Reactive oxygen species mediate central cardiorespiratory network responses to acute intermittent hypoxia

Although oxidative stress and reactive oxygen species generation is typically associated with localized neuronal injury, reactive oxygen species have also recently been shown to act as a physiological signal in neuronal plasticity. Here we define an essential role for reactive oxygen species as a critical stimulus for cardiorespiratory reflex responses to acute episodic hypoxia in the brain stem. To examine central cardiorespiratory responses to episodic hypoxia, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and synaptic neurotransmission to cardioinhibitory vagal neurons. We show that whereas continuous hypoxia does not stimulate excitatory neurotransmission to cardioinhibitory vagal neurons, acute intermittent hypoxia of equivalent duration incrementally recruits an inspiratory-evoked excitatory neurotransmission to cardioinhibitory vagal neurons during intermittent hypoxia. This recruitment was dependent on the generation of reactive oxygen species. Further, we demonstrate that reactive oxygen species are incrementally generated in glutamatergic neurons in the ventrolateral medulla during intermittent hypoxia. These results suggest a neurochemical basis for the pronounced bradycardia that protects the heart against injury during intermittent hypoxia and demonstrates a novel role of reactive oxygen species in the brain stem.