Ionic current changes underlying action potential repolarization responses to physiological pacing and adrenergic stimulation in adult rat ventricular myocytes

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% APD(90) 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.