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 release from the sarcoplasmic reticulum (SR), which can generate rhythmic Ca release (limit cycle revealed by the bifurcation analysis) when total Ca within the cell increased. Ca overload in SR increased resting Ca efflux through the type II inositol 1,4,5-trisphosphate (IP) receptors (InsPR) as well as ryanodine receptors (RyRs), which finally triggered massive Ca release through activation of RyRs via local Ca accumulation in the vicinity of RyRs. The new PVC model exhibited a resting potential of -68 mV. Under NA effects, repetitive Ca release from SR triggered spontaneous action potentials (APs) by evoking transient depolarizations (TDs) through Na/Ca exchanger (APs). Marked and variable latencies initiating APs could be explained by the time courses of the α1- and β1-adrenergic influence on the regulation of intracellular Ca content and random occurrences of spontaneous TD activating the first AP. Positive and negative feedback relations were clarified under AP generation.