Nonselective I(Kr)-blockers do not induce torsades de pointes in the anesthetized rabbit during alpha1-adrenoceptor stimulation.
Selective I(Kr)- (the rapid component of the delayed rectifier potassium current) blockers are known to induce torsades de pointes (TdPs) in anesthetized rabbits during alpha1-adrenoreceptor stimulation. However, effects of nonselective I(Kr)-blockers, which produce TdPs in other animal models and in humans, are not known in this model. We examined two nonselective I(Kr)-blockers (quinidine, 1.25 mg/kg/min i.v [n = 7]; and terfenadine, 0.31 mg/kg/min i.v. [n = 7]) for their effects on electrocardiographic parameters and on incidence of cardiac arrhythmias in anesthetized rabbits during alpha1-adrenoceptor stimulation with methoxamine. We compared the drugs with two highly selective I(Kr)-blockers (dofetilide, 0.04 mg/kg/min i.v. [n = 7]; and clofilium, 0.08 mg/kg/min i.v. [n = 6]). Polymorphic ventricular tachycardia or TdPs were induced by dofetilide and clofilium at mean doses > or =0.33 mg/kg and 0.4 mg/kg i.v., in all animals tested (vs. none in solvent; p < 0.05). TdPs usually developed into ventricular fibrillation and developed after prolongation of QT/JT interval and of QT dispersion. Terfenadine and quinidine significantly increased PQ, QT, and QTc interval and largely increased QRS duration and QT dispersion. These compounds elicited intraventricular conduction defects and cardiac arrest, due to asystole, in all animals tested (vs. 0% in solvent; p < 0.05). Interestingly, these two nonselective I(Kr)-blockers did not produce TdPs or ventricular fibrillation in any animals tested. Our results thus indicate that selective I(Kr)-blockers elicit TdPs, whereas nonselective I(Kr)-blockers do not induce this type of arrhythmia in this rabbit model. Consequently, it should be noted that this rabbit model is not always useful to evaluate nonselective I(Kr)-blocker-induced TdPs and QT interval and QT dispersion, rather than TdPs, are also important indicators for drug-induced cardiac arrhythmias.
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Department of Cardiovascular Safety Pharmacology, Janssen Research Foundation, Beerse, Belgium. hlu@janbe.jnj.com
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De Clerck
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D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D051668:Delayed Rectifier Potassium Channels; D004562:Electrocardiography / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008729:Methoxamine / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011802:Quinidine / Q000494:pharmacology; D011817:Rabbits; D016593:Terfenadine / 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; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D016593:Terfenadine; D008729:Methoxamine; D011802:Quinidine