Purines and Carotid Body: New Roles in Pathological Conditions

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.

Do Changes in Hemodynamic Parameters Depend Upon Length of Sleep Deprivation? Comparison Between Subjects With Normal Blood Pressure, Prehypertension, and Hypertension

“…Several pathologies including hypertension, diabetes and obstructive sleep apnea have been associated with changes in carotid bodies activity ( Conde et al, 2017 ). Increase in carotid sinus nerve activity drives excitation in medullary presympathetic pathways and is integrated in the brain stem to induce cardiorespiratory compensatory responses.…”

Contribution of adenosine and ATP to the carotid body chemosensory activity in ageing

“…Among the neurotransmitters released from the chemoreceptor cells are ATP and adenosine. In the last few years a large body of evidence has demonstrated the significance of adenosine and ATP in the hypoxic chemotransduction in the CB (Buttigieg & Nurse, 2004;Conde et al 2009Conde et al , 2017Murali & Nurse, 2016). The CB releases adenosine and ATP simultaneously in response to hypoxia, the release of ATP and its extracellular catabolism to adenosine being the main origin of extracellular adenosine at high-intensity hypoxia (Conde & Monteiro, 2004;Conde et al 2012a).…”

Evidence for protein kinase involvement in the 5‐HT–[Ca2+]i–pannexin‐1 signalling pathway in type II glial cells of the rat carotid body

“…Previous studies from this laboratory demonstrated that 5-HT acts on ketanserin-sensitive 5-HT2Rs on type II cells leading to an increase in intracellular Ca 2+ that appears necessary for the activation of ATP-permeable Panx-1 channels (Murali et al, 2017). ATP is a key excitatory sensory neurotransmitter in the CB, and although type I cells are generally presumed to be the major source of ATP during chemotransduction (Buttigieg & Nurse, 2004;Conde et al, 2017;Conde, Monteiro, Rigual, Obeso, & Gonzalez, 2012;Leonard et al, 2018;Nurse, 2014;Nurse & Piskuric, 2013;, type II cells might provide an alternative pathway for boosting synaptic ATP concentrations and therefore increase the safety factor for purinergic transmission (Leonard et al, 2018;Nurse, 2014;Nurse & Piskuric, 2013;Tse et al, 2012;Zhang et al, 2012). We found that inhibitors of SFK and PKA, but not PKC, reversibly blocked Panx-1-like currents activated by 5-HT in type II cells.…”

“…The mammalian carotid bodies (CBs) are sensory organs that play a key role in the maintenance of O 2 and CO 2 /H + homeostasis via the initiation of respiratory and cardiovascular reflexes (Gonzalez, Almaraz, Obeso, & Rigual, 1994;Kumar & Prabhakar, 2012). The purines ATP and adenosine are among a broad spectrum of neurotransmitters/neuromodulators that mediate the increase in afferent discharge during exposure to low O 2 (hypoxia) and elevated CO 2 /H + (hypercapnic acidosis) (Conde, Monteiro, & Sacramento, 2017;Nurse, 2014). Several pathophysiological conditions, including sleep apnoea, c 2018 The Authors.…”