TY - JOUR

T1 - Pharmacological inhibition of acetylcholine-regulated potassium current (IK,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events

AU - Linz, Benedikt

AU - Thostrup, Anne Hauge

AU - Saljic, Arnela

AU - Rombouts, Karlijn

AU - Hertel, Julie Norup

AU - Hohl, Mathias

AU - Milnes, James

AU - Tfelt-Hansen, Jacob

AU - Linz, Dominik

AU - Jespersen, Thomas

N1 - © 2021 Heart Rhythm Society. Published by Elsevier Inc.

PY - 2022/2

Y1 - 2022/2

N2 - BackgroundIn obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.ObjectiveTo investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (IK,ACh) activated by the M2 receptor.MethodsIn sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced IK,ACh activation, protein levels of protein kinase C (PKCƐ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an IK,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.ResultsIn vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKCƐ content relative to cytosolic levels. Upon INAP recovery, ratio of PKCƐ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.ConclusionShort-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological IK,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of IK,ACh in the transient arrhythmogenic AF substrate in OSA.

AB - BackgroundIn obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.ObjectiveTo investigate short-term atrial electrophysiological consequences of obstructive respiratory events, simulated by intermittent negative upper airway pressure (INAP), and the role of atrial acetylcholine-regulated potassium current (IK,ACh) activated by the M2 receptor.MethodsIn sedated (2% isoflurane), spontaneously breathing rats, INAP was applied noninvasively by a negative pressure device for 1 minute, followed by a resting period of 4 minutes. INAP was applied repeatedly throughout 70 minutes, followed by a 2-hour recovery period. Atrial effective refractory period (AERP) and AF inducibility were determined throughout the protocol. To study INAP-induced IK,ACh activation, protein levels of protein kinase C (PKCƐ) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an IK,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.ResultsIn vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; P = .001) and increased LA membrane PKCƐ content relative to cytosolic levels. Upon INAP recovery, ratio of PKCƐ membrane to cytosol content normalized and INAP-induced AERP shortening reversed. Both XAF-1407 and atropine increased baseline AERP (control vs XAF-1407: 61 ± 4 ms; P > .001 and control vs atropine: 58 ± 3 ms; P = .011) and abolished INAP-associated AERP shortening.ConclusionShort-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological IK,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of IK,ACh in the transient arrhythmogenic AF substrate in OSA.

U2 - 10.1016/j.hroo.2021.11.013

DO - 10.1016/j.hroo.2021.11.013

M3 - Journal article

C2 - 35243441

VL - 3

SP - 97

EP - 104

JO - Heart Rhythm O2

JF - Heart Rhythm O2

SN - 2666-5018

IS - 1

ER -