Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, C018

Oral Communications

The pro-arrhythmic effect of adenosine A1-receptor activation in the atrium

L. Soattin1, A. F. Lubberding1, B. H. Bentzen1, T. Christ2, T. Jespersen1

1. Department of Biomedical Sciences, University of Copenhagen, København N, Denmark. 2. Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

G protein-coupled Inwardly Rectifying K+ channels (GIRK) play a key role in the physiological regulation of the heart. GIRKs are responsible for the vagus-induced negative chronotropy and rapid repolarization of atrial action potential (AP) through the activation of muscarinic receptor. In the atrium, GIRKs activation shortens AP duration and the effective refractory period (ERP). Dysregulation of these currents is associated with atrial fibrillation (AF). Evidences have shown that adenosine (Ado), via A1-receptor (A1-R), increases GIRK channels conductance. Ado naturally occurs from Ado triphosphate breakdown. Both in animal models and humans, extracellular Ado raises under oxygen demand due to CD73 activity that catalyzes the conversion of Ado monophosphate to Ado. To study the electrophysiological role of A1-R in the atrium, rat isolated beating heart preparations were tested in a Langendorff configuration with a selective commercial A1-R agonist (50 nM CCPA) or with a potent commercial A1-R antagonist (40 nM PSB36). In addition, to interfere with CD73 activity, the commercial inhibitor AMPCP (500 μM) was perfused. To translate the results from rodents to humans, AP measurements were conducted on isolated contracting muscles in right atrial appendages (hRAAs) superfused with 1 μM CCPA or 1 μM PSB36 from sinus rhythm patients. Data are summarized using the mean ± SEM compared by ANOVA. Animal experiments were performed in accordance with the Danish guidelines according to the European Commission Directive 86/609/EEC. Wistar rats were anesthetized with sodium pentobarbital (40 mg/kg PI) and sacrificed subsequently. Investigation on human samples conforms to all principles outlined by the Declaration of Helsinki. According to the guidelines of the Medical Association Ethical Review Committee (Hamburg, Germany), patient data were used anonymized and donors gave informed consent. A1-R agonist CCPA shortened AP duration at 90% of repolarization (APD90) and refractoriness both in rats and humans. Thus, we showed for the first time the activation of A1-R in hRAAs. By contrast, the A1-R antagonist PSB36 prolonged APD90 and ERP both in rats and humans, suggesting that an intrinsic release of Ado has an effect on atrial electrophysiology. Confirmatory, AMPCP significantly prolonged refractoriness in rats. Rat hearts treated with CCPA revealed a profound increase in AF inducibility (control 54.5% ± 10.7 vs CCPA 82.7% ± 0.8, P<0.05). In contrast, PSB36 and AMPCP significantly prevented AF events (PSB36 20.1% ± 0.8, P<0.05; AMPCP 25.6% ± 12.0) and reduced AF duration (control 11.5s ± 2.5; CCPA 27.3s ± 10.0, P<0.005; PSB36 2.9s ± 1.8, P<0.005; AMPCP 3.0s ± 1.6, P<0.005). In conclusion, in these experimental models, A1-R activation, probably due to a local Ado release, promotes AF vulnerability.

Where applicable, experiments conform with Society ethical requirements