Cerebral Ischemia: The failure of central
nervous system vascular and metabolic recovery
mechanisms is responsible for most of the morbidity
and mortality following initially successful
resuscitation from cardiac arrest. Fundamental
questions concerning the pathophysiology of ischemic
damage and the contribution to neuronal survival by
the metabolic and vascular recovery mechanisms still
remain unanswered. One issue of primary significance
is the role of tissue
acidosis
in the process of ischemia and
recovery from ischemia. It is not known if the
levels of tissue acidosis reached during ischemia
directly produce neuronal damage, nor is it known if
mild acidosis during recovery is protective (the pH
paradox ) or contributory to further tissue damage.
In order to examine the role of pH, we have designed
four different but related specific aims.
The
first
aim examines metabolic and vascular factors that
affect acute (<6 hrs) survival and involves
determination of the spatial and temporal
heterogeneity of pHi changes during cardiac arrest
and subsequent reperfusion in relevant regions of
the rat brain stem and correlate these data with
metabolic demand and capacity as indicated by
2-deoxyglucose autoradiography and metabolic enzyme
histochemistry.
The
second aim examines the metabolic and vascular
factors that influence longer term (> 4 days) death
or survival of neurons. This aim involves microregional analysis of pHi, metabolic enzymes and
metabolites, and energy demand and capacity in
hippocampus from gerbils after reversible bilateral
carotid occlusion.
The
third aim makes use of in
vitro brain slice preparations of brain stem and
hippocampus in order to better define the cellular
location of the pHi signals generated by the neutral
red and SNARF methods and to examine the potential
mechanisms by which pHi affects cell and tissue
edema.
Our fourth aim involves the refinement of a dynamic
mathematical model of brain metabolism and blood
flow in order to quantitatively and mechanistically
explain the results so that we will be better able
to generalize our conclusions in a wider context. As
a result of our previous work, we have shown that
there is significant spatial heterogeneity in brain
pHi after ischemia and reperfusion. In order to
focus more directly on the role of pHi in ischemic
survival, it is a necessity that tissue
heterogeneity be taken into account.
