THE EFFECTS OF THE ATP-DEPENDENT POTASSIUM CHANNEL ANTAGONIST, GLYBURIDE, ON CORONARY BLOOD-FLOW AND SUSCEPTIBILITY TO VENTRICULAR-FIBRILLATION IN UNANESTHETIZED DOGS
THE EFFECTS OF THE ATP-DEPENDENT POTASSIUM CHANNEL ANTAGONIST, GLYBURIDE, ON CORONARY BLOOD-FLOW AND SUSCEPTIBILITY TO VENTRICULAR-FIBRILLATION IN UNANESTHETIZED DOGS
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DOI：
10.1097/00005344-199302000-00003
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发表时间：
1993-02-01
影响因子：
3
通讯作者：
BURROUGHS, JM
中科院分区：
文献类型：
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作者：
BILLMAN, GE;AVENDANO, CE;BURROUGHS, JM
细胞外钾在心肌缺血期间迅速增加，并与心室颤动（VF）的发展有关。最近的证据表明，缺血引起的钾外排是由atp依赖性钾通道的打开引起的。如果细胞外钾的积累有助于室性心律失常，那么可以预测阻断atp依赖性钾通道的药物应该可以预防这些心律失常。因此，15只心肌梗死愈合的杂种狗在运动过程中冠脉阻断2分钟诱导VF。这种练习（Ex）加缺血试验在每次对照（载药）期间都一致诱导VF。然而，格列本脲，一种选择性阻断atp依赖性钾通道的磺脲类药物，在15只实验动物中有13只动物预防了VF （p < 0.001, chi2）。格列本脲(G)在运动前和运动中均显著降低左心室dP/dt(max)（对照组，5,031 +/- 386.4；G, 3,286 +/- 116.6 mm Hg/s）和平均冠状动脉血流量（对照组，49.6 +/- 8.7；G, 31.3 +/- 5.5 ml/min）。运动和冠状动脉闭塞的心率反应也降低了。由于心率降低可能有助于心脏保护，在心室起搏保持心率不变的情况下，重复运动加缺血试验。格列伯里德在这种情况下仍然保护了五分之四的动物。这些数据表明格列本脲，一种阻断atp依赖性钾通道的药物，可以独立于心率的变化来预防室性心动过速。这些数据进一步表明，这些通道可能有助于运动期间代谢需求增加引起的冠状动脉血管舒张。
Extracellular potassium rapidly increases during myocardial ischemia and has been implicated in the development of ventricular fibrillation (VF). Recent evidence suggests that ischemically induced potassium efflux results from the opening of ATP-dependent potassium channels. If extracellular potassium accumulation contributes to VF, one would predict that drugs that block the ATP-dependent potassium channels should protect against these arrhythmias. Therefore, VF was induced in 15 mongrel dogs with healed myocardial infarctions by a 2-min coronary occlusion during exercise. This exercise (Ex) plus ischemia test consistently induced VF during each control (vehicle) presentation. However, glyburide, a sulfonylurea drug that selectively blocks the ATP-dependent potassium channel, prevented VF in 13 of 15 animals tested (p < 0.001, chi2). Glyburide (G) elicited significant reductions in left ventricular dP/dt(max) (Ex: control, 5,031 +/- 386.4; G, 3,286 +/- 116.6 mm Hg/s) and mean coronary blood flow (Ex: control, 49.6 +/- 8.7; G, 31.3 +/- 5.5 ml/min) both before and during exercise. The heart rate responses to exercise and coronary occlusion were also reduced. Since heart rate reductions could contribute to the cardioprotection, the exercise plus ischemia test was repeated with the heart rate held constant by ventricular pacing. Glyburide still protected four of five animals under these conditions. These data indicate that glyburide, a drug that blocks the ATP-dependent potassium channels, can prevent VF independently of changes in the heart rate. The data further suggest that these channels may contribute to the coronary vasodilation elicited by an increase in metabolic demand during exercise.