Proarrhythmic effects of intravenous quinidine, amiodarone, D-sotalol, and almokalant in the anesthetized rabbit model of torsade de pointes.
The proarrhythmic effects of four antiarrhythmic agents were examined during alpha1-adrenoceptor stimulation in chloralose-anesthetized rabbits. Each dose of almokalant (26, 88, and 260 microg/kg), D-sotalol, quinidine, or amiodarone (each 3, 10, and 30 mg/kg) was infused i.v. over 5 min and there was a 20-min interval between each infusion. D-sotalol and almokalant evoked torsade de pointes (TdP) and other arrhythmics, frequently. The incidences of TdP were 0, 50, and 40% after administering the first, second, and third doses of the nonselective I(Kr) inhibitor D-sotalol, respectively. Similarly, these values were 20, 40, and 33% after administering the first, second, and third doses, respectively, of the selective I(Kr) inhibitor almokalant. Quinidine elicited only a few arrhythmics, but not TdP. Quinidine, D-sotalol, and almokalant evoked conduction blocks in a dose-related manner (p < 0.05) and prolonged QT and QT(c) intervals (p < 0.05). Amiodarone neither prolonged QT and QT(c) nor evoked ventricular tachyarrhythmias, blocks, or other proarrhythmias. In conclusion, these results show no direct correlation between the occurrence of TdP and the infusion rate or dose of anti-arrhythmics. Furthermore, the lack of TdP with quinidine warns of false-negative results in the applied model.
Farkas
András
A
Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Szeged, Szeged, Hungary.
Leprán
István
I
Papp
Julius Gy
JG
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000638:Amiodarone / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology; D001794:Blood Pressure; D004562:Electrocardiography; D006339:Heart Rate; D007262:Infusions, Intravenous; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D011412:Propanolamines / Q000009:adverse effects* / Q000494:pharmacology; D011802:Quinidine / Q000009:adverse effects* / Q000494:pharmacology; D011817:Rabbits; D013015:Sotalol / Q000009:adverse effects* / Q000494:pharmacology; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000889:Anti-Arrhythmia Agents; D011412:Propanolamines; D010656:Phenylephrine; D013015:Sotalol; C074334:almokalant; D011802:Quinidine; D000638:Amiodarone