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(2022)
摘要
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,I-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,I- ACh activation, protein levels of protein kinase C (PKC epsilon) were determined in membrane and cytosolic fractions of left atrial (LA) tissue by Western blotting. Moreover, an I-K,I- ACh inhibitor (XAF-1407: 1 mg/kg) and a muscarinic receptor inhibitor (atropine: 1 mg/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 PKC. content relative to cytosolic levels. Upon INAP recovery, ratio of PKC. membrane to cytosol content normalized and INAPinduced 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 PKC. 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.
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关键词
Sleep apnea,Atrial fibrillation,I-K,I-ACh,Cholinergic,activation,Rats
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