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Calcium-Activated Potassium Channels Inhibition in Autonomically Stimulated Human Atrial Myocytes

Abstract:

The autonomic nervous system has been reported to play a major role in the generation and maintenance of atrial fibrillation. Various investigations have suggested small-conductance calcium-activated potassium (SK) channels as potential targets for more effective pharmacological therapies. In this study, we used in silico modeling and simulation to investigate the effects of SK channel inhibition on the action potential (AP) of autonomically stimulated human atrial cardiomyocytes. The Grandi AP model, with a new formulation for the ISK current, was used to represent human atrial electrophysiology. Choliner-gic stimulation by different concentrations of acetylcholine (ACh) hyperpolarized the AP and shortened the AP duration (APD) in a dose-dependent manner, with up to 7 mV resting membrane potential elevation and >200 ms APD shortening for 1 μM ACh at 1 Hz pacing frequency. Additional β-adrenergic stimulation by 1 μM Isoproterenol (Iso) partially attenuated the effects of cholinergic stimulation by prolonging the APD by 41.6%. ISK inhibition was able to reverse the effects of cholinergic activation, but only for moderate ACh doses and when combined with 1 μM Iso, leading to 58.3% prolongation of the AP stimulated with 0.01 μM ACh. In conclusion, ISK inhibition combined with β-adrenergic stimulation can be effective in antagonizing cholinergic effects on human atrial myocytes.