Pharmacological inhibition of acetylcholine-regulated potassium current (IK,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 (IK,ACh) activated by the M2-receptor. Methods In sedated (2% isoflurane), spontaneously breathing rats, INAP was applied non-invasively by a negative pressure device for one minute followed by a resting period of four 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 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: 1mg/kg) and a muscarinic receptor inhibitor (atropine: 1μg/kg) were investigated. Results In vehicle-treated rats, repetitive INAP shortened AERP (37±3ms v. baseline 44±3ms; p=0.001) 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 (CTR vs. XAF-1407: 61±4ms; p>0.001 and CTR vs. atropine: 58±3ms; p=0.011) 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 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.