Ecto-5'-nucleotidase (CD73) regulates peripheral chemoreceptor activity and cardiorespiratory responses to hypoxia
Research output: Contribution to journal › Article › peer-review
- Institute of Cardiovascular Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK; Celentyx Ltd, Birmingham Research Park, Edgbaston, Birmingham B15 2SQ, UK.
- Mouse Pipelines, Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
Augmented sensory neuronal activity from the carotid body (CB) has emerged as a principal cause of hypertension in a number of cardiovascular related pathologies including obstructive sleep apnoea, heart failure and diabetes. Development of new targets and pharmacological treatment strategies aiming to reduce CB sensory activity may thus improve outcomes in these key patient cohorts. The current study tested whether ecto-5'-nucleotidase (CD73), an enzyme that generates adenosine, is functionally important in modifying CB sensory activity and cardiovascular respiratory responses to hypoxia. Inhibition of ecto-5'-nucleotidase by α,β-methylene ADP (AOPCP) in the whole CB preparation in vitro reduced basal discharge frequency by 76 ± 5% and reduced sensory activity throughout graded hypoxia. AOPCP also significantly attenuated elevations in sensory activity evoked by mitochondrial inhibition. These effects were mimicked by antagonism of adenosine receptors with 8-(p-sulfophenyl) theophylline. Infusion of AOPCP in vivo significantly decreased the hypoxic ventilatory response (ΔV˙E control 74 ± 6%, ΔV˙E AOPCP 64 ± 5%, P < 0.05). AOPCP also modified cardiovascular responses to hypoxia, as evidenced by reduced elevations in heart rate and exaggerated changes in femoral vascular conductance and mean arterial blood pressure. Thus we identify ecto-5'-nucleotidase as a novel regulator of CB sensory activity. Future investigations are warranted to evaluate whether inhibition of ecto-5'-nucleotidase can effectively reduce CB activity in CB-mediated cardiovascular pathology. This article is protected by copyright. All rights reserved.
|Journal||The Journal of Physiology|
|Early online date||31 May 2017|
|Publication status||E-pub ahead of print - 31 May 2017|