Acute Hypoxia: Hypoxia is one of the more
common and serious stresses challenging
homeostasis.
Investigations on the CNS responses to oxygen
deprivation are of obvious importance in revealing
mechanisms which participate in coordinated behavior
of respiratory and
vasomotor
responses to hypoxia. Specific, qualitatively and
quantitatively time-related changes in the brainstem
neurons occur during hypoxic exposure. Fundamental
questions concerning the mechanisms responsible for
these different responses remain to be answered. One
issue of primary significance is the role of
metabolic and vascular factors in determining
responses of the brainstem neuronal network to
hypoxic loading of different severity and duration.
Our goal is to test the hypothesis that metabolic
and vascular changes in the neuronal network
involved in regulation of respiratory output and
sympathetic
activity are coordinated processes, and that changes
in intracellular pH are an important factor
determining the global behavior of respiratory and
cardiovascular outputs. A multi-tiered group of
specific aims was designed to test this hypothesis.
We will use 2-deoxyglucose autoradiography and
enzyme histochemistry to determine regional
differences in metabolic demand and enzymatic
capacity during hypoxic exposure. In addition, in
rats with carotid sinus nerves intact and in
sinoaortal denervated animals, we will define the
metabolic and vascular changes by determination of
the spatial and temporal heterogeneity of
intracellular pH and regional blood flow during
transient and sustained hypoxic exposure. Observed
changes will be compared with metabolic responses to
local hypoxic loading of the brainstem by topical
administration of sodium cyanide. Based on obtained
results, a functional map of the brainstem responses
to altered arterial oxygen and carbon dioxide will
be generated.
Chronic Hypoxia:
Adaptation to continued moderate hypoxia in the rat
brain includes structural and metabolic changes. The
most striking evidence of this hypoxia induced
metabolic and vascular plasticity is capillary
angiogenesis characterized by increased capillary
density. We are studying the time course of
angiogenesis in response to continued and
intermittent hypoxia, and return to normoxia. The
appearance and disappearance of capillaries will be
documented in the standard adult Wistar rat model
and compared to the response of obese/hypertensive,
lean/hypertensive, and streptozotocin-induced
chronic
hyperglycemic
rats. Functional consequences of vascular
re-structuring will be examined through measurements
of blood flow and mean transit time and blood volume
under resting conditions and in response to
challenges of acute hypoxia, acute
hypercapnia
and acetazolamide. Brain energy metabolites and
intracellular pH will be measured to characterize
the metabolic adaptations in these models. These
studies will help to define the boundaries of the
structural and metabolic changes that occur in
response to continued hypoxic exposures. It is our
long term goal to provide a basic understanding of
the physiological and patho-physiological responses
triggered by hypoxic exposure.
