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

Figures

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  Figure 1. Potential pathways for increased atrial acetylcholine-regulated potassium current (IK,ACh) and the rodent model. A: Conceptual overview of potential increase in IK,ACh. In atrial myocardium, acetylcholine may activate muscarinic receptors, which might increase IK,ACh. Alternatively, a translocation of protein kinase C from cytosol to membrane might contribute to an increase in IK,ACh. Pharmacological interventions: atropine as a muscarinic receptor inhibitor or XAF-1407 as a direct IK,ACh inhibitor. G-protein gated acetylcholine-activated inward rectifier channel (GIRK channel)–mediated potassium current (IK,ACh). Figure was created in BioRender.com. B: Representative traces of an atrial electrogram (EGM) and airway pressure during intermittent negative upper airway pressure application (INAP). C: Overview of the experimental protocol and visualization of different study groups. AERP = atrial effective refractory period.

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  Figure 2. Transient shortening in atrial effective refractory period. Shortening in atrial effective refractory period (AERP) throughout the protocol of 14 consecutive intermittent upper airway pressure (INAP) applications (n = 6). Upon recovery, AERPs reversed to baseline values. Data are expressed as mean ± SEM.

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  Figure 3. Transient translocation of subtype of protein kinase C (PKCƐ) from cytosol to membrane. For analyzing inner-cell translocation of PKCƐ in left atrial tissue lysate, membranes (Mem) were separated from cytosol (Cyto). Time controls without intermittent upper airway pressure (INAP) (control) depicted a balanced ratio of PKCƐ in the membrane and cytosol fraction. After 70 minutes of INAP protocol, when rats were sacrificed immediately (14∗INAP), the percentage of PKCƐ in the membrane fraction increased, whereas it decreased in the cytosolic fraction. While this ratio persisted in rats that recovered 1 hour from the INAP protocol (1hr), rats with 2-hour recovery (2hr) demonstrated again a balanced ratio of PKCƐ in membrane and cytosolic fraction. Data are expressed as mean ± SEM. For statistical analysis a paired t test was used.

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  Figure 4. Effects of pharmacological intervention. A: Progressive shortening of atrial effective refractory period (AERP) in control rats (n = 11) undergoing the intermittent upper airway pressure (INAP) protocol. Prevention of INAP-induced AERP shortening in rats pretreated with acetylcholine-regulated potassium current (IK,ACh) inhibitor XAF-1407 (B, n = 11) and M2-receptor inhibitor atropine (C, n = 4). Data are expressed as mean ± SEM. For statistical analysis a 2-way ANOVA with a Dunnett’s multiple comparisons test was used. ∗: P = .01; ∗∗: P = .026; §:P = .001; §§:P = .001; demonstrated as respective comparisons to baseline.

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  Figure 5. Atrial fibrillation (AF) susceptibility. AF inducibility (A) and inducible AF duration (B) by burst pacing in the second half of the intermittent upper airway pressure (INAP) protocol. Comparison between controls (control, n = 7) and XAF-1407 (n = 6). Data are expressed as mean ± SEM. No statistical analysis was performed owing to too few AF inductions in the XAF-1407-treated group.