Abstract
It is known that adenosine and adenosine-5′-triphosphate (ATP) are excitatory mediators involved in carotid body (CB) hypoxic signaling. The CBs are peripheral chemoreceptors classically defined by O2, CO2, and pH sensors. When hypoxia activates the CB, it induces the release of neurotransmitters from chemoreceptor cells leading to an increase in the action potentials frequency at the carotid sinus nerve (CSN). This increase in the firing frequency of the CSN is integrated in the brainstem to induce cardiorespiratory compensatory responses. In the last decade several pathologies, as, hypertension, diabetes, obstructive sleep apnea and heart failure have been associated with CB overactivation. In the first section of the present manuscript we review in a concise manner fundamental aspects of purine metabolism. The second section is devoted to the role of purines on the hypoxic response of the CB, providing the state-of-the art for the presence of adenosine and ATP receptors in the CB; for the role of purines at presynaptic level in CB chemoreceptor cells, as well as, its metabolism and regulation; at postsynaptic level in the CSN activity; and on the ventilatory responses to hypoxia. Recently, we have showed that adenosine is involved in CB hypersensitization during chronic intermittent hypoxia (CIH), which mimics obstructive sleep apnea, since caffeine, a non-selective adenosine receptor antagonist that inhibits A2A and A2B adenosine receptors, decreased CSN chemosensory activity in animals subjected to CIH. Apart from this involvement of adenosine in CB sensitization in sleep apnea, it was recently found that P2X3 ATP receptor in the CB contributes to increased chemoreflex hypersensitivity and hypertension in spontaneously hypertension rats. Therefore the last section of this manuscript is devoted to review the recent findings on the role of purines in CB-mediated pathologies as hypertension, diabetes and sleep apnea emphasizing the potential clinical importance of modulating purines levels and action to treat pathologies associated with CB dysfunction.
Highlights
Reviewed by: Eric Boué-Grabot, UMR5293 Institut des Maladies Neurodégénératives (IMN), France Ana Paula Abdala, University of Bristol, United Kingdom
We have showed that adenosine is involved in carotid body (CB) hypersensitization during chronic intermittent hypoxia (CIH), which mimics obstructive sleep apnea, since caffeine, a non-selective adenosine receptor antagonist that inhibits A2A and A2B adenosine receptors, decreased carotid sinus nerve (CSN) chemosensory activity in animals subjected to CIH
We have showed that approximately 40% of adenosine present extracellularly in the CB came from extracellular adenosine-5 -triphosphate (ATP) degradation, both under normoxic and hypoxic conditions and that low pO(2) triggers adenosine efflux through the activation of NBTI-sensitive ENT
Summary
Adenosine and adenosine-5 -triphosphate (ATP) are the only ones that are known to have a role in cell to cell communication and they act extracellularly to mediate several biological effects via cell-surface receptors, the purine receptors. The concept of purinergic neurotransmission was only established in the nineties, when receptors for adenosine and ATP were cloned and sequenced (for a review see Ralevic and Burnstock, 1998). Adenosine is a product of ATP catabolism, which can be used to resynthesize ATP itself This mediator is an ubiquitous substance that is not stored or released as a classical neurotransmitter, being released by almost all cell types through nucleoside transporters (Fredholm et al, 2001). It has key roles in pathways as purinergic nucleic acid base synthesis, amino acid metabolism and modulation of cellular metabolic status (Conde et al, 2009). Adenosine modulates the activity of several systems at presynaptic level (inhibiting or facilitating neurotransmitters release), at postsynaptic or at non-synaptic level (e.g., modulating blood flow or the metabolism of sustentacular cells)
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