Ca2+ current-mediated regulation of action potential by pacing rate in rat ventricular myocytes

Objective: Pacing rate regulates the duration of the cardiac action potential (AP). It also regulates the decay kinetics of the L-type Ca2+ current (ICa-L) which occurs via modulation of Ca2+-dependent inactivation. We investigated whether and how this latter process contributes to frequency-dependent (FD) changes in the AP waveform in rat ventricular cells. Methods: We recorded APs using a microelectrode technique in rat papillary muscles, and using the whole-cell current patch-clamp technique in single rat ventricular cells. Results: The AP duration (APD) was increased by high rates encompassing the physiological range (0.1-5.7 Hz) in both papillary muscles and single cells. This prolongation was accompanied by concomitant depolarisation (similar to7 mV at 5.7 Hz) of the membrane potential (NIP) in papillary muscles. Equivalent artificial depolarisation of the NIP enhanced the FD prolongation in single cells. The FD prolongation was enhanced in presence of the K+ current blocker 4-aminopyridine (5 mmol/l), and decreased in absence of extracellular Ca2+. It was antagonised by Ca2+ channel blockers (Co2+, nifedipine, nitrendipine) and decreased by use of high EGTA (10 vs. 0.5 mmol/l EGTA) or BAPTA (20 mmol/l) in the patch-pipette. It was prevented by ryanodine or thapsigargin, two drugs that reduce or abolish SR-Ca2+ function. Conclusion: ICa-L contributes to the FD modulation of the AP, which occurs following a sudden change in cardiac frequency in rat ventricular cells. This highly dynamic physiological process is related to SR-Ca2+ release and occurs through beat-to-beat adaptation of Ca2+-dependent inactivation of ICa-L. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.