Effects of the chromanol 293B, a selective blocker of the slow, component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes.
OBJECTIVE
The slow component of the delayed rectifier K+ current (IKs) is believed to be important in cardiac repolarization, and may be a potential target for antiarrhythmic drugs, but its study has been limited by a lack of specific blockers. The chromanol derivate 293B blocks currents expressed by minK and not HERG in Xenopus oocytes, but little is known about its effects on native currents and action potentials. We aimed to establish the effects of 293B on K+, Na+ and Ca2+ currents and action potentials in human and guinea pig cardiomyocytes.


METHODS
Whole-cell patch clamp techniques were applied to assess the effects of 293B on isolated myocytes at 36 degrees C.


RESULTS
Delayed rectifier current (IK) elicited by pulses to +60 mV from a holding potential of -50 mV in guinea pig myocytes was strongly inhibited by 293B (maximum inhibition 96.9 +/- 0.8%; 50% inhibitory concentration, EC50, 1.02 microM), but IK during pulses to -10 mV was unaffected (3.9 +/- 8.4% inhibition at 50 microM). Half-activation voltages, current-voltage relations, and current densities of drug-resistant and drug-sensitive IK correspond to those of IKr and IKs respectively. Inward rectifier K+ current, Na+ current and L-type Ca2+ current were unaffected by 293B. Transient outward current in human ventricular myocytes was inhibited by 293B at an EC50 of 24 microM, less than one twentieth the potency for IKs inhibition in guinea pig myocytes. While dofetilide prolonged action potential duration (APD) with strong reverse use dependence, 293B prolonged guinea pig and human ventricular APD to a similar fractional extent at all frequencies.


CONCLUSIONS
293B is a selective IKs blocker, and the frequency dependence of APD prolongation caused by this IKs blocker is different from that caused by IKr blockade: 293B may be an interesting tool to study the physiologic role of IKs and the antiarrhythmic potential of IKs blockade.
Department of Medicine and Research Center, Montreal Heart Institute, Quebec, Canada.
R F
RF
Bosch
R
R
Gaspo
A E
AE
Busch
H J
HJ
Lang
G R
GR
Li
S
S
Nattel
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D002839:Chromans / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
D015220:Calcium Channels; D002839:Chromans; D015221:Potassium Channels; D015222:Sodium Channels; D013449:Sulfonamides; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane