Sympathetic activation, ventricular repolarization and Ikr blockade: implications for the antifibrillatory efficacy of potassium channel blocking agents.
OBJECTIVE
The aim of the present study was to test, in vivo and in vitro, the influence of adrenergic activation on action potential prolongation induced by the potassium channel blocking agent d-sotalol.


BACKGROUND
d-Sotalol is not effective against myocardial ischemia-dependent ventricular fibrillation in the presence of elevated sympathetic activity. Most potassium channel blockers, such as d-sotalol, affect only one of the two components of Ik (Ikr) but not the other (Iks). Iks is activated by isoproterenol. An unopposed activation of Iks might account for the loss of anti-fibrillatory effect by d-sotalol in conditions of high sympathetic activity.


METHODS
In nine anesthetized dogs we tested at constant heart rate (160 to 220 beats/min) the influences of left stellate ganglion stimulation on the monophasic action potential prolongation induced by d-sotalol. In two groups of isolated guinea pig ventricular myocytes we tested the effect of isoproterenol (10(-9) mol/liter) on the action potential duration at five pacing rates (from 0.5 to 2.5 Hz) in the absence (n = 6) and in the presence (n = 8) of d-sotalol.


RESULTS
In control conditions, both in vivo and in vitro, adrenergic stimulation did not significantly change action potential duration. d-Sotalol prolonged both monophasic action potential duration in dogs and action potential duration of guinea pig ventricular myocytes by 19% to 24%. Adrenergic activation, either left stellate ganglion stimulation in vivo or isoproterenol in vitro, reduced by 40% to 60% the prolongation of action potential duration produced by d-sotalol.


CONCLUSIONS
Sympathetic activation counteracts the effects of potassium channel blockers on the duration of repolarization and may impair their primary antifibrillatory mechanism. An intriguing clinical implication is that potassium channel blockers may not offer effective protection from malignant ischemic arrhythmias that occur in a setting of elevated sympathetic activity.
Vanoli
E
E
Istituto di Clinica Medica Generale e Terapia Medica, University of Milan, Italy.
Priori
S G
SG
Nakagawa
H
H
Hirao
K
K
Napolitano
C
C
Diehl
L
L
Lazzara
R
R
Schwartz
P J
PJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004285:Dogs; D004558:Electric Stimulation; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D015221:Potassium Channels / Q000187:drug effects* / Q000502:physiology; D013015:Sotalol / Q000494:pharmacology*; D013233:Stellate Ganglion / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology*; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control*
D015221:Potassium Channels; D013015:Sotalol; D007545:Isoproterenol