Reactive Oxygen Species Mediate Central Cardiorespiratory Network Responses to Acute Intermittent Hypoxia

Abstract

. 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.

Intermittent hypoxia modulates nitric oxide-dependent vasodilation and capillary perfusion during ischemia-reperfusion-induced damage

“…These authors suggested that this is the hematocrit increase at which the increase of NO due to increased SS is balanced by increased NO scavenging and increased blood viscosity. Nevertheless, persistent hypertension is a common response maladaptation to severe, sustained IH, and central cardiorespiratory network responses to IH are mediated by the level of oxidative stress (20,23). However, our results are in agreement with Tamisier et al (40) who showed persistent sympathoexcitation following continuous hypoxia but not following IH, possibly because the hypoxic protocols were hypocapnic, and hypocapnic hypoxia does not lead to a significant poststimulus sympathoexcitation.…”

“…Cai et al (15) reported that 24 h after the treatment of mice with five cycles of 6 min of 6% O 2 plus 6 min of 21% O 2 , the heart was protected against myocardial injury induced by 30 min of global ischemia followed by reperfusion. Nitric oxide (NO) and reactive oxygen species (ROS) levels have been proposed to be involved in the protective mechanisms provided by IH against I/R injury (18,23,27); however, the mechanisms in which IH preconditioning increases resistance to I/R injury are not well understood.Previous studies have shown that the beneficial effects of treatments that reduce I/R injury are inversely correlated with enhanced oxidative stress that subsequently modulates shear stress (SS), thus reducing NO bioavailability and endotheliumdependent vasodilation in postischemic reperfusion (9,11,12,31). Blood vessels are constantly exposed to SS, a frictional force exerted on the vessel that can influence vascular function by stimulating the production of NO, endothelial NO synthase (eNOS) expression, and oxidant signaling mechanisms involved in the control of fundamental physiological processes (42).…”

“…Cai et al (15) reported that 24 h after the treatment of mice with five cycles of 6 min of 6% O 2 plus 6 min of 21% O 2 , the heart was protected against myocardial injury induced by 30 min of global ischemia followed by reperfusion. Nitric oxide (NO) and reactive oxygen species (ROS) levels have been proposed to be involved in the protective mechanisms provided by IH against I/R injury (18,23,27); however, the mechanisms in which IH preconditioning increases resistance to I/R injury are not well understood.…”

Purinergic P2X receptors facilitate inhibitory GABAergic and glycinergic neurotransmission to cardiac vagal neurons in the nucleus ambiguus

“…Following the tachycardia, a bradycardia develops which serves to reduce the metabolic demand on cardiac and respiratory muscles and acts to extend survival by increasing parasympathetic outflow to the heart (Neff et al, 1998). The P2X receptor mediated increase in inhibitory glycinergic and GABAergic neurotransmission observed in this study may serve a vital role in the initial tachycardia, whereas a decrease in the purinergic facilitation of inhibitory neurotransmission, coupled with recruitment of an excitatory neurotransmission to CVNs is likely involved in the protective slowing of the heart (Griffioen et al, 2007a;Griffioen et al, 2007b). P2X receptors are permeable to small cations such as sodium and potassium and have varying permeability to calcium (Evans et al, 1996).…”

“…After the initial increase in inhibitory inputs to CVNs and the resulting tachycardia, the inhibitory inputs to CVNs are reduced and a parasympathetic mediated bradycardia occurs. This increase in parasympathetic cardiac activity is likely not only mediated by disinhibition, a reduction of the GABAergic and glycinergic inputs to CVNs, but also by the recruitment of an excitatory neurotransmission to CVNs post hypoxia (Griffioen et al, 2007a;Griffioen et al, 2007b). Consistent with an important role of purinergic pathways and receptors in mediating the heart rate responses to hypoxia, previous work has shown that activation of purinergic pathways and activation of P2X receptors is responsible for the excitatory neurotransmission to CVNs upon recovery from hypoxia and/or hypercapnia (Griffioen et al, 2007a).…”