In vivo antiarrhythmic and cardiac electrophysiologic effects of a novel diphenylphosphine oxide IKur blocker (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide.
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.
Stump
Gary L
GL
Department of Stroke Research, Merck Research Laboratories, West Point, PA 19486, USA.
Wallace
Audrey A
AA
Regan
Christopher P
CP
Lynch
Joseph J
JJ
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001282:Atrial Flutter / Q000503:physiopathology; D016275:Atrial Function / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D004594:Electrophysiology; D005260:Female; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors; D008297:Male; D010720:Phosphines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D011405:Propafenone / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
C507236:(2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; D000889:Anti-Arrhythmia Agents; D051666:Kv1.5 Potassium Channel; D010720:Phosphines; D026902:Potassium Channel Blockers; D013449:Sulfonamides; C067192:ibutilide; D011405:Propafenone