Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, IKs, 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. Methods and 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.