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

Benedikt Linz; Anne Hauge Thostrup; Arnela Saljic; Karlijn Rombouts; Julie Norup Hertel; Mathias Hohl; James Milnes; Jacob Tfelt-Hansen; Dominik Linz; Thomas Jespersen

doi:10.1016/j.hroo.2021.11.013

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

Benedikt Linz^*, Anne Hauge Thostrup, Arnela Saljic, Karlijn Rombouts, Julie Norup Hertel, Mathias Hohl, James Milnes, Jacob Tfelt-Hansen, Dominik Linz, Thomas Jespersen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background: In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.

Objective: To 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 (I K,ACh) activated by the M2 receptor.

Methods: In 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 I K,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 I K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.

Results: In 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.

Conclusion: Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological I K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I K,ACh in the transient arrhythmogenic AF substrate in OSA.

Original language	English
Pages (from-to)	97-104
Number of pages	8
Journal	Heart Rhythm O2
Volume	3
Issue number	1
DOIs	https://doi.org/10.1016/j.hroo.2021.11.013
Publication status	Published - Feb 2022

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Linz, B., Thostrup, A. H., Saljic, A., Rombouts, K., Hertel, J. N., Hohl, M., Milnes, J., Tfelt-Hansen, J., Linz, D., & Jespersen, T. (2022). Pharmacological inhibition of acetylcholine-regulated potassium current (I K,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events. Heart Rhythm O2, 3(1), 97-104. https://doi.org/10.1016/j.hroo.2021.11.013

@article{a1635ed35eb548afa072b7fe307b48f5,

title = "Pharmacological inhibition of acetylcholine-regulated potassium current (I K,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events",

abstract = "Background: In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.Objective: To 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 (I K,ACh) activated by the M2 receptor.Methods: In 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 I K,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 I K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.Results: In 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.Conclusion: Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological I K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I K,ACh in the transient arrhythmogenic AF substrate in OSA.",

author = "Benedikt Linz and Thostrup, {Anne Hauge} and Arnela Saljic and Karlijn Rombouts and Hertel, {Julie Norup} and Mathias Hohl and James Milnes and Jacob Tfelt-Hansen and Dominik Linz and Thomas Jespersen",

note = "{\textcopyright} 2021 Heart Rhythm Society. Published by Elsevier Inc.",

year = "2022",

month = feb,

doi = "10.1016/j.hroo.2021.11.013",

language = "English",

volume = "3",

pages = "97--104",

journal = "Heart Rhythm O2",

issn = "2666-5018",

publisher = "Elsevier BV",

number = "1",

}

Linz, B, Thostrup, AH, Saljic, A, Rombouts, K, Hertel, JN, Hohl, M, Milnes, J, Tfelt-Hansen, J, Linz, D & Jespersen, T 2022, 'Pharmacological inhibition of acetylcholine-regulated potassium current (I K,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events', Heart Rhythm O2, vol. 3, no. 1, pp. 97-104. https://doi.org/10.1016/j.hroo.2021.11.013

Pharmacological inhibition of acetylcholine-regulated potassium current (I K,ACh) prevents atrial arrhythmogenic changes in a rat model of repetitive obstructive respiratory events. / Linz, Benedikt; Thostrup, Anne Hauge; Saljic, Arnela et al.
In: Heart Rhythm O2, Vol. 3, No. 1, 02.2022, p. 97-104.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Pharmacological inhibition of acetylcholine-regulated potassium current (I K,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

PY - 2022/2

Y1 - 2022/2

N2 - Background: In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.Objective: To 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 (I K,ACh) activated by the M2 receptor.Methods: In 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 I K,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 I K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.Results: In 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.Conclusion: Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological I K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I K,ACh in the transient arrhythmogenic AF substrate in OSA.

AB - Background: In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.Objective: To 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 (I K,ACh) activated by the M2 receptor.Methods: In 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 I K,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 I K,ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.Results: In 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.Conclusion: Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKCƐ translocation to LA membrane. Pharmacological I K,ACh and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of I K,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 - Article

C2 - 35243441

SN - 2666-5018

VL - 3

SP - 97

EP - 104

JO - Heart Rhythm O2

JF - Heart Rhythm O2

IS - 1

ER -

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

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