Comparison Of Computationally And Experimentally Determined Single I-Kr Channel Activity During Pacemaking In Sinoatrial Node Cells

Background: The contribution of the rapidly activating delayed rectifier current (IKr) to sinoatrial (SA) node pacemaking, is mainly derived from computational models. The mathematical representation of IKr therein, is based on voltage-clamp data in SA-node cells, but to what extent computational IKr activity accurately describes true dynamic behavior of IKr during the SA-node action potential (AP), remains to be established. Methods: With the dual electrode patch clamp technique, we simultaneously recorded spontaneous APs (whole-cell) and single IKr channel activity (cell-attached-patch) from isolated rabbit SA-node cells. To allow comparison between measured IKr channel activity and computational IKr activity, a model rabbit SA-node cell (Zhang et al. Am J Physiol Heart Circ Physiol. 2000; 279: H397-H421) was action potential clamped by our experimentally recorded APs. Results: In experiments, IKr channel openings were detected during AP repolarization and diastolic depolarization. The open probability (Po) was very low (<0.15) early during repolarization, but rapidly increased towards final repolarization, reaching a maximum of 0.27±0.03 (mean±SEM, n = 4) shortly before the maximum diastolic potential (MDP). During the subsequent diastolic depolarization, Po gradually declined to a value of 0.08±0.02 (mean±SEM, n = 4) just before take-off of the next AP. Po obtained from the computational model followed a qualitatively similar course during SA-node automaticity, but values were doubled. That is: Po rapidly increased from zero to a maximal value of 0.63 shortly before MDP, and then declined to 0.18 towards the end of diastolic depolarization. Conclusions: The computational model well-described the time- and voltage dependent changes in Po of IKr channels during SA-nodal pacemaking, however, Po was over-estimated by a factor of 2 in all phases of the pacemaker cycle.