Ionic current changes underlying action potential repolarization responses to physiological pacing and adrenergic...

This study aimed to simulate ventricular responses to elevations in myocyte pacing and adrenergic stimulation using a novel electrophysiological rat model and investigate ion channel responses underlying action potential (AP) modulations. Peak ion currents and AP repolarization to 50% and 90% of full repolarization (APD_50-90 ) were recorded during simulations at 1-10 Hz pacing under control and adrenergic stimulation conditions. Further simulations were performed with incremental ion current block (L-type calcium current, I_Ca ; transient outward current, I_to ; slow delayed rectifier potassium current, I_Ks ; rapid delayed rectifier potassium current, I_Kr ; inward rectifier potassium current, I_K1 ) to identify current influence on AP response to exercise. Simulated APD_50-90 closely resembled experimental findings. Rate-dependent increases in I_Ks (6%-101%), I_Kr (141%-1339%), and I_Ca (0%-15%) and reductions in I_to (11%-57%) and I_K1 (1%-9%) were observed. Meanwhile, adrenergic stimulation triggered moderate increases in all currents (23%-67%) except I_K1 . Further analyses suggest AP plateau is most sensitive to modulations in I_to and I_Ca while late repolarization is most sensitive to I_K1 , I_Ca , and I_Ks , with alterations in I_Ks predominantly stimulating the greatest magnitude of influence on late repolarization (35%-846% APD₉₀ prolongation). The modified Leeds rat model (mLR) is capable of accurately modeling APs during physiological stress. This study highlights the importance of I_Ca , I_to , I_K1, and I_Ks in controlling electrophysiological responses to exercise. This work will benefit the study of cardiac dysfunction, arrythmia, and disease, though future physiologically relevant experimental studies and model development are required.