Background: More than 50% of patients with atrial fibrillation (AF) suffer from sleep disordered breathing (SDB). Obstructive respiratory events contribute to a transient, vagally mediated atrial arrhythmogenic substrate, which is resistant to most available antiarrhythmic drugs. Objective: The purpose of this study was to investigate the effect of pharmacologic inhibition of the G-protein–gated acetylcholine-regulated potassium current (I_K,ACh) with and without acute autonomic nervous system activation by nicotine in a pig model for obstructive respiratory events. Methods: In 21 pigs, SDB was simulated by applying an intermittent negative upper airway pressure (INAP). AF inducibility and atrial effective refractory periods (aERPs) were determined before and during INAP by an S1S2 atrial pacing-protocol. Pigs were randomized into 3 groups—group 1: vehicle (n = 4); group 2: XAF-1407 (I_K,ACh inhibitor) (n = 7); and group 3: nicotine followed by XAF-1407 (n = 10). Results: In group 1, INAP shortened aERP (ΔaERP –42.6 ms; P = .004) and transiently increased AF inducibility from 0% to 31%. In group 2, XAF-1407 prolonged aERP by 25.2 ms (P = .005) during normal breathing and prevented INAP-induced aERP shortening (ΔaERP –3.6 ms; P = .3) and AF inducibility. In group 3, INAP transiently shortened aERP during nicotine perfusion (ΔaERP –33.6 ms; P = .004) and increased AF inducibility up to 61%, which both were prevented by XAF-1407. Conclusion: Simulated obstructive respiratory events transiently shorten aERP and increase AF inducibility, which can be prevented by the I_K,ACh-inhibitor XAF-1407. XAF-1407 also prevents these arrhythmogenic changes induced by obstructive respiratory events during nicotine perfusion. Whether I_K,ACh channels represent a target for SDB-related AF in humans warrants further study.