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.

The role of mammalian cardiac t‐tubules in excitation–contraction coupling: experimental and computational approaches

“…Since many membrane currents are heterogeneously distributed between the surface and t-tubule membranes, it might be expected that the action potential would be different at the two sites. In support of this idea, the action potential of detubulated ventricular myocytes is shorter than that of intact myocytes Salle et al 2008), which suggests that loss of the t-tubules is associated with loss of net inward current, consistent with the measured current distributions (Table 1). Thus, it appears that the surface membrane action potential is shorter than that of the t-tubule membrane.…”

Transient receptor potential melastatin 4 inhibitor 9‐phenanthrol abolishes arrhythmias induced by hypoxia and re‐oxygenation in mouse ventricle

“…Myocytes were isolated from mice ventricles using an adapted enzymatic dissociation protocol (Sallé et al ., 2008). Briefly, after the mice had been killed, the heart was rapidly removed and mounted on a Langendorff apparatus and perfused retrogradely with a HEPES‐based isolation solution containing (in mmol·L −1 ): NaCl 130, KCl 5.4, NaH 2 PO 4 0.4, MgCl 2 1.4, CaCl 2 1, HEPES 10, glucose 10, taurine 20 and creatine 10 (pH 7.4 with NaOH).…”

The Complex QT/RR Relationship in Mice

“…Nevertheless, these electrophysiological determinants of the frequency-dependence of the APD differ between species. For example, in lagomorphs or rodents, with a short to very short refractory period, the dependence of the APD on frequency is less clear and could be contrary to the effects seen in humans 4 9 10 .…”