Project Details


The respiratory response to hypoxia reflects the integration of peripheral
stimulation of carotid chemoreceptors and the modulation of the
respiratory neuronal network by the effects of central hypoxia. The
effect of central hypoxia on the net integrated respiratory output is
determined by the summation of the inhibitory and excitatory effects of
CNS hypoxia. Although the predominant effect of brain hypoxia is to cause
a reduction in neuronal excitability, recent work suggests that there may
be unique sites within the brain that are directly stimulated by hypoxia.
For example, while respiratory premotor ventral respiratory group (VRG)
neurons are depressed by hypoxia, sympathoexcitatory and pre-Botzinger
respiratory-related neurons in the rostral ventrolateral medulla (RVLM)
have been shown to increase their activity in response to local hypoxia.
The cellular events that distinguish these two contrasting neuronal
responses to hypoxia have not been defined. The studies outlined in this
application will investigate the mechanisms underlying these responses in
retrogradely labeled (fluorescent latex beads) premotor VRG (hypoxia-
depressed) and RVLM (hypoxia-excited) neurons dissociated and cultured
from neonatal rats using perforated patch clamp recording techniques to
identify the ionic currents that distinguish the different membrane
responses of these excited and depressed neurons. Identification of the
ionic changes that characterize these neuronal responses to hypoxia will
then allow us to explore the cellular mechanisms important for
transduction of the hypoxic signal in RVLM oxygen sensing neurons. Since
heme oxygenase (HO) has been shown to be an important factor in the oxygen
in the oxygen sensing mechanism of excitation of the carotid body and we
have found that HO is expressed in the RVLM, we will also test the
hypothesis that activation of HO is important for oxygen sensitivity of
RVLM neurons. Hypoxic excitation of central cardiorespiratory neurons
promotes an effective autoresuscitative response (in the form of intense
sympathetic discharge synchronized with respiratory gasping)which may be
critical for surviving life-threatening hypoxic events. In fact, failure
to gasp has been proposed as a potential cause of sudden infant death
Effective start/end date7/1/976/30/03


  • National Heart, Lung, and Blood Institute: $246,308.00
  • National Heart, Lung, and Blood Institute
  • National Heart, Lung, and Blood Institute


  • Pulmonary and Respiratory Medicine


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