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首页> 外文期刊>British Journal of Pharmacology >Electrocardiographic interactions between pinacidil, a potassium channel opener and class I antiarrhythmic agents in guinea-pig isolated perfused heart
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Electrocardiographic interactions between pinacidil, a potassium channel opener and class I antiarrhythmic agents in guinea-pig isolated perfused heart

机译：吡那地尔，钾通道开放剂和豚鼠离体灌注心脏中的I类抗心律不齐药物之间的心电图相互作用

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1. Drugs that shorten action potential duration could decrease the Na-channel blocking effect of class I antiarrhythmic agents by reducing the availability of Na channel in the inactivated state. 2. This hypothesis was tested in guinea-pig perfused heart, measuring the surface ECG effects of three class I drugs endowed with different binding kinetics (15 μM mexiletine, 10 μM quinidine and 3 μM flecainide) in the presence of increasing concentrations of pinacidil (10 μM, 30 μM, 50 μm), a potassium channel opener that shortens action potential duration. 3. The ECG parameters measured were: the QRS interval, i.e. the intraventricular conduction time; the JT interval, which reflects the duration of ventricular repolarization; the ratio between JTpeak (the time from the end of QRS and the peak of T wave) and JT interval, which quantifies changes in the morphology of the T wave. 4. At the concentrations tested all the antiarrhythmic drugs widened the QRS complex by 55-60%. Flecainide did not significantly change JT interval, but quinidine prolonged and mexiletine shortened it. Mexiletine also decreased the JTpeak/JT ratio. Pinacidil by itself decreased the JT interval and the JT peak/JT ratio in a dose-dependent way, but did not affect QRS duration. 5. In the presence of fixed antiarrhythmic drug concentrations, however, pinacidil decreased the QRS prolongation induced by mexiletine (-17%) and quinidine (-8%), but not that induced by flecainide: this effect was already maximal at the lower concentration tested (10 μm) and there was no relationship between pinacidil-induced JT shortening and QRS changes. To explain this unexpected result it has been supposed that, at the driving frequency used (4 Hz), myocardial cells were partially depolarized and that pinacidil could repolarize them, thus decreasing the number of inactivated Na channels and the effects of drugs that (mainly or partly) block the channels in the inactivated state. In agreement with this hypothesis, an additional series of experiments carried out with 15 μM mexiletine at a lower stimulation rate (2 Hz) showed only a negligible loss of QRS effect (-2.3%) at any pinacidil concentration. 6. Flecainide, but not quinidine and mexiletine, antagonized the JT shortening induced by pinacidil; furthermore, no drug modified the JTp/JT decrease induced by pinacidil. 7. These results indicate that: (a) an antagonism between class I antiarrhythmic drugs and pinacidil is possible; (b) mexiletine is the most involved among the drugs tested; (c) the interaction is not related to pinacidil-induced repolarization shortening, but probably to changes in membrane resting potential. The possible clinical implications need to be defined.
机译：1.缩短动作电位持续时间的药物可能会通过降低灭活状态下的Na通道利用率来降低I类抗心律不齐药物的Na通道阻滞作用。 2.此假设在豚鼠灌注心脏中进行了测试，测量了在浓度不断增加的吡那地尔（ 10μM，30μM，50μm），钾通道开放剂可缩短动作电位持续时间。 3.测得的ECG参数为：QRS间隔，即心室内传导时间； JT间隔，反映了心室复极的持续时间； JTpeak（从QRS结束到T波的峰值的时间）与JT间隔之间的比率，量化了T波形态的变化。 4.在所测试的浓度下，所有抗心律不齐药物均使QRS络合物增宽55-60％。氟卡尼特没有显着改变JT间隔，但奎尼丁延长了，美西律缩短了它。美西律汀还降低了JTpeak / JT比。吡那地尔本身以剂量依赖的方式降低了JT间隔和JT峰/ JT比，但不影响QRS持续时间。 5.然而，在存在固定的抗心律不齐药物浓度的情况下，吡那地尔降低了美西律（-17％）和奎尼丁（-8％）诱导的QRS延长，但未由氟卡尼引起的QRS延长：在较低浓度下这种作用已达到最大测试（10μm），并且吡那地尔诱导的JT缩短与QRS变化之间没有关系。为了解释这种意外结果，可以认为在所用的驱动频率（4 Hz）下，心肌细胞被部分去极化，而吡那地尔可以使它们重新极化，从而减少了失活的Na通道的数量以及药物（主要是部分地）在非激活状态下阻塞通道。与此假设相符，在较低的刺激速率（2 Hz）下用15μM美西律进行的另一系列实验显示，在任何吡那地尔浓度下，QRS效应的损失均很小（-2.3％）。 6.氟卡尼，但不抑制奎尼丁和美西律，拮抗吡那地尔引起的JT缩短。此外，没有药物改变吡那地尔诱导的JTp / JT降低。 7.这些结果表明：（a）可能在I类抗心律不齐药物与吡那地尔之间产生拮抗作用； （b）美西律汀是所测试药物中涉及最多的药物； （c）相互作用与吡那地尔引起的复极缩短无关，但可能与膜静息电位的改变有关。需要定义可能的临床意义。

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