In an article by Silva and Rudy (Circ Res. 2003;92:261–263), “Mechanism of Pacemaking in IK1-Downregulated Myocytes,” simulations of β-adrenergic effects on genetically engineered biological pacemaker cells did not take into account changes in [Ca2+]i due to ICa,L increase under β-adrenergic stimulation (βAS). Such changes were fully accounted for during pacemaking in the absence of βAS (intrinsic pacemaker rate of 101 bpm). When βAS-induced changes in [Ca2+]i were accounted for, a steady state could not be achieved with a 300% ICa,L increase. We repeated the simulations with a βAS-induced 100% increase of ICa,L, taking into account the dynamic [Ca2+]i changes. The pacemaking rate increased transiently (110 bpm after 27.2 seconds) and then reached a steady state at a rate slightly below control (73 bpm). The long-term decrease in rate was a result of [Na+]i accumulation that acted to increase outward INaK and reduce inward INaCa and INa, thus reducing net depolarizing current. As in the original publication, upregulation of INaCa by 100% increased sensitivity to βAS, resulting in a maximum transient increase of pacemaking rate to 139 bpm after 17.9 seconds. The new simulations that account for [Ca2+]i changes confirm the original finding that responsiveness to βAS depends on the level of INaCa expression and that even for high expression levels the responsiveness is very limited, much smaller than that of native sinus-node cells
For reference, all simulations used the current version of the Luo-Rudy cell model, which can be found online at http://www.cwru.edu/med/CBRTC/LRdOnline./ [Na+]o was set to 132 mmol/L and [K+]o to 5.4 mmol/L.