Amantadine-induced afterpotentials and automaticity in guinea pig ventricular myocytes.
The ionic mechanisms of amantadine-induced changes in membrane potential and automatic activity in guinea pig ventricular myocytes were studied using the suction-pipette whole-cell clamp method. While 25-100 microM amantadine decreased the action potential amplitude and duration, 200 and 400 microM amantadine lengthened the action potential duration and decreased the maximum diastolic potential with an appearance of diastolic depolarization and automaticity. In the presence of 25-100 microM amantadine, the preparations developed an afterpotential due to incomplete repolarization and a delayed afterdepolarization that eventually brought about triggered automaticity. The former type of afterpotential was abolished by tetrodotoxin (TTX) and the latter by Co2+. Spontaneous activity from the diastolic depolarization was also abolished by Co2+ but not by Cs+. Amantadine suppressed the calcium current to as much as half of the control at the concentrations used (25-200 microM). The drug also produced a depression of the inward rectifier K+ current. The outward current showing time-dependent decay was activated at the plateau voltages by concentrations lower than 100 microM, whereas the delayed outward K+ current was depressed by the drug in a concentration-dependent manner at more positive potentials. Amantadine activated the TTX-sensitive and TTX-insensitive inward currents on repolarization from depolarized states, without producing the transient inward current. These results indicate that the amantadine-induced diastolic depolarization and afterpotentials are caused by changes in multiple ionic currents and that, therefore, the drug can be used as a unique model for the study of arrhythmogenesis.
Hiraoka
M
M
Department of Cardiovascular Diseases, Tokyo Medical and Dental University, Japan.
Hirano
Y
Y
Kawano
S
S
Fan
Z
Z
Sawanobori
T
T
D000547:Amantadine / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000502:physiology; D002462:Cell Membrane / Q000502:physiology; D002469:Cell Separation; D002586:Cesium / Q000494:pharmacology; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles; D008564:Membrane Potentials / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000648:ultrastructure; D013997:Time Factors
D002586:Cesium; D000547:Amantadine; D002118:Calcium