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Journal of Cardiovascular Pharmacology:
doi: 10.1097/FJC.0b013e3181fda7c4
Original Article

Ionic Mechanisms of Pacemaker Activity in Spontaneously Contracting Atrial HL-1 Cells

Yang, Zhenjiang MD, PhD; Murray, Katherine T MD

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Abstract

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.

© 2011 Lippincott Williams & Wilkins, Inc.

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