From the Johns Hopkins Medical Institutions, Department of Anesthesiology
and Critical Care Medicine, Baltimore, Md.
Correspondence to Dr Patricia D. Hurn, Department of Anesthesiology/Critical Care, Blalock 1404, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore. MD 21287-4963. E-mail phurn{at}welchlink.welch.jhu.edu
Background and
Purpose—Iron-catalyzed radical generation is a potentially
significant mechanism by which extensive tissue acidosis exacerbates
brain injury during ischemia/reperfusion. We hypothesized that
levels of low-molecular-weight (LMW) iron increase during in vivo
global cerebral ischemia in a pH-dependent manner, potentially
catalyzing oxidant injury. The present study quantified regional
differences in LMW iron during global cerebral incomplete
ischemia and determined whether augmenting the fall in
ischemic tissue pH with hyperglycemia also amplifies free
iron availability.
Methods—Dogs anesthetized with pentobarbital-fentanyl
were treated with 30 minutes of global incomplete cerebral
ischemia produced by intracranial pressure elevation. Cerebral
energy metabolites (ATP, phosphocreatine) and intracellular pH
(pHi) were measured by 31P magnetic resonance
spectroscopy. Preischemic plasma glucose level was
manipulated to titrate end-ischemic pHi. After
ischemia, brains were perfused with cold phosphate-buffered
saline solution; then 16 different brain areas were sampled, filtered
to separate the LMW fraction (<30 000 D), and assayed by rapid
colorimetric assay for tissue iron. Total iron, LMW
iron, and protein in each sample were measured in sham-operated (no
ischemia, n=8), normoglycemic ischemia (ISCH [glucose
7±4 mmol/L], n=7), and hyperglycemic (GLU-ISCH [glucose
31±3 mmol/L], n=9) groups.
Results—High-energy phosphates fell to near zero values in both
ISCH and GLU-ISCH groups by 30 minutes but remained unchanged in the
sham-operated group. As expected, pHi decreased during
ischemia but to a greater extent in GLU-ISCH (6.20±0.05 in
ISCH, 6.08±0.04 in GLU-ISCH, P<.05). Iron could be
detected in all areas of the brain in sham-operated animals, with the
highest amounts obtained from subcortical areas such as the
hippocampus, pons, midbrain, and medulla. Total iron was higher in ISCH
relative to sham-operated animals and higher in cortex and pons
relative to GLU-ISCH. Regional LMW (as a percentage of total iron;
LMW/total iron) was elevated in numerous brain areas in ISCH, including
cortical gray matter, cerebellum, hippocampus, caudate, and midbrain.
LMW/total iron was higher in GLU-ISCH versus ISCH in cortical gray
matter only. In other brain areas, ischemic LMW/total iron was
equivalent in glucose-treated or normoglycemic animals (white matter,
thalamus, pons, medulla) or lower in the glucose-treated group
(cerebellum, hippocampus, caudate, midbrain).
Conclusions—These data demonstrate that levels of total and LMW
iron increase with global cerebral ischemia in the majority of
cortical and subcortical regions of normoglycemic brain. However,
exacerbation of ischemic acidosis via glucose administration
does not increase tissue iron and produces a greater increase in the
LMW fraction in cortical gray matter only. In other brain regions,
total and LMW iron availability is similar to that of
nonischemic animals.
Laboratory
of Cerebrovascular Biology and Stroke,
Department of Neurology University of Minnesota,
Minneapolis, Minnesota
© 1998 American Heart Association, Inc.
Original Contributions
Low Molecular Weight Iron in Cerebral Ischemic Acidosis In Vivo
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