Mechanisms Underlying Spontaneous Action Potential Generation Induced by Catecholamine in Pulmonary Vein Cardiomyocytes: A Simulation Study.

Cardiomyocytes and myocardial sleeves dissociated from pulmonary veins (PVs) potentially generate ectopic automaticity in response to noradrenaline (NA), and thereby trigger atrial fibrillation. We developed a mathematical model of rat PV cardiomyocytes (PVC) based on experimental data that incorporates the microscopic framework of the local control theory of Ca ²⁺ release from the sarcoplasmic reticulum (SR), which can generate rhythmic Ca ²⁺ release (limit cycle revealed by the bifurcation analysis) when total Ca ²⁺ within the cell increased. Ca ²⁺ overload in SR increased resting Ca ²⁺ efflux through the type II inositol 1,4,5-trisphosphate (IP ₃ ) receptors (InsP ₃ R) as well as ryanodine receptors (RyRs), which finally triggered massive Ca ²⁺ release through activation of RyRs via local Ca ²⁺ accumulation in the vicinity of RyRs. The new PVC model exhibited a resting potential of -68 mV. Under NA effects, repetitive Ca ²⁺ release from SR triggered spontaneous action potentials (APs) by evoking transient depolarizations (TDs) through Na ⁺ /Ca ²⁺ exchanger (AP _TD s). Marked and variable latencies initiating AP _TD s could be explained by the time courses of the α1- and β1-adrenergic influence on the regulation of intracellular Ca ²⁺ content and random occurrences of spontaneous TD activating the first AP _TD . Positive and negative feedback relations were clarified under AP _TD generation.