Single cells isolated from human sinoatrial node: action potentials and numerical reconstruction of pacemaker current

Abstract

Pacemaker activity of the sinoatrial node has extensively been studied in laboratory animals of various species, but is virtually unexplored in man. Most experimental data have been obtained from rabbit, where the hyperpolarization-activated 'funny' current (If), also known as the 'pacemaker current', plays an important role in diastolic depolarization and thus in setting pacing rate. Recently, we isolated pacemaker cells from excised human sinoatrial node tissue, and recorded action potentials and If using the whole-cell patch-clamp technique in current clamp and voltage clamp mode, respectively. Single sinoatrial node pacemaker cells showed a spontaneous beating rate of 73 +/- 3 beats/min (mean +/- SEM, n = 3) with a remarkably slow diastolic depolarization. If was identified in voltage clamp experiments as the 2 mmol/L Cs+-sensitive inward current activating upon 2-s hyperpolarizing voltage clamp steps. The If reversal potential and (de)activation kinetics were similar to those in rabbit. However, the fully-activated If conductance was 3-4 times smaller than typically found in rabbit. Furthermore, the half-maximal activation voltage was approximately 20 mV more negative than in rabbit. These differences would both act to reduce the functional role of If in human pacemaker cells. To assess this functional role, we carried out a numerical reconstruction of the If time course during an experimentally recorded human sinoatrial node action potential, based on the obtained data on If amplitude and kinetics. This reconstruction revealed that If provides a small but significant inward current in the voltage range of diastolic depolarization. We conclude that human sinoatrial node pacemaker cells functionally express If and that this If contributes to pacemaking in human sinoatrial node.