Novel transient outward and ultra-rapid delayed rectifier current antagonist, AVE0118, protects against ventricular fibrillation induced by myocardial ischemia

被引:9
作者
Billman, George E. [1 ]
Kukielka, Monica [1 ]
机构
[1] Ohio State Univ, Dept Physiol & Cell Biol, Columbus, OH 43210 USA
关键词
ventricular fibrillation; myocardial ischemia; myocardial infarction; potassium channel antagonists; transient outward current; ultra-rapid delayed rectifier current;
D O I
10.1097/FJC.0b013e31816586bd
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
AVE0118 is a novel drug that blocks the transient outward current (I-to), the ultra rapid component of the delayed rectifier current (I-Kur), and the acetylcholine dependent potassium channel (I-Kach). The latter 2 channels are more abundant in atrial tissue. It is possible that AVE0118 could reduce regional differences in repolarization and thereby prevent malignant arrhythmias provoked by ischemia. To test this hypothesis, ventricular fibrillation was induced by a 2-minute occlusion of the left circumflex coronary artery during the last min of exercise in dogs with healed myocardial infarctions (n = 9). On a subsequent day, this exercise plus ischemia test was repeated after pretreatment with AVE0118 (1.0 mg/kg, W). AVE0118 did not change QTc (Van de Water's correction) interval [245 +/- 6.0 ms (control) versus 242 +/- 2.3 ms (AVE)] and attenuated the dispersion of repolarization as measured by the duration of the descending portion of the T wave (T-peak - T-end) induced by ischemia [ischemic changes: +11.1 (+/-) 2.4 ms (no drug) versus +2.2 +/- 3.7 ms (AVE)]. AVE0118 also significantly reduced the incidence of ventricular fibrillation, protecting 7 of 9 animals. Thus, AVE0118 abolished ischemically induced repolarization abnormalities and prevented malignant arrhythmias induced by ischemia without altering QTc interval.
引用
收藏
页码:352 / 358
页数:7
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