Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, I(Ks), in canine models of malignant ischemic ventricular arrhythmia.

Abstract

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.

• Authors: J J Lynch Jr, M S Houle, G L Stump, A A Wallace, D B Gilberto, H Jahansouz, G R Smith, A J Tebben, N J Liverton, H G Selnick, D A Claremon, G E Billman
• Journal: Circulation (Circulation) Vol. 100 Issue 18 Pg. 1917-22 (Nov 02 1999) ISSN: 1524-4539 [Electronic] United States
• PMID: 10545437 (Publication Type: Journal Article)

Chemical References

• Acetamides
• Anti-Arrhythmia Agents
• Benzodiazepinones
• L 768673

Topics

• Acetamides (therapeutic use)
• Animals
• Anti-Arrhythmia Agents (therapeutic use)
• Arrhythmias, Cardiac (drug therapy, etiology)
• Benzodiazepinones (therapeutic use)
• Disease Models, Animal
• Dogs
• Electrocardiography
• Heart Block (therapy)
• Myocardial Ischemia (complications, drug therapy)
• Sympathetic Nervous System (physiology)
• Ventricular Dysfunction (drug therapy, etiology)