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

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 ( ) activated by the M 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 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.

RESULTS

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.

CONCLUSION

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.