Antiarrhythmic and electrophysiological effects of GYKI-16638, a novel N-(phenoxyalkyl)-N-phenylalkylamine, in rabbits.
The effect of N-[4-[2-N-methyl-N-[1-methyl-2-(2, 6-dimethylphenoxy)ethylamino]-ethyl]-phenyl]-methanesulfonamide. hydrochloride (GYKI-16638; 0.03 and 0.1 mg/kg, i.v.), a novel antiarrhythmic compound, was assessed and compared to that of D-sotalol (1 and 3 mg/kg, i.v.) on arrhythmias induced by 10 min of coronary artery occlusion and 10 min of reperfusion in anaesthetized rabbits. Also, its cellular electrophysiological effects were studied in rabbit right ventricular papillary muscle preparations and in rabbit single isolated ventricular myocytes. In anaesthetized rabbits, intravenous administration of 0.03 and 0.1 mg/kg GYKI-16638 and 1 and 3 mg/kg D-sotalol significantly increased survival during reperfusion (GYKI-16638: 82% and 77%, D-sotalol: 75% and 83% vs. 18% in controls, P<0.05, respectively). GYKI-16638 (0.1 mg/kg) significantly increased the number of animals that did not develop arrhythmias during reperfusion (46% vs. 0% in controls, P<0.05). In isolated rabbit right ventricular papillary muscle, 2 microM GYKI-16638, at 1 Hz stimulation frequency, lengthened the action potential duration at 50% and 90% repolarization (APD(50-90)) without influencing the resting membrane potential and action potential amplitude (APA). It decreased the maximal rate of depolarization (V(max)) in a use-dependent manner. This effect was statistically significant only at stimulation cycle lengths shorter than 700 ms. The offset kinetics of this V(max) block were relatively rapid, the corresponding time constant for recovery of V(max) was 328.2+/-65.0 ms. In patch-clamp experiments, performed in rabbit ventricular myocytes, 2 microM GYKI-16638 markedly depressed the rapid component of the delayed rectifier outward and moderately decreased the inward rectifier K(+) current without significantly altering the slow component of the delayed rectifier and transient outward K(+) currents. These results suggest that in rabbits, GYKI-16638 has an in vivo antiarrhythmic effect, comparable to that of D-sotalol, which can be best explained by its combined Class I/B and Class III actions.
Baczkó
I
I
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged and Research Unit of the Hungarian Academy of Sciences, Dóm tér 12, P.O. Box 427, H-6701, Szeged, Hungary.
El-Reyani
N E
NE
Farkas
A
A
Virág
L
L
Iost
N
N
Leprán
I
I
Mátyus
P
P
Varró
A
A
Papp
J G
JG
D000200:Action Potentials / Q000187:drug effects; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D017202:Myocardial Ischemia / Q000503:physiopathology; D009206:Myocardium; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology / Q000627:therapeutic use*; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D015424:Reperfusion / Q000009:adverse effects; D013015:Sotalol / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D016276:Ventricular Function
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D015221:Potassium Channels; D013449:Sulfonamides; C420122:GYKI 16638; D013015:Sotalol