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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...