L-768673

The analysis of cardiac electrical restitution (the relationship between an action potential duration and its preceding diastolic interval) has been used to predict arrhythmia liability. However, the procedure to measure restitution is invasive and disrupts normal physiological autonomic balance. Dynamic analysis of sequential beat-to-beat ECG data was used to study restitution under normal sinus rhythm and to quantify changes in temporal hysteresis with heart rate acceleration/deceleration during QT prolongation. Congenital long QT (LQT) 1 and LQT2 syndromes during sympathetic stimulation were modeled because of their association with increased risk of ventricular arrhythmia. Temporal heterogeneity and hysteresis of restitution were examined in the conscious dog under varying conditions of delayed repolarization using either the selective inhibitors of the slowly activating delayed rectifier potassium current (R)-2-(4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide (L-768,673); the rapidly activating delayed rectifier potassium current (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methyl-sulfonylaminobenzoyl)-piperidine (E-4031); or a combination of both at rest and during heart rate acceleration with sympathetic stimulation using isoproterenol challenges. Impaired repolarization with the combination of E-4031 and L-768,673 increased heterogeneity of restitution at rest 55 to 91%, increased hysteresis during heart rate acceleration after isoproterenol challenge by approximately 40 to 60%, and dramatically reduced the minimum TQ interval by 72% to only 28 ms. Impaired repolarization alters restitution during normal sinus rhythm and increases hysteresis/heterogeneity during heart rate acceleration following sympathetic stimulation. Thus, dynamic beat-to-beat measurements of restitution could lead to clinically applicable ECG obtained biomarkers for assessment of changes associated with arrhythmogenic risk.

The slowly (I(Ks)) and rapidly (I(Kr)) activating delayed rectifier K(+) currents play important roles in cardiac ventricular repolarization. Compared with I(Kr), however, I(Ks) has important distinguishing characteristics, including beta-adrenergic receptor stimulation and accumulation at rapid rates that may impart significant therapeutic relevance. Therefore, development of selective I(Ks) inhibitors has been pursued as a strategy for providing potentially safer and more effective Class III antiarrhythmic agents and pharmacological tools for elucidating the normal physiological and potential pathological role of I(Ks) in cardiac repolarization. We have identified a series of 3-Acylamino-1,4 benzodiazepines that are very potent and selective inhibitors of I(Ks). A representative compound, L-768,673 (1) (IC(50)~8nM), has been extensively characterized for its pharmacologic activity. L-768,673 concentration-dependently prolongs action potential duration in a frequency-independent manner in vitro, but decreases transmural dispersion of refractoriness, a risk factor for arrhythmia induction. In conscious dogs, L 768,673 administered IV (0.3-100 micro g/kg) and PO (0.03-1 mg/kg) elicits consistent but limited (5-15%) QT(c) prolongation, and increases ventricular refractory period more at fast than at slow pacing rates, indicating a "forward" rate-dependence in vivo. In an anesthetized canine model of anterior myocardial infarction, I(Ks) blockers suppress the development of ischemic ventricular fibrillation at intravenous doses that minimally prolong the QT interval. I(Ks) blockers display an interesting and intriguing profile of effects on cardiac electrophysiologic parameters that differ in remarkable ways from other selective Class III agents such as I(Kr) blockers. It remains to be determined if these properties can be exploited clinically to provide more effective and safer treatment of cardiac arrhythmias.