Class III effects of dofetilide and arrhythmias are modulated by [K+]o in an in vitro model of simulated-ischemia and reperfusion in guinea-pig ventricular myocardium.
To evaluate class III effects of clinically relevant concentrations of dofetilide (5 and 10 nmol/l) and the effects of extracellular potassium [K+]o modulation of arrhythmias onset at the level of the "border zone," we used a previously reported in vitro model whereby normoxic and ischemic/reperfused zones were studied. Guinea-pig right ventricular strips (driven at 1 Hz at 36.5+/-0.5 degrees C) were superfused with Tyrode's solution in oxygenated (HCO3- 25 mmol/l, K+ 4 mmol/l, pH 7.35+/-0.05, glucose 5.5 mmol/l: normal zone) and ischemia-simulating conditions (HCO3- 9 mmol/l, pH 6.90+/-0.05, no oxygen and no glucose: altered zone) having either [K+]o 4 (n=20), 8 (n=20) or 12 (n=20) mmol/l. Action potentials in normal and altered zones were recorded simultaneously during 30 min of simulated-ischemia and after 30 min of reperfusion with oxygenated Tyrode's solution. Each preparation served as control for successive phases of dofetilide studies (at 5 and 10 nmol/l) and action potential values were normalized to those present at the beginning of the experiment. During simulated-ischemia, the higher the [K+]o the worse were action potential changes, although full recovery was seen upon 30 min of reperfusion in all [K+]o groups. A high incidence of ischemia/reperfusion arrhythmias was observed in 4 and 12 mmol/l [K+]o groups as opposed to a low incidence of arrhythmias in 8 mmol/l [K+]o group. Dofetilide at 5 and 10 nmol/l with all [K+]o explored: (i) exhibited class III effects, (ii) was effective (or neutral) against ventricular arrhythmias during both simulated-ischemia and reperfusion, and (iii) did not globally increase the dispersion of action potential durations between normal and altered zones. Different arrhythmogenic mechanisms are involved in this model at different [K+]o with 8 mmol/l providing relative protection. Class III effects of dofetilide are evident in the normal zone when in the ischemic-like zone [K+]o ranges from 4 to 12 mmol/l. Thus dofetilide did not increase dispersion of repolarization and had either an antiarrhythmic or a neutral effect during ischemia/reperfusion.
Laboratoire d'Anesthésiologie Expérimentale et de Physiologie Cellulaire E3212, University of Caen, France.
Joffrey
J
Ducroq
René
R
Rouet
Laurent
L
Sallé
Paolo Emilio
PE
Puddu
Yohann
Y
Repessé
Mathieu
M
Ghadanfar
Pierre
P
Ducouret
Jean-Louis
JL
Gérard
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006352:Heart Ventricles; D006947:Hyperkalemia / Q000188:drug therapy / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D010627:Phenethylamines / Q000494:pharmacology* / Q000627:therapeutic use; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C063533:dofetilide; D011188:Potassium