to 35 IU/g/h in
livers from control rats. Glycine (0.06-2.00 mM) minimized enzyme
release in a dose-dependent manner (half-maximal decrease =133
[mu]M), with maximal values only reaching 5 IU/g/h when glycine was
increased to 2 mM. Reflow for 40 minutes following 75 minutes of low
-flow hypoxia caused death in about 30% of previously anoxic
parenchymal cells in pericentral regions; however, infusion of
glycine (2 mM) decreased cell death to less than 10%. Strychnine (1
mM), which was found to mimic the cytoprotective effect of glycine in
proximal renal tubules, also reduced LDH release to 11 IU/g/h in this
study. Bile was released at rates of around 42 [mu]l/g/h in livers
from control rats but values were not altered significantly by
glycine. Maximal MDA production during reperfusion decreased by 35%
with 0.6 mM of glycine. Trypan blue distribution time, an indicator
of hepatic microcirculation, was reduced significantly by glycine at
5 and 40 minutes after reflow, but changes were about 2-fold greater
at later than earlier time points (half-maximal decrease = 225
[mu]M). Time for oxygen to reach steady state upon reflow was reduced
by glycine in a dose-dependent manner, and the rates of entry and
exit of a dye confined to vascular space (fluorescein-dextran) were
increased 2 to 3-fold by glycine, respectively. Taken together, these
data indicate that a reperfusion injury, which occurs in previously
hypoxic pericentral regions of the liver upon reintroduction of
oxygen, is minimized by glycine, possibly by action on a glycine
-sensitive anion channel to improve microcirculation during the
reperfusion period.
Received 18 January 1995; accepted in final form 17 July 1995.
APS Manuscript Number G23-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 10 August 1995.