Effects of β-adrenergic stimulation on the ventricular action potential:: a simulation study

Cathecholamines increase heart rate and contraction force. This effect is mainly mediated by their interaction with the beta-adrenergic receptor (beta-AR) and its downstream ability to modulate Ca2+ cycling and fluxes of a number of ions through specific channels across the cell membrane. The complex nature and broad cellular influence of the beta-AR signaling cascade suggests that an integrative modelling approach is appropriate to size the relative weight of each of the single mechanisms by which P-adrenergic inputs modulate whole-cell action potential (AP) and Ca2+ handling in cardiac myocytes. The ventricular AP was simulated by using the Luo-Rudy model. The transmural heterogeneity of the AP (epicardial, mid-myocardial and endocardial cells) was reproduced by considering three different levels of expression of the transient outward current (I-To) and three different ratios of the slow vs. the rapid component of the delayed rectifier K+ current (I-Ks / I-Kr). The beta-AR stimulation was modelled by incorporating its effects on L-type Ca2+ current, phospholamban, I-Kr, I-Ks, Na+-K+ pump and Na+/Ca2+ exchanger. Simulation of beta-AR stimulation showed significant changes in the AP and in Ca2+ handling, depending on the cell type and on the levels of ion fluxes alterations due to P-adrenergic inputs. Notably, the occurrence of early- and delayed-after-depolarizations (EADs and DADs respectively) was also reproduced. In the present analysis, EADs and DADs are suggested as mechanisms responsible for the arrhythmogenic effect of the adrenergic stimulation.