Effects of sustained hypoxia on the electrophysiological properties and purinergic signaling of the carotid chemoreceptors of rats

Abstract

In mammals, the exposure to low levels of O2 (hypoxia) stimulates several compensatory cellular and systemic adjustments to re-establish the homeostasis of this gas in the blood. Increases in pulmonary ventilation represent the first and most prominent adaptative changes to acute hypoxia. However, the exposure to Sustained Hypoxia (SH) evokes progressive and time-dependent increases in pulmonary ventilation, and this phenomenon is known as ventilatory acclimation to hypoxia. The peripheral chemoreceptors located bilaterally at the bifurcation of the carotid arteries (Carotid Bodies - CBs) are essential for the process of ventilatory acclimation to hypoxia. CBs are formed by type I and II cells, closely involved with chemosensory responses to reductions of PaO2. After their activation, several neurotransmitters are realised increasing the excitability of the afferent sensory endings in the carotid sinus and glossopharyngeal nerves, which cell bodies are found in the petrosal ganglion and make the first synapse in the dorsal region of the brainstem. The activation of the brainstem respiratory neurons stimulates efferent responses to increase the pulmonary ventilation, by the inspiratory and expiratory responses, in addition to autonomic and behavioural responses. One of the main neurotransmitters released by the chemosensitive cells of CBs is the ATP, an important energy molecule and intercellular excitatory neurotransmitter. Important morphological and functional changes have been described in the CBs of rats and humans in response to SH, including increases in their volume and in the activity of carotid sinus nerve in normoxia (tonicity) and its sensitivity to hypoxia (hyperreflexia). However, the contribution of the purinergic transmission to these functional changes has not yet been determined. In view of this, the hypothesis of the present research project is as follows: 24 hours of SH increase the excitability and the release of ATP by the peripheral chemoreceptors of rats, contributing to the increase in its sensitivity to hypoxia and tonicity. To test this hypothesis, we will analyse: (i) the effects of SH on the electrophysiological properties of the CBs cells and chemoreceptor neurons of the petrosal ganglion of rats, as well as their expression of purinergic receptors; (ii) the effects of SH on the electrophysiological responses of the CBs cells and chemoreceptor neurons of the petrosal ganglion of rats in response to the activation of purinergic receptors; (iii) the effects of SH on the release of ATP by CBs cells, and; (iv) the effects of SH on the inspiratory and expiratory responses of rats to the stimulation of purinergic receptors in the CBs. The data to be obtained with the development of this research project will allow us to advance in the better understanding of the cellular mechanisms involved in the important respiratory adaptations, mediated by the peripheral chemoreceptors, in response to acute reductions of the O2 in rats. (AU)