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(Circulation. 1999;100:1917-1922.)
© 1999 American Heart Association, Inc.

Basic Science Reports

Antiarrhythmic Efficacy of Selective Blockade of the Cardiac Slowly Activating Delayed Rectifier Current, I_Ks, in Canine Models of Malignant Ischemic Ventricular Arrhythmia

Joseph J. Lynch, Jr, PhD; Melanie S. Houle, MS; Gary L. Stump, BS; Audrey A. Wallace, BS; David B. Gilberto, DVM; Hossain Jahansouz, PhD; Garry R. Smith, BS; Andrew J. Tebben, MS; Nigel J. Liverton, PhD; Harold G. Selnick, PhD; David A. Claremon, PhD; George E. Billman, PhD

From the Departments of Pharmacology, Laboratory Animal Medicine, Pharmaceutical Research and Development, and Medicinal Chemistry, Merck Research Laboratories, West Point, Pa, and the Department of Physiology, The Ohio State University, Columbus.

Correspondence to Dr Joseph J. Lynch, Jr, WP46-300, Merck Research Laboratories, West Point, PA 19486.

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.

Key Words: antiarrhythmia agents • arrhythmia • myocardial infarction • fibrillation

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