Antiarrhythmic Agent Specific Block of Rapidly Activating Delayed Rectifier K' Current by Dofetilide

Class III antiarrhythmic agents act by selective prolongation of cardiac action potential duration (APD). Methanesulfonanilide class III agents (e.g., E-4031 and dofetilide) are extremely potent and lengthen action potentials in a "reverse" rate-dependent manner; i.e., effects are greater at low compared with high rates of stimulation. By using the whole-cell current-clamp technique in isolated guinea pig ventricular myocytes, APD was shortened by rapid pacing (244±16 msec at 30 pulses per minute, 166+8 msec at 240 pulses per minute; n=8). Dofetilide (1 ,iM) prolonged APD more when cells were stimulated at the rate of 30 pulses per minute (44±10 -msec increase) than at 240 pulses per minute (21 +5-msec increase). We investigated the mechanism of APD prolongation using voltage-clamp techniques. Dofetilide selectively inhibited IKr (IC50, 31.5 nM), defined as the rapidly activating inward rectifying component of net delayed rectifier K' current (IK) without effects on the larger but more slowly activating component of IK ('KS) or on the inward rectifier K' current (IK1). To examine the rate-dependent effects of dofetilide on APD, trains of conditioning pulses to 0 mV (200 -msec duration) were applied at either 30 or 240 pulses per minute to mimic the action potential experiments. Test pulses or ramps were given after the conditioning train to quantitate changes in 'K1S IKr, or IKs. The magnitude of neither lK1 nor IKr was dependent on the rate of the preceding train of depolarizations. Sensitivity to block of IKr by dofetilide was rate independent. In contrast, the magnitude of IKS was increased by rapid pacing, a result of incomplete deactivation of IKS during the abbreviated interpulse intervals. It was concluded that APD prolongation by dofetilide is a result of IKr block; however, incomplete deactivation of IKS partially offsets the rate-independent block of IKr resulting in reverse rate dependence. (Circulation Research 1993;72:75-83)