Differential efficacy of the class III agent MK-499 against programmed stimulation-induced and ischemic-induced ventricular arrhythmias in a canine model of previous myocardial infarction.
Class III activity has been proposed as a potential mechanism for the treatment of reentrant arrhythmias. The purpose of the present study was to assess the concordance in antiarrhythmic efficacy of MK-499, a selective blocker of IKr, the rapidly activating component of cardiac delayed rectifier K+ current, against programmed ventricular stimulation (PVS)-induced ventricular tachycardias and thrombotically induced lethal ischemic arrhythmias, and to characterize the electrophysiologic determinants of antiarrhythmic efficacy in the canine model of previous myocardial infarction. Single i.v. doses of 1.0, 3.0 and 10.0 micrograms/kg MK-499 were administered to anesthetized dogs with anterior myocardial infarctions. Protection (suppression + stabilization/slowing) vs. PVS-induced ventricular tachycardias occurred in 5/11 (45%) preparations at 1.0 microgram/kg, in 9/12 (75%) preparations at 3.0 micrograms/kg and in 10/11 (91%) preparations at 10.0 micrograms/kg i.v. MK-499. The incidences of lethal ventricular arrhythmias developing in response to thrombotically induced posterolateral myocardial ischemia were 34/40 (85%) in vehicle controls, 7/11 (64%) at 1.0 microgram/kg, 6/12 (50%, P < .05) at 3.0 micrograms/kg and 4/11 (36%, P < .01) at 10.0 micrograms/kg i.v. MK-499. Low-dose i.v. MK-499 prolonged ECG QT interval and increased noninfarct zone and infarct zone ventricular refractoriness. However, there was a poor concordance (56%) between response to PVS with MK-499 and response to thrombotically induced acute myocardial ischemia. Furthermore, different trends of association between site and magnitude of Class III effect and antiarrhythmic efficacy were observed for PVS- vs. ischemia-induced arrhythmias. Hence, although low-dose i.v. MK-499 provided significant protection against both electrically and ischemically triggered arrhythmias in the setting of previous myocardial infarction, protection against PVS-induced ventricular tachycardias was not highly predictive of protection against lethal ischemic arrhythmias in this preparation.
Lynch
J J
JJ
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania, USA.
Wallace
A A
AA
Stump
G L
GL
Stupienski
R F
RF
Kothstein
T
T
Gehret
J R
JR
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D001578:Benzopyrans; D010880:Piperidines; C087257:L 706000