Mechanism of antiarrhythmic drug-induced changes in defibrillation threshold: role of potassium and sodium channel conductance.
OBJECTIVE
We sought to determine which ion current predominantly affects defibrillation outcomes by using specific pharmacologic probes (lidocaine [a sodium channel blocking agent] and cesium [an outward potassium channel blocking agent]) in 26 swine.


BACKGROUND
The effect of a drug on sodium or potassium channel conductance, or both, may affect defibrillation threshold values. However, it is unknown which ion channel predominates.


METHODS
Each pig was randomly assigned to one of four treatment groups with two treatment phases: group 1 = placebo (D5W) in treatment phase I followed by placebo plus cesium in treatment phase II (n = 6); group 2 = lidocaine followed by lidocaine plus placebo (n = 7); group 3 = lidocaine followed by lidocaine plus cesium (n = 7); group 4 = placebo followed by placebo plus placebo (n = 6). Defibrillation threshold values and electrocardiographic measurements were obtained at baseline and at treatment phases I and II.


RESULTS
Lidocaine increased defibrillation threshold values from baseline by 71% in group 2 (p = 0.02) and by 92% in group 3 (p < 0.01). There were no changes in defibrillation threshold values from baseline to D5W in groups 1 and 4. When D5W was added to lidocaine in group 2 and D5W in group 4, there were no significant changes in defibrillation threshold values. However, when cesium was added to lidocaine in group 3, the elevated defibrillation threshold values (mean +/- SD) returned to baseline values (from 15.7 +/- 3.46 to 7.55 +/- 3.19 J, p < 0.01). Cesium added to D5W in group 1 also significantly reduced defibrillation threshold values from 7.10 +/- 1.27 to 4.14 +/- 1.75 J (p < 0.01). The effect of cesium on defibrillation threshold values was similar between groups 1 and 3, regardless of lidocaine, such that these values were reduced by 40 +/- 14% and 51 +/- 18%, respectively (p = 0.28).


CONCLUSIONS
Cesium, through potassium blockade, reverses lidocaine-induced elevation in defibrillation threshold values. The magnitude of defibrillation threshold reduction when cesium was added to lidocaine was similar to the defibrillation threshold reduction when cesium was added to placebo. Thus, inhibiting outward potassium conductance and prolonging repolarization decreases defibrillation threshold values independent of sodium channel blockade.
Ujhelyi
M R
MR
University of Georgia College of Pharmacy and Medical College of Georgia School of Medicine, Augusta 30912-2390, USA.
Schur
M
M
Frede
T
T
Bottorff
M B
MB
Gabel
M
M
Markel
M L
ML
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002586:Cesium / Q000494:pharmacology / Q000627:therapeutic use; D008012:Lidocaine / Q000494:pharmacology / Q000627:therapeutic use; D015221:Potassium Channels / Q000187:drug effects*; D015222:Sodium Channels / Q000187:drug effects*; D013552:Swine; D014693:Ventricular Fibrillation / Q000188:drug therapy*
D000889:Anti-Arrhythmia Agents; D015221:Potassium Channels; D015222:Sodium Channels; D002586:Cesium; D008012:Lidocaine