Ionic mechanisms of pacemaker activity in spontaneously contracting atrial HL-1 cells.

Yang Z, Murray KT
J Cardiovasc Pharmacol. 2011 57 (1): 28-36

PMID: 20881602 · PMCID: PMC3023001 · DOI:10.1097/FJC.0b013e3181fda7c4

Although normally absent, spontaneous pacemaker activity can develop in human atrium to promote tachyarrhythmias. HL-1 cells are immortalized atrial cardiomyocytes that contract spontaneously in culture, providing a model system of atrial cell automaticity. Using electrophysiologic recordings and selective pharmacologic blockers, we investigated the ionic basis of automaticity in atrial HL-1 cells. Both the sarcoplasmic reticulum Ca release channel inhibitor ryanodine and the sarcoplasmic reticulum Ca ATPase inhibitor thapsigargin slowed automaticity, supporting a role for intracellular Ca release in pacemaker activity. Additional experiments were performed to examine the effects of ionic currents activating in the voltage range of diastolic depolarization. Inhibition of the hyperpolarization-activated pacemaker current, If, by ivabradine significantly suppressed diastolic depolarization, with modest slowing of automaticity. Block of inward Na currents also reduced automaticity, whereas inhibition of T- and L-type Ca currents caused milder effects to slow beat rate. The major outward current in HL-1 cells is the rapidly activating delayed rectifier, IKr. Inhibition of IKr using dofetilide caused marked prolongation of action potential duration and thus spontaneous cycle length. These results demonstrate a mutual role for both intracellular Ca release and sarcolemmal ionic currents in controlling automaticity in atrial HL-1 cells. Given that similar internal and membrane-based mechanisms also play a role in sinoatrial nodal cell pacemaker activity, our findings provide evidence for generalized conservation of pacemaker mechanisms among different types of cardiomyocytes.

MeSH Terms (14)

Action Potentials Biological Clocks Calcium Cell Line, Transformed Diastole Heart Atria Humans Ions Myocytes, Cardiac Ryanodine Sarcolemma Sarcoplasmic Reticulum Sinoatrial Node Thapsigargin

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