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CARDIOVASCULAR

In Vivo Antiarrhythmic and Cardiac Electrophysiologic Effects of a Novel Diphenylphosphine Oxide I_Kur Blocker (2-Isopropyl-5-methylcyclohexyl) Diphenylphosphine Oxide

Departments of Stroke Research (G.L.S., C.P.R., J.J.L.) and Medicinal Chemistry (A.A.W.), Merck Research Laboratories, West Point, Pennsylvania

The antiarrhythmic efficacy of the novel ultrarapid delayed rectifier potassium current (I_Kur) 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 (I_Kr) 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 I_Kur for the development of potentially safer and more effective atrial antiarrhythmic agents.

Address correspondence to: Dr. Joseph J. Lynch, Jr., WP46-300, Merck Research Laboratories, West Point, PA 19486. E-mail: joseph_lynch{at}merck.com

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