Key result
The combination of SK channel block and isoproterenol prolonged APD90 and stopped stable rotors in human atrial computational models with acetylcholine concentrations up to 0.01 μM.
Why the study?
Parasympathetic hyperactivity via acetylcholine promotes paroxysmal AF by reducing action potential duration and increasing resting membrane potential, and the impact of SK channel block and adrenergic stimulation in counteracting these effects required evaluation.
Does the combination of SK channel block and isoproterenol improve action potential duration and prevent re-inducibility of rotors in cholinergically-stimulated human atrial computational models?
Does the combination of SK channel block and isoproterenol improve action potential duration and prevent re-inducibility of rotors in cholinergically-stimulated human atrial computational models?
Computational modeling suggests that combining SK channel blockade with beta-adrenergic stimulation synergistically counteracts acetylcholine-induced action potential shortening and terminates atrial fibrillation rotors.
Answers are grounded in this paper and cite their sources.
May warrant no clinical use in AF; leaves open whether SK blockade plus beta-stimulation terminates rotors beyond computational models.
Hyperactivity of the parasympathetic nervous system has been linked to the development of paroxysmal atrial fibrillation (AF). The parasympathetic neurotransmitter acetylcholine (ACh) causes a reduction in action potential (AP) duration (APD) and an increase in resting membrane potential (RMP), both of which contribute to enhance the risk for reentry. Research suggests that small-conductance calcium activated potassium (SK) channels may be an effective target for treating AF. Therapies targeting the autonomic nervous system, either alone or in combination with other drugs, have been explored and have been shown to decrease the incidence of atrial arrhythmias. This study uses computational modeling and simulation to examine the impact of SK channel block (SKb) and β-adrenergic stimulation through Isoproterenol (Iso) on countering the negative effects of cholinergic activity in human atrial cell and 2D tissue models. The steady-state effects of Iso and/or SKb on AP shape, APD at 90% repolarization (APD90) and RMP were evaluated. The ability to terminate stable rotational activity in cholinergically-stimulated 2D tissue models of AF was also investigated. A range of SKb and Iso application kinetics, which reflect varying drug binding rates, were taken into consideration. The results showed that SKb alone prolonged APD90 and was able to stop sustained rotors in the presence of ACh concentrations up to 0.01 μM. Iso terminated rotors under all tested ACh concentrations, but resulted in highly-variable steady-state outcomes depending on baseline AP morphology. Importantly, the combination of SKb and Iso resulted in greater APD90 prolongation and showed promising anti-arrhythmic potential by stopping stable rotors and preventing re-inducibility.
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Celotto et al. (2023) studied Paroxysmal atrial fibrillation. SK channel block and Isoproterenol was evaluated on Action potential duration at 90% repolarization (APD90) and termination of stable rotational activity. The combination of SK channel block and isoproterenol prolonged APD90 and stopped stable rotors in human atrial computational models with acetylcholine concentrations up to 0.01 μM.
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