Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, IKs, in canine models of malignant ischemic ventricular arrhythmia
Antiarrhythmic efficacy of selective blockade of the cardiac slowly activating delayed rectifier current, IKs, in canine models of malignant ischemic ventricular arrhythmia
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DOI：
10.1161/01.cir.100.18.1917
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发表时间：
1999-11-02
期刊：
影响因子：
37.8
通讯作者：
Billman, GE
中科院分区：
文献类型：
--
作者：
Lynch, JJ;Houle, MS;Billman, GE
背景-到目前为止，缺乏有效的和选择性的抑制剂阻碍了对心脏缓慢激活延迟整流电流（I-Ks）调节的生理学评估。本研究使用I-Ks阻断剂L-768，673，代表了选择性I-Ks阻断的心脏电生理和抗心律失常作用的首次体内评估。（8.5 +/- 0.4天）前壁心肌梗死，0.003 - 0.03 mg/kg L-768，673 IV显著抑制电诱导的室性快速性心律失常，并降低急性血栓诱导的后外侧心肌缺血引起的致死性心律失常的发生率，L-768，673提供的抗心律失常保护伴随着非梗死区心室有效不应期适度增加7%至10%，梗死区心室有效不应期增加3%至5%，QTc间期增加4%至6%。（3 - 4周）前壁心肌梗死，次极量运动期间左回旋支冠状动脉短暂闭塞引起室颤，0.03 mg/kg L-768，673 IV预处理引起QTc适度增加7%，预防室颤的6只动物中的5只，并抑制心律失常的2个额外的animals. Conclusions目前的研究结果表明，选择性阻断I-Ks可能是一个潜在的有用的干预措施，用于预防恶性缺血性室性心律失常。
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.