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Fundam Clin Pharmacol. 2018 Aug;32(4):378-391. doi: 10.1111/fcp.12365. Epub 2018 Apr 23.

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

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Normandie Univ, UNICAEN, CHU Caen, Signalization, Électrophysiologie et Imagerie des Lésions d'Ischémie-Reperfusion Myocardique, Caen, F-14032, France.
Department of Biochemistry, CHU de Caen, Caen, F-14032, France.
Department of Cardiology, CHU de Caen, Caen, F-14032, France.
Department of Hematology, CHU de Caen, Caen, F-14032, France.
Department of Nuclear Medicine, CHU de Caen, Caen, F-14032, France.
Department of Cardiovascular Sciences, Sapienza University, Rome, Italy.
Department of Pharmacology, CHU de Caen, Caen, F-14032, France.


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.


PAR1; anti-arrhythmic drugs; atrial fibrillation; electrophysiology; oral anticoagulants

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