Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine and amiodarone.
Prolongation of cardiac action potentials may mediate some of the arrhythmia-suppressing and arrhythmia-aggravating actions of antiarrhythmic agents. In this study, suppression of time-dependent outward current by quinidine and amiodarone was assessed in guinea pig ventricular myocytes. The net time-dependent outward current contained at least two components: a slowly activating, La(3+)-resistant delayed rectifier current (IK) and a rapidly activating, La(3+)-sensitive current. Quinidine block of total time-dependent outward current during clamp steps to positive potentials was relieved as a function of time, whereas that induced by amiodarone was enhanced. In contrast, at negative potentials, suppression of current, whereas amiodarone reduced IK but not the La(3+)-sensitive current, suggesting that differential block of the two components of time-dependent current underlies the distinct effects of the two agents. In contrast to these disparate effects on total time-dependent outward current, steady-state reduction of IK by both drugs increased at positive voltages and saturated at approximately +40 mV; the voltage dependence of block by quinidine (17% per decade, +10 to +30 mV) was steeper than that by amiodarone (5% per decade, +10 to +20 mV). Block by quinidine was time dependent at negative potentials: on stepping from +50 to -30 mV, block initially increased very rapidly, and subsequent deactivation of IK was slowed. This effect was not seen with amiodarone. At -80 mV, quinidine block was relieved with a time constant of 40 +/- 15 msec (n = 4, twin-pulse protocol). The effects of quinidine on IK were compatible with neither a purely voltage-dependent model of quinidine binding nor a model incorporating both voltage- and state-dependent binding of quinidine to delayed rectifier channels having only one open state. The voltage- and time-dependent features of quinidine block were well described by a model in which quinidine has greater affinity for one of two open states of the channel. We conclude that the effects of quinidine and amiodarone on time-dependent outward current reflects block of multiple channels. Quinidine block of IK was far more voltage dependent than that produced by amiodarone, suggesting the drugs act by different mechanisms.
Balser
J R
JR
Department of Medicine, Vanderbilt University School of Medicine, Nashville 37232-6602.
Bennett
P B
PB
Hondeghem
L M
LM
Roden
D M
DM
D000200:Action Potentials; D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D004594:Electrophysiology; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects*; D066298:In Vitro Techniques; D008564:Membrane Potentials; D008955:Models, Cardiovascular; D011188:Potassium / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology; D011802:Quinidine / Q000494:pharmacology*; D013997:Time Factors; D016276:Ventricular Function
D015221:Potassium Channels; D011802:Quinidine; D000638:Amiodarone; D011188:Potassium