Abstract
BackgroundAdenosine leads to atrial action potential (AP) shortening through activation of adenosine 1 receptors (A1-R) and subsequent opening of G-protein-coupled inwardly rectifying K+ channels. Extracellular production of adenosine is drastically increased during stress and ischemia.ObjectiveThe aim of this study was to address whether the pharmacological blockade of endogenous production of adenosine and of its signaling prevents atrial fibrillation (AF).MethodsThe role of A1-R activation on atrial action potential duration, refractoriness, and AF vulnerability was investigated in rat isolated beating heart preparations (Langendorff) with an A1-R agonist [2-chloro-N6-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 trabeculae from human right atrial appendages (hRAAs) were used for comparison.ResultsAs expected, CCPA shortened AP duration at 90% of repolarization (APD90) and effective refractory period (ERP) in rat atria. PSB36 prolonged APD90 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 APD90, 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; P < 0.0001).ConclusionA1-R activation by intrinsic adenosine release alters atrial electrophysiology and promotes AF. Inhibition of adenosine pathway protects atria from arrhythmic events.
Highlights
G-protein-coupled inwardly rectifying K+ channels (GIRK) play a key role in the physiological regulation of the heart
We show that the activation of A1-R shortens atrial action potential duration (APD) and effective refractory period (ERP) and promotes atrial fibrillation (AF) susceptibility and duration
To study the effects of adenosine signaling in the atrium, we exposed the heart to vehicle (n = 10), the specific A1-R agonist CCPA (n = 11), the A1-R antagonist PSB36 (n = 10), and the specific CD73 antagonist AMPCP (n = 7) (Figure 1)
Summary
G-protein-coupled inwardly rectifying K+ channels (GIRK) play a key role in the physiological regulation of the heart. Since the shortening of APD and refractoriness represents hallmarks of pro-arrhythmicity, adenosine can evoke atrial arrhythmias in humans, as well as in animal models (Drury and Szent-Gyorgyi, 1929; Belhassen et al, 1984; Kabell et al, 1994; Bertolet et al, 1997; Strickberger et al, 1997; Tebbenjohanns et al, 1997). For this reason, adenosine can be used as a tool to detect the location of possible AF foci during ablation procedures (Li et al, 2016; Letsas et al, 2017). Extracellular production of adenosine is drastically increased during stress and ischemia
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