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.