Rate dependency of repolarization in rat myocytes paced with linearly changing cycle length sequences

Aim: Action potential duration at -60 mV (APD60) of isolated rat cardiomyocytes, displays rate dependency, i.e. increasing in pacing rate results in both APD60 rate-dependent shortening (RDS) or prolongation (RDP) and vice-versa . The aim of this work is to investigate how APD60 correlates with the preceding cycle length (CL) when this is made changing linearly. Methods: Action potentials were recorded from patch-clamped rat cardiomyocytes in current clamp mode. Starting from a basic cycle length (BCL) of 250 ms, CL was linearly first increased, and then decreased within a range of BCL ±20% by steps of 5 ms (protocol A), or BCL±12% by steps of 3 ms (protocol B), and finally returned to BCL. Both protocols were tested in turn in Normal Tyrode (NT), 5 mM 4-aminopyridine (4AP) or 10 µM Nifedipine. Results: In 6 cells with RDS following protocol A, the correlation coefficient (R) between APD60 and preceding CL calculated in NT over the entire CL frequency (R=0.5) was significantly increased in 4AP (R=0.84) and decreased in Nifedipine (R= -0.13). Same results were found in protocol B, both for NT vs 4AP (R=0.45 vs 0.8) and NT vs Nifedipine (R=0.45 vs -0.04). Interestingly, even in 2 cells that displayed a slight RDP in NT during protocol A, application of 4AP resulted in a RDS (R= -0.29 vs 0.71). Conclusion: The tendency of APD60 to correlate with a linearly changing preceding CL can be pharmacologically modulated. Specifically our results suggest a role of Ito and ICaL in respectively decrease and increase correlation between APD60 and CL. These results might be relevant for the understanding of the mechanisms of class III prolonging and class IV shortening antiarrhythmic drugs.