The antiarrhythmic efficacy of the novel ultrarapid delayed rectifier
potassium current (IKur) blocker
(2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide (DPO-1) was compared with efficacies of the standard class III rapidly activating component of delayed rectifier
potassium current (IKr) blockers [+-N-[1'-(6-cyano-1,2,3,4-tetrahydro-2-napthalenyl)-3,4-dihydro-4-hydroxyspiro[2H-1-
benzopyran-2,4'-piperidin]-6-yl]
methanesulfonamide hydrochloride (MK499) and
ibutilide and the class IC agent
propafenone in a canine model of Y-shaped intracaval and right atrial free wall surgical lesions producing the substrate for reentrant
atrial flutter. Electrocardiographic and cardiac electrophysiologic effects also were assessed at the effective antiarrhythmic doses of test agents. DPO-1 terminated atrial
arrhythmia (six/six preparations; 5.5 +/- 2.0 mg/kg i.v.) while significantly increasing atrial relative and effective refractory periods (+15.7 and +15.2%, respectively) but having no significant effects on ventricular refractory periods or electrocardiogram (ECG) intervals. Effective antiarrhythmic doses of MK499 (five/five preparations; 0.004 +/- 0.002 mg/kg i.v.) and
ibutilide (five/five preparations; 0.003 +/- 0.001 mg/kg i.v.) similarly increased atrial relative (+23.2 and +25.1%, respectively) and effective (+21.6 and +31.9%, respectively) refractory periods. However, antiarrhythmic doses of MK499 and
ibutilide also consistently and significantly increased ventricular relative (+9.9 and +7.6%, respectively) and effective (+10.4 and +9.9%, respectively) refractory periods, rate-corrected ECG QTc (+6.7 and +7.8%, respectively), and paced QT (+7.3 and +8.5%, respectively) intervals. Doses of
propafenone that terminated atrial
arrhythmia (five/five preparations; 0.94 +/- 0.54 mg/kg i.v.) significantly increased ECG QRS interval (+11.1%). These findings support the approach of atrial selective modulation of refractoriness through block of IKur for the development of potentially safer and more effective atrial antiarrhythmic agents.