Release of ATP in the Ventral Medulla during Hypoxia in Rats: Role in Hypoxic Ventilatory Response

Abstract

P2X 2 receptor subunits of the ATP-gated ion channels are expressed by physiologically identified respiratory neurons in the ventral respiratory column, implicating ATP in the control of respiratory activity. We now show that, during hypoxia, release of ATP in the ventrolateral medulla (VLM) plays an important role in the hypoxic ventilatory response in rats. By measuring ATP release in real time at the ventral surface of the medulla with novel amperometric biosensors, we found that hypoxia (10% O 2 ; 5 min) induced a marked increase in the concentration of ATP (ϳ3 M). This ATP release occurred after the initiation of enhanced respiratory activity but coincided with the later hypoxia-induced slowing of the respiratory rhythm. ATP was also released at the ventral surface of the medulla during hypoxia in peripherally chemodenervated animals (vagi, aortic, and carotid sinus nerve sectioned). By using horizontal slices of the rat medulla, we found that, during hypoxia, ATP is produced throughout the VLM in the locations corresponding to the ventral respiratory column. Blockade of ATP receptors in the VLM (microinjection of P2 receptor antagonist pyridoxal-5Ј-phosphate-6-azophenyl-2Ј,4Ј-disulphonic acid; 100 M) augmented the hypoxia-induced secondary slowing of the respiratory rhythm. Our findings suggest that ATP released within the ventral respiratory column is involved in maintenance of the respiratory activity in conditions when hypoxia-induced slowing of respiration occurs. These data illustrate a new functional role for ATP-mediated purinergic signaling in the medullary mechanisms controlling respiratory activity.

P2Y1Receptor Modulation of the Pre-Bötzinger Complex Inspiratory Rhythm Generating NetworkIn Vitro

“…In summary, recent data have established an endogenous role for ATP in central respiratory control; it is released during hypoxia from the brainstem and attenuates the secondary hypoxic depression of respiratory frequency (Gourine et al, 2005a). The significance of the present study is that it advances our understanding of mechanisms through which purinergic signaling can modulate respiratory rhythm by establishing that ATP potently increases respiratory frequency by activating P2Y 1 Rs in the preBötC.…”

“…During hypoxia, ATP is released from the ventrolateral surface of the medulla as well as the VRC. It stimulates respiratory frequency, reducing the secondary hypoxic depression of respiration (Gourine et al, 2005a). Our data indicate that this effect could be mediated, in whole or in part, by the activation of P2Y 1 Rs in the preBötC.…”

“…Although ATP acts as an excitatory neurotransmitter within many brain regions, including autonomic nuclei (Nieber et al, 1997;Scislo et al, 1998;Thomas et al, 1999;Gourine et al, 2003Gourine et al, , 2005a, its physiological significance is only just emerging. In respiratory networks, ATP is important for peripheral (Rong et al, 2003) and central chemoreception (Gourine et al, 2005a,b).…”

“…ATP release from the ventral medullary surface is common to hypoxia and hypercapnia, but ATP release from the ventral respiratory column (VRC) occurs in hypoxia only (Gourine et al, 2005a,b). In addition, ATP release in hypoxia is delayed relative to hypercapnia, occurring shortly after the initial increase in respiratory frequency when it attenuates the secondary hypoxic depression of ventilation (Gourine et al, 2005a). Based on the observations that the ATP component of the respiratory response to hypoxia is to increase frequency, and that ATP is released within the VRC only during hypoxia (Gourine et al, 2005a), we hypothesize that ATP acts directly in the VRC to stimulate frequency.…”

ATP release from non-excitable cells

“…Recent breakthroughs in this field include the role of adenosine triphosphate (ATP) as neurotransmitter and/or modulator in sensory transduction [1][2][3][4][5][6][7][8][9][10], the role of released ATP as a precursor signalling molecule in renal tubulo-glomerular feedback [11,12], the role of released nucleotides for migrating neutrophils [13] and the crucial function of nucleotides in the control of thrombocyte aggregation and haemostasis [14]. The essential features of the purinergic signalling system are well characterised.…”