Barrington P L, Ten Eick R E
Department of Pharmacology, Northwestern University, Chicago, Illinois.
J Pharmacol Exp Ther. 1990 Mar;252(3):1043-52.
Metoprolol is considered to be a class II antiarrhythmic agent that is highly specific for cardiac beta-1 adrenergic receptors, yet long-term administration can produce prolongation of the rate-corrected Q-T interval in humans. Action potentials and sodium (INa), "L"-type calcium (ICa) and transient outward (Ito) or inward rectifying potassium (IKl) currents were recorded from isolated cat ventricular myocytes using the whole-cell-patch technique to determine if metoprolol can directly affect cellular electrophysiological activity. External and pipette solutions, holding potentials and voltage-clamp protocols appropriate to isolate and examine INa, IKl, Ito and ICa were used. Metoprolol reversibly decreased both the duration and voltage of the action potential plateau but had no effect on upstroke velocity, the repolarization rate during phase 3 or the resting potential. Confirming previous reports suggesting that metoprolol appears to have little or no local anesthetic activity, INa was not affected by metoprolol at concentrations up to 100 microM during voltage-clamp pulses applied at less than 1 Hz when holding potential was negative to -110 mV. However, when trains of pulses to -10 mV from a holding potential of -110 mV were applied at 1 to 5 Hz, use-dependent inhibition of INa occurred, suggesting that 100 microM metoprolol may interact with inactivated Na channels to inhibit INa. Metoprolol (10 and 100 microM) also caused a concentration-dependent decrease in peak inward IKl elicited in response to hyperpolarizing from -40 mV to potentials negative to the IKl reversal potential. In addition, during strong hyperpolarizations (i.e., less than or equal to -150 mV) an inward (i.e., downward) droop in current was observed during the inactivation phase approximately 20 to 30 msec after pulse onset. Metoprolol (10 microM) also reduced peak Ito and ICa without altering the time courses of inactivation of either current or the level of the steady-state outward current elicited positive to -40 mV; steady-state ICa, on the other hand, was reduced. The sensitivity to block by metoprolol was: IKl greater than ICa greater than or equal to Ito greater than INa.
美托洛尔被认为是一种II类抗心律失常药物，对心脏β-1肾上腺素能受体具有高度特异性，但长期给药可导致人体心率校正后的Q-T间期延长。采用全细胞膜片钳技术，从分离的猫心室肌细胞记录动作电位以及钠（INa）、“L”型钙（ICa）和瞬时外向（Ito）或内向整流钾（IKl）电流，以确定美托洛尔是否能直接影响细胞电生理活动。使用了适合分离和检测INa、IKl、Ito和ICa的细胞外液和微管内液、钳制电位和电压钳制方案。美托洛尔可逆地降低动作电位平台期的持续时间和电压，但对去极化速度、第3期复极化速率或静息电位无影响。先前的报道表明美托洛尔似乎几乎没有或没有局部麻醉活性，在钳制电位为负至-110 mV、以小于1 Hz施加电压钳制脉冲时，浓度高达100 μM的美托洛尔对INa没有影响。然而，当从-110 mV的钳制电位以1至5 Hz施加到-10 mV的脉冲序列时，出现了对INa的使用依赖性抑制，表明100 μM美托洛尔可能与失活的钠通道相互作用以抑制INa。美托洛尔（10和100 μM）还导致响应于从-40 mV超极化到IKl反转电位负值时引发的内向IKl峰值浓度依赖性降低。此外，在强超极化期间（即小于或等于-150 mV），在脉冲开始后约20至30毫秒的失活期内观察到电流内向（即向下）衰减。美托洛尔（10 μM）还降低了Ito和ICa峰值，而不改变任一电流的失活时间进程或在-40 mV正向引发的稳态外向电流水平；另一方面，稳态ICa降低。美托洛尔阻断的敏感性为：IKl＞ICa≥Ito＞INa。
