Kinetics of rate‐dependent shortening of action potential duration in guinea‐pig ventricle; effects of IK1 and IKr blockade

The kinetics of shortening of action potential duration (APD) following an increase in pacing rate, from 2 to 3.3 Hz, was characterized in guinea‐pig ventricular preparations. Terikalant (RP62719), an inhibitor of the inwardly rectifying K+ current (IK1), and dofetilide, a specific inhibitor of the rapidly activating delayed‐rectifier current (IKr), were applied to determine the effect of inhibition of these ion currents on slow APD shortening. Action potentials were recorded from isolated guinea‐pig ventricular myocytes using the perforated‐patch patch‐clamp technique, and monophasic action potentials were recorded from Langendorff‐perfused guinea‐pig ventricles using a contact epicardial probe. Under control conditions, after an increase in pacing rate, APD immediately decreased, and then shortened slowly with an exponential time course. In ventricular myocytes, the time constant of this exponential shortening was 28±4 s and the amount of slow shortening was 21.9±0.9 ms (n=8) for an increase in rate from 2 to 3.3 Hz. Similar values were observed in Langendorff‐perfused ventricles. Terikalant dose‐dependently increased APD and the increase was enhanced by rapid pacing (‘positive’ rate‐dependence). The drug dose‐dependently decreased the time constant of shortening and amount of slow APD shortening. In contrast, dofetilide, an inhibitor of IKr, which shows ‘reverse’ rate‐dependent APD widening, had no significant effect on the time constant or amount of slow shortening. These observations suggest that IK1 plays a role in rate‐dependent shortening of APD. The results appear to support the hypothesis that ‘reverse’ rate‐dependent effects of IKr blockers are due to these drugs not affecting the ion current(s) mediating intrinsic rate‐dependent slow shortening of APD. British Journal of Pharmacology (1999) 126, 1426–1436; doi:10.1038/sj.bjp.0702443