Pacher P, Magyar J, Szigligeti P, Bányász T, Pankucsi C, Korom Z, Ungvári Z, Kecskeméti V, Nánási P P
Department of Pharmacology, Semmelweis University of Medicine, Budapest, Hungary.
Naunyn Schmiedebergs Arch Pharmacol. 2000 Jan;361(1):67-73. doi: 10.1007/s002109900154.
Fluoxetine is a widely used antidepressant compound having selective serotonin reuptake inhibitor properties. In this study, the actions of fluoxetine were analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac preparations using conventional microelectrode and whole cell voltage clamp techniques. Low concentrations of fluoxetine (1-10 micromol/l) caused significant shortening of action potential duration (APD) and depression of the plateau potential in guinea pig and rabbit papillary muscles and single canine ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine (up to 100 micromol/l), however, the drug decreased the force of contraction with EC50 of 10 micromol/l. Fluoxetine (10 micromol/l) also decreased the maximum velocity of depolarization and action potential overshoot in each species studied. At this concentration no effect was observed on the resting membrane potential; high concentration (100 micromol/l), however, caused depolarization. In voltage clamped canine ventricular myocytes, fluoxetine caused concentration-dependent block of the peak Ca2+ current at 0 mV with EC50 of 5.4+/-0.94 micromol/l and Hill coefficient of 1.1+/-0.14 (n=6). In addition, 10 micromol/l fluoxetine shifted the midpoint of the steady-state inactivation curve of the Ca2+ current from -20.7+/-0.65 to -26.7+/-1 mV (P<0.001, n=8) without changing its slope factor. These effects of fluoxetine developed rapidly and were fully reversible. Fluoxetine did not alter voltage-dependence of activation or time constant for inactivation of I(Ca). Fluoxetine had no effect on the amplitude of K+ currents (I(K1) and I(to)). The inhibition of cardiac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side effects observed occasionally with the drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV type), as well as proarrhythmic properties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Therefore, in depressed patients with cardiac disorders, ECG control may be suggested during fluoxetine therapy.
氟西汀是一种广泛使用的具有选择性5-羟色胺再摄取抑制剂特性的抗抑郁化合物。在本研究中，运用传统微电极和全细胞电压钳技术，对豚鼠、大鼠、兔和犬的心室肌制备物中氟西汀的作用进行了分析。低浓度的氟西汀（1 - 10微摩尔/升）可使豚鼠和兔乳头肌以及单个犬心室肌细胞的动作电位时程（APD）显著缩短，并使平台期电位降低。在大鼠乳头肌中，氟西汀（高达100微摩尔/升）对APD无影响，然而，该药物使收缩力降低，其半数有效浓度（EC50）为10微摩尔/升。氟西汀（10微摩尔/升）还降低了所研究的每个物种的最大去极化速度和动作电位超射值。在此浓度下，未观察到对静息膜电位的影响；然而，高浓度（100微摩尔/升）会导致导致。在电压钳制的犬心室肌细胞中，氟西汀在0 mV时引起峰值Ca2+电流的浓度依赖性阻滞，其EC50为5.4±0.94微摩尔/升，希尔系数为1.1±0.14（n = 6）。此外，10微摩尔/升的氟西汀使Ca2+电流稳态失活曲线的中点从 - 20.7±0.65移至 - 26.7±1 mV（P < 0.001，n = 8），而不改变其斜率因子。氟西汀的这些作用迅速产生且完全可逆。氟西汀未改变I(Ca)激活的电压依赖性或失活的时间常数。氟西汀对K+电流（I(K1)和I(to)）的幅度无影响。氟西汀对心脏Ca2+和Na+通道的抑制作用可能解释了该药物偶尔观察到的大多数心脏副作用。我们的结果表明，氟西汀可能具有抗心律失常（I类 + IV类）以及促心律失常特性（由于房室或室内传导受损和复极化缩短）。因此，对于患有心脏疾病的抑郁症患者，在氟西汀治疗期间可能建议进行心电图监测。 引起去极化。
