Rate-dependent effects of sematilide on action potential duration in isolated guinea pig ventricular myocytes.

We examined the underlying mechanism for rate-dependent effects of sematilide on action potential duration (APD) in guinea pig ventricular myocytes. Sematilide at 10 microM or higher concentrations caused prolongation of the APD without changing other electrical parameters at a stimulation rate of 0.2 Hz. Although 30 microM sematilide significantly prolonged APD by 20 to 40% at 0.2 Hz, the drug-induced prolongation became non-significant at 2.5 Hz, exhibiting a reverse use-dependent effect. Sematilide depressed the delayed outward K+ current (IK) without affecting the inward rectifier K+ current and the L-type Ca++ current. Suppression of IK by sematilide was more prominent on the tail current elicited by short pulses than on those elicited by long pulses, suggesting that its main action was on the rapidly activating component of IK. Sematilide was shown to have an affinity to the rested state of the IK channel, because the inhibition was increased with prolongation of diastolic intervals at -80 mV. Rapid-rate depolarizations induced a transient outward current that was abolished by 5 mM caffeine. This caffeine-sensitive transient outward current could contribute to the shortening of the APD at rapid pulsation, but sematilide had no effects on this current. Therefore, we conclude that sematilide principally blocked the rapidly activating component of IK with affinity for the rested state of the IK channel and did not block the slowly activating component. Also the drug did not affect the caffeine-sensitive transient outward current during rapid-rate depolarizations. All of these factors may contribute to reverse use-dependent effects on action potential prolongation by sematilide.