title: Ecto-5'-Nucleotidase, Adenosine and Transmembrane Adenylyl Cyclase Signalling Regulate Basal Carotid Body Chemoafferent Outflow and Establish the Sensitivity to Hypercapnia.
abstract: Carotid body (CB) stimulation by hypercapnia causes a reflex increase in ventilation and, along with the central chemoreceptors, this prevents a potentially lethal systemic acidosis. Control over the CB chemoafferent output during normocapnia and hypercapnia most likely involves multiple neurotransmitters and neuromodulators including ATP, acetylcholine, dopamine, serotonin and adenosine, but the precise role of each is yet to be fully established. In the present study, recordings of chemoafferent discharge frequency were made from the isolated in vitro CB in order to determine the contribution of adenosine, derived specifically from extracellular catabolism of ATP, in mediating basal chemoafferent activity and responses to hypercapnia. Pharmacological inhibition of ecto-5'-nucleotidase (CD73), a key enzyme required for extracellular generation of adenosine from ATP, using α,β-methylene ADP, virtually abolished the basal normocapnic single fibre discharge frequency (superfusate PO(2) ~ 300 mmHg, PCO(2) ~ 40 mmHg) and diminished the chemoafferent response to hypercapnia (PCO(2) ~ 80 mmHg). These effects were mimicked by the blockade of adenosine receptors with 8-(p-sulfophenyl) theophylline. The excitatory impact of adenosinergic signalling on CB hypercapnic sensitivity is most likely to be conferred through changes in cAMP. Here, inhibition of transmembrane, but not soluble adenylate cyclases, reduced normocapnic single fibre activity and inhibited the elevation evoked by hypercapnia by approximately 50 %. These data therefore identify a functional role for CD73 derived adenosine and transmembrane adenylate cyclases, in modulating the basal chemoafferent discharge frequency and in priming the CB to hypercapnic stimulation.
authors: Level 1 IBR, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK, a.p.holmes@bham.ac.uk.
authors: Andrew P
authors: AP
authors: Holmes
authors: Ana Rita
authors: AR
authors: Nunes
authors: Martin J
authors: MJ
authors: Cann
authors: Prem
authors: P
authors: Kumar
mesh_terms: D015720:5'-Nucleotidase / Q000502:physiology*; D000241:Adenosine / Q000502:physiology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D002344:Carotid Body / Q000502:physiology*; D000242:Cyclic AMP / Q000096:biosynthesis; D006935:Hypercapnia / Q000503:physiopathology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D015720:5'-Nucleotidase; D000262:Adenylyl Cyclases; D000241:Adenosine