PAR1 contribution in acute electrophysiological properties of oral anticoagulants in rabbit pulmonary vein sleeve preparations.

Abstract

Whether oral anticoagulants, vitamin K antagonists (VKAs), and nonvitamin K oral anticoagulant (NOACs) frequently prescribed to atrial fibrillation (AF) patients, do themselves have a pro- or anti-arrhythmic effect have never been addressed. Transmembrane action potentials were recorded in an acute rabbit model of superfused pulmonary veins (PVs) sleeves preparations using standard microelectrode technique. Fluindione 10 μm (n = 6) increased the AP (action potential) duration (APD), induced a significantly Vmax depression (from 95 ± 14 to 53 ± 5 V/s, P < 0.05), and 2 : 1 blocks during rapid atrial pacing thus evoking class I anti-arrhythmic properties, and prevented spontaneous trigger APs. Apixaban 10 μm (n = 6) increased the APD, significantly prolonged the effective refractory period (from 56.3 ± 4.2 to 72.0 ± 8.6 ms, P < 0.05), and prevented triggered APs occurrence. Fluindione and apixaban effects were suppressed with the addition of the protease-activated receptors 1 (PAR 1) agonist SFLLR-NH2 . Warfarin 10 μm (n = 6) significantly abbreviated the early refractory period (from 56.3 ± 4.2 to 45.0 ± 2.2 ms, P < 0.05) and increased triggered APs occurrence that were successfully prevented by nifedipine but not by the addition of the protease-activated receptors 1 agonist SFLLR-NH2 . In this acute rabbit PVs model, VKAs and NOACs, at physiological concentrations, exhibited very different pharmacological properties that influence PVs electrophysiology, implying PAR1, with fluindione and apixaban which exhibited more anti-arrhythmic properties, whereas warfarin exhibited more pro-arrhythmic properties.

• Authors: Jonaz Font, Mathilda Simeon, Christophe Simard, Stéphane Allouche, Anne-Flore Plane, Virginie Ferchaud, Marie Brionne, René Rouet, Marie Nowoczyn, Alain Manrique, Paolo Emilio Puddu, Paul Milliez, Joachim Alexandre
• Journal: Fundamental & clinical pharmacology (Fundam Clin Pharmacol) Vol. 32 Issue 4 Pg. 378-391 (Aug 2018) ISSN: 1472-8206 [Electronic] England
• PMID: 29526032 (Publication Type: Journal Article)
• Copyright: © 2018 Société Française de Pharmacologie et de Thérapeutique.

Chemical References

• Anti-Arrhythmia Agents
• Anticoagulants
• Pyrazoles
• Pyridones
• Receptor, PAR-1
• apixaban

Topics

• Administration, Oral
• Animals
• Anti-Arrhythmia Agents (pharmacology)
• Anticoagulants (pharmacology)
• Atrial Fibrillation (drug therapy, metabolism)
• Electrophysiological Phenomena (drug effects)
• Female
• Pulmonary Veins (drug effects, metabolism)
• Pyrazoles (pharmacology)
• Pyridones (pharmacology)
• Rabbits
• Receptor, PAR-1 (metabolism)