Ecto-5′-nucleotidase, adenosine and transmembrane adenylyl cyclase signalling regulate basal carotid body chemoafferent outfl ow and establish the sensitivity to hypercapnia

Andrew P. Holmes, Ana Rita Nunes, Martin J. Cann, Prem Kumar

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Carotid body (CB) stimulation by hypercapnia causes a refl ex 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 specifi cally 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 fi bre 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 fi bre 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.

Original languageEnglish
Pages (from-to)279-289
Number of pages11
JournalAdvances in Experimental Medicine and Biology
Volume860
DOIs
Publication statusPublished - 2015

Keywords

  • Adenosine
  • CAMP
  • Carotid body
  • Ecto-5′-nucleotidasem
  • Hypercapnia

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