Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity

Abstract

Conde SV, Monteiro EC, Rigual R, Obeso A, Gonzalez C. Hypoxic intensity: a determinant for the contribution of ATP and adenosine to the genesis of carotid body chemosensory activity. J Appl Physiol 112: 2002-2010, 2012. First published April 12, 2012 doi:10.1152/japplphysiol.01617.2011.-Excitatory effects of adenosine and ATP on carotid body (CB) chemoreception have been previously described. Our hypothesis is that both ATP and adenosine are the key neurotransmitters responsible for the hypoxic chemotransmission in the CB sensory synapse, their relative contribution depending on the intensity of hypoxic challenge. To test this hypothesis we measured carotid sinus nerve (CSN) activity in response to moderate and intense hypoxic stimuli (7 and 0% O 2) in the absence and in the presence of adenosine and ATP receptor antagonists. Additionally, we quantified the release of adenosine and ATP in normoxia (21% O 2) and in response to hypoxias of different intensities (10, 5, and 2% O 2) to study the release pathways. We found that ZM241385, an A 2 antagonist, decreased the CSN discharges evoked by 0 and 7% O 2 by 30.8 and 72.5%, respectively. Suramin, a P 2X antagonist, decreased the CSN discharges evoked by 0 and 7% O 2 by 64.3 and 17.1%, respectively. Simultaneous application of both antagonists strongly inhibited CSN discharges elicited by both hypoxic intensities. ATP release by CB increased in parallel to hypoxia intensity while adenosine release increased preferably in response to mild hypoxia. We have also found that the lower the O 2 levels are, the higher is the percentage of adenosine produced from extracellular catabolism of ATP. Our results demonstrate that ATP and adenosine are key neurotransmitters involved in hypoxic CB chemotransduction, with a more relevant contribution of adenosine during mild hypoxia, while vesicular ATP release constitutes the preferential origin of extracellular adenosine in high-intensity hypoxia.adenosine; hypoxia; carotid body CAROTID BODIES (CB) are major peripheral chemoreceptor organs that release neurotransmitters in response to hypoxia, generating action potentials at the carotid sinus nerve (CSN) that are integrated in the brain stem to induce a hyperventilatory compensatory response (17). Among the neurotransmitters released in the CB are adenosine and ATP (1-3). One of the first studies on the effects of ATP on CSN activity was carried out by McQueen and Ribeiro (24) where they showed in vivo in the cat CB that ATP increased CSN activity in a dosedependent manner. Additional experiments led them to conclude that the excitatory action of ATP was due to the adenosine formed by its extracellular degradation. More recently, Zhang and co-workers (47) showed that the coapplication of blockers of nicotinic and P2X receptors, hexamethonium and suramin, respectively, in cocultures of glomus cells and "juxtaposed" petrosal ganglions completely abolished the hypoxiaevoked excitatory postsynaptic responses. They concluded that ATP and ACh, acting as cotransmitters, supported the s...

Chronic Caffeine Intake in Adult Rat Inhibits Carotid Body Sensitization Produced by Chronic Sustained Hypoxia but Maintains Intact Chemoreflex Output

“…5, B and C. In normoxic rats (Fig. 5B), the release elicited by moderate hypoxia (7% O 2 ) equaled or overcame that elicited by intense hypoxia (2% O 2 ) (Conde et al, 2006(Conde et al, , 2012a; the hypoxia-induced release of adenosine in caffeine-treated normoxic rats was not different from that seen in normoxic animals. In a comparison of Fig.…”

“…Although Chen et al (2002Chen et al ( , 2007 showed that endothelin contributes to it, available data indicate that endothelin receptors are expressed on chemoreceptor cells, and, therefore, its action must be mediated via modification of neurotransmitter release from the cells. We believe that increased adenosine release during CB stimulation is mainly responsible for generating the augmented CSN activity observed in chronically hypoxic animals during acute CB stimulation (Conde et al, 2006(Conde et al, , 2012a.…”

“…Finally, although ATP is a potent excitatory neurotransmitter in the CB (Nurse 2010;Conde et al, 2012a), it has been proposed that chronic hypoxia does not change P2X 2 receptor density in PG and that contribution of endogenous ATP to the genesis of acute responses to hypoxia decreases in the CB of chronically hypoxic rats (He et al, 2006). An explanation for these observations is that the DA/ATP ratio in the dense-core neurotransmitter storage granules increases due to ATP decrease.…”

“…Hypoxia and hypercapnia/acidosis activate CB chemoreceptor cells, increasing their rate of neurotransmitter release (Gonzalez et al, 1994;Conde et al, 2012a), which augments action potential frequency in the fibers of the carotid sinus nerve (CSN), whose cell bodies are located in the petrosal ganglion (PG). Central integration of CSN activity elicits reflex hyperventilation and cardiocirculatory responses with the aim of normalizing blood gases and adequately distributing O 2 in the organism (Gonzalez et al, 1994).…”

Enhanced adenosine A2breceptor signaling facilitates stimulus-induced catecholamine secretion in chronically hypoxic carotid body type I cells

“…Walsh et al (56) concluded that the increased HVR in CHox rats was due to activation of A 2 receptors by endogenous Ado released in the CB. Moreover, Ado A 2a and A 2b receptors are expressed in CB type I cells (10,17), and Ado signaling contributes to chemoexcitation via presynaptic and postsynaptic mechanisms involving A 2 receptors (9). Also, acute hypoxia leads to Ado accumulation (7), and exogenous Ado increases cAMP content (41) and stimulates catecholamine secretion (6) from whole CBs.…”