AUTHOR=Soattin Luca , Lubberding Anniek Frederike , Bentzen Bo Hjorth , Christ Torsten , Jespersen Thomas 

TITLE=Inhibition of Adenosine Pathway Alters Atrial Electrophysiology and Prevents Atrial Fibrillation

JOURNAL=Frontiers in Physiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2020.00493

DOI=10.3389/fphys.2020.00493

ISSN=1664-042X

ABSTRACT=<sec><title>Background</title><p>Adenosine leads to atrial action potential (AP) shortening through activation of adenosine 1 receptors (A<sub>1</sub>-R) and subsequent opening of G-protein-coupled inwardly rectifying K<sup>+</sup> channels. Extracellular production of adenosine is drastically increased during stress and ischemia.</p></sec><sec><title>Objective</title><p>The aim of this study was to address whether the pharmacological blockade of endogenous production of adenosine and of its signaling prevents atrial fibrillation (AF).</p></sec><sec><title>Methods</title><p>The role of A<sub>1</sub>-R activation on atrial action potential duration, refractoriness, and AF vulnerability was investigated in rat isolated beating heart preparations (Langendorff) with an A<sub>1</sub>-R agonist [2-chloro-<italic>N</italic><sup>6</sup>-cyclopentyladenosine (CCPA), 50 nM] and antagonist [1-butyl-3-(3-hydroxypropyl)-8-(3-noradamantyl)xanthine (PSB36), 40 nM]. Furthermore, to interfere with the endogenous adenosine release, the ecto-5′-nucleotidase (CD73) inhibitor was applied [5′-(α,β-methylene) diphosphate sodium salt (AMPCP), 500 μM]. Isolated <italic>trabeculae</italic> from human right atrial appendages (hRAAs) were used for comparison.</p></sec><sec><title>Results</title><p>As expected, CCPA shortened AP duration at 90% of repolarization (APD<sub>90</sub>) and effective refractory period (ERP) in rat atria. PSB36 prolonged APD<sub>90</sub> and ERP in rat atria, and CD73 inhibition with AMPCP prolonged ERP in rats, confirming that endogenously produced amount of adenosine is sufficiently high to alter atrial electrophysiology. In human atrial appendages, CCPA shortened APD<sub>90</sub>, while PSB36 prolonged it. Rat hearts treated with CCPA are prone to AF. In contrast, PSB36 and AMPCP prevented AF events and reduced AF duration (vehicle, 11.5 ± 2.6 s; CCPA, 40.6 ± 16.1 s; PSB36, 6.5 ± 3.7 s; AMPCP, 3.0 ± 1.4 s; <italic>P</italic> &lt; 0.0001).</p></sec><sec><title>Conclusion</title><p>A<sub>1</sub>-R activation by intrinsic adenosine release alters atrial electrophysiology and promotes AF. Inhibition of adenosine pathway protects atria from arrhythmic events.</p></sec>