Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, I(Ks), in canine models of malignant ischemic ventricular arrhythmia.
BACKGROUND
To date, the lack of potent and selective inhibitors has hampered the physiological assessment of modulation of the cardiac slowly activating delayed rectifier current, I(Ks). The present study, using the I(Ks) blocker L-768,673, represents the first in vivo assessment of the cardiac electrophysiological and antiarrhythmic effects of selective I(Ks) blockade.


RESULTS
In an anesthetized canine model of recent (8.5+/-0.4 days) anterior myocardial infarction, 0.003 to 0.03 mg/kg L-768,673 IV significantly suppressed electrically induced ventricular tachyarrhythmias and reduced the incidence of lethal arrhythmias precipitated by acute, thrombotically induced posterolateral myocardial ischemia. Antiarrhythmic protection afforded by L-768,673 was accompanied by modest 7% to 10% increases in noninfarct zone ventricular effective refractory period, 3% to 5% increases in infarct zone ventricular effective refractory period, and 4% to 6% increases in QTc interval. In a conscious canine model of healed (3 to 4 weeks) anterior myocardial infarction, ventricular fibrillation was provoked by transient occlusion of the left circumflex coronary artery during submaximal exercise. Pretreatment with 0.03 mg/kg L-768,673 IV elicited a modest 7% increase in QTc, prevented ventricular fibrillation in 5 of 6 animals, and suppressed arrhythmias in 2 additional animals.


CONCLUSIONS
The present findings suggest that selective blockade of I(Ks) may be a potentially useful intervention for the prevention of malignant ischemic ventricular arrhythmias.
Lynch
J J
JJ
Departments of Pharmacology, Laboratory Animal Medicine, Pharmaceutical Research and Development, and Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
Houle
M S
MS
Stump
G L
GL
Wallace
A A
AA
Gilberto
D B
DB
Jahansouz
H
H
Smith
G R
GR
Tebben
A J
AJ
Liverton
N J
NJ
Selnick
H G
HG
Claremon
D A
DA
Billman
G E
GE
D000081:Acetamides / Q000627:therapeutic use*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D001570:Benzodiazepinones / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004562:Electrocardiography; D006327:Heart Block / Q000628:therapy*; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy*; D013564:Sympathetic Nervous System / Q000502:physiology; D018754:Ventricular Dysfunction / Q000188:drug therapy* / Q000209:etiology
D000081:Acetamides; D000889:Anti-Arrhythmia Agents; D001570:Benzodiazepinones; C109598:L 768673