title: Mechanisms underlying adaptation of action potential duration by pacing rate in rat myocytes.
abstract: Heart rate is an essential determinant of cardiac performance. In rat ventricular myocytes, a sudden increase in rate yields to a prolongation of the action potential duration (APD). The mechanism underlying this prolongation is controversial: it has been proposed that the longer APD is due to either: (1) a decrease in K+ currents only or (2) an increase in Ca2+ current only. The aim of this study was to quantitatively investigate the contribution of Ca2+ and K+ currents in the adaptation of APD to pacing rate. Simulation using a mathematical model of ventricular rat cardiac cell model [Pandit, S.V., Clark, R.B., Giles, W.R., Demir, S.S., 2001. A mathematical model of action potential heterogeneity in adult rat left ventricular myocytes. Biophys. J. 81, 3029-3051] predicted a role in the prolongation of APD for K+ currents only. In patch clamp experiments, increasing the pacing rate leads to a significant increase in APD in both control and detubulated myocytes, although it was more marked in control than detubulated myocytes. Supporting the model prediction, we observed that increasing stimulation frequency leads to a decrease in K+ currents in voltage clamped rat ventricular myocytes (square and action potential waveforms), and to a similar extent in both cell types. We have also observed that frequency-dependent facilitation of Ca2+ current occurred in control cells but not in detubulated cells (square and action potential waveforms). From these experiments, we calculated that the relative contribution of Ca2+ and K+ currents to the longer APD following an increase in pacing rate is approximately 65% and approximately 35%, respectively. Therefore, in contrast to the model prediction, Ca2+ current has a significant role in the adaptation of APD to pacing rate. Finally, we have introduced a simplistic modification to the Pandit's model to account for the frequency-dependent facilitation of Ca2+ current.
authors.affiliation: Laboratoire de Physiologie Cellulaire, EA3212, Université de Caen, 14032 Caen, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Sallé
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kharche
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Fabien
authors.initials: F
authors.lastname: Brette
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000222:Adaptation, Physiological; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006339:Heart Rate / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D032383:Myocytes, Cardiac / Q000502:physiology*; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016276:Ventricular Function
chemical_list: D011188:Potassium; D002118:Calcium