Linz Benedikt, Thostrup Anne Hauge, Saljic Arnela, Rombouts Karlijn, Hertel Julie Norup, Hohl Mathias, Milnes James, Tfelt-Hansen Jacob, Linz Dominik, Jespersen Thomas
Faculty of Health and Medical Sciences, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
Institute of Pharmacology, West German Heart and Vascular Centre, University of Duisburg-Essen, Duisburg, Germany.
Heart Rhythm O2. 2021 Nov 19;3(1):97-104. doi: 10.1016/j.hroo.2021.11.013. eCollection 2022 Feb.
In obstructive sleep apnea (OSA), intermittent hypoxemia and intrathoracic pressure fluctuations may increase atrial fibrillation (AF) susceptibility by cholinergic activation.
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 ( ) activated by the M receptor.
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 activation, protein levels of protein kinase C (PKC) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 μg/kg) were investigated.
In vehicle-treated rats, repetitive INAP shortened AERP (37 ± 3 ms vs baseline 44 ± 3 ms; = .001) and increased LA membrane PKC content relative to cytosolic levels. Upon INAP recovery, ratio of PKC 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; > .001 and control vs atropine: 58 ± 3 ms; = .011) and abolished INAP-associated AERP shortening.
Short-term simulated OSA is associated with a progressive, but transient, AERP shortening and a PKC translocation to LA membrane. Pharmacological and muscarinic receptor inhibition prevented transient INAP-induced AERP shortening, suggesting an involvement of in the transient arrhythmogenic AF substrate in OSA.
在阻塞性睡眠呼吸暂停（OSA）中，间歇性低氧血症和胸内压波动可能通过胆碱能激活增加心房颤动（AF）易感性。
研究由间歇性上气道负压（INAP）模拟的阻塞性呼吸事件的短期心房电生理后果，以及M受体激活的心房乙酰胆碱调节钾电流（ ）的作用。
在使用2%异氟醚麻醉、自主呼吸的大鼠中，通过负压装置无创施加INAP 1分钟，随后休息4分钟。在70分钟内反复施加INAP，随后是2小时的恢复期。在整个实验过程中测定心房有效不应期（AERP）和AF诱发率。为研究INAP诱导的 激活，通过蛋白质印迹法测定左心房（LA）组织膜和胞质部分蛋白激酶C（PKC）的蛋白水平。此外，研究了一种 抑制剂（XAF - 1407：1 mg/kg）和一种毒蕈碱受体抑制剂（阿托品：1 μg/kg）。
在给予赋形剂的大鼠中，重复性INAP缩短了AERP（37±3毫秒对基线44±3毫秒； = 0.001），并且相对于胞质水平增加了LA膜PKC含量。INAP恢复后，PKC膜与胞质含量的比值恢复正常，INAP诱导的AERP缩短逆转。XAF - 1407和阿托品均增加了基线AERP（对照组对XAF - 1407：61±4毫秒； > 0.001，对照组对阿托品：58±3毫秒； = 0.011），并消除了与INAP相关的AERP缩短。
短期模拟OSA与AERP进行性但短暂的缩短以及PKC易位至LA膜有关。药理学上的 抑制和毒蕈碱受体抑制可防止INAP诱导的短暂AERP缩短，提示 在OSA短暂的致心律失常性AF底物中起作用。
