Adaptation of rat ventricular action potential repolarization to random fluctuations in pacing rate

Aim: Action potential duration (APD) of rat cardiomyocytes displays both adaptation to pacing cycle length (CL) and beat-to-beat variability (BTBV). The aim of this study is to investigate both properties via classical rate-dependency and restitution protocols as well as by means of a new random stimulation protocol. Methods: Patch-clamped cells were paced in current-clamp mode at a basic cycle length (BCL) of 250 ms, then underwent one of the following protocols: a) CL was made change randomly around BCL with percentages of variability (CLR) from 2 to 10% (step 2%), in turn in Normal Tyrode (NT), 5 mM 4-aminopyridine (4AP) or 10 M Nifedipine; b) CL was switched from BCL to different constant values up to 20% (step 4%). c) BCL trains were followed by pre/postmature stimuli with different delays. APD was measured at -60 mV (APD60). Results: a) BTBV calculated as coefficient of variability (CV) of APD60 in NT was 1.16 at BCL, and increased for CLR >4%. 4AP decreased CV at BCL (0.81), while Nifedipine increased it (1.59). Correlation between 10 consecutive APD60 and preceding CLs at CLR=10% increased in 4AP (R = 0.72) and decreased in Nifedipine (R = 0.18) with respect to NT (R = 0.43). In b) and c) protocols, changes in pacing CL became detectable as APD60 changes only when >5%. Conclusion: BTBV masks small random changes (4%) in CL, setting up a limit for the detection of APD60 rate-dependency. 4AP and Nifedipine respectively increase and decrease correlation between APD60 and the preceding CL. This finding might help to clarify the still not completely understood mechanism of class III prolonging and class IV shortening antiarrhythmic drugs, which display in vivo similar electrical effects.