Cheng J, Niwa R, Kamiya K, Toyama J, Kodama I
School of Life Science and Medical Engineering, Tongji University, Shanghai, China.
Eur J Pharmacol. 1999 Jul 2;376(1-2):189-201. doi: 10.1016/s0014-2999(99)00368-4.
Carvedilol ((+/-)-1-(carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]am ino]-2-propanol), a beta-adrenoceptor-blocking agent with vasodilator properties, has been reported to produce dose-related improvements in left ventricular function and reduction in mortality in patients with chronic heart failure. However, its electrophysiological effects have not been elucidated. We studied ion channel and action potential modulation by carvedilol in rabbit ventricular preparations using whole-cell voltage-clamp and standard microelectrode techniques. In ventricular myocytes, carvedilol blocked the rapidly activating component of the delayed rectifier K+ current (I(Kr)) in a concentration-dependent manner (IC50 = 0.35 microM). This block was voltage- and time-independent; a prolongation of the depolarizing pulses from a holding potential of -50 mV to +10 mV within the range of 100-3000 ms did not affect the extent of I(Kr) block. Carvedilol also inhibited the L-type Ca2+ current (I(Ca)), the transient outward K+ current (I(to)) and the slowly activating component of the delayed rectifier K+ current (I(Ks)) with IC50 of 3.59, 3.34, and 12.54 microM, respectively. Carvedilol (0.3-30 microM) had no significant effects on the inward rectifier K+ current. In papillary muscles from rabbits pretreated with reserpine, action potential duration was prolonged by 7-12% with 1 microM and by 12-24% with 3 microM carvedilol at stimulation frequencies of 0.1-3.0 Hz. No further action potential duration prolongation was observed at concentrations higher than 3 microM. These results suggest that concomitant block of K+ and Ca2+ currents by carvedilol resulted in a moderate prolongation of action potential duration with minimal reverse frequency-dependence. Such electrophysiological effects of carvedilol would be beneficial in the treatment of ventricular tachyarrhythmias.
卡维地洛（(+/-)-1-(咔唑-4-基氧基)-3-[[2-(邻甲氧基苯氧基)乙基]氨基]-2-丙醇），一种具有血管舒张特性的β-肾上腺素受体阻滞剂，据报道可使慢性心力衰竭患者的左心室功能得到与剂量相关的改善，并降低死亡率。然而，其电生理效应尚未阐明。我们使用全细胞膜片钳和标准微电极技术，研究了卡维地洛对兔心室标本中离子通道和动作电位的调节作用。在心室肌细胞中，卡维地洛以浓度依赖性方式阻断延迟整流钾电流（I(Kr)）的快速激活成分（IC50 = 0.35 microM）。这种阻断与电压和时间无关；在100 - 3000毫秒范围内，将去极化脉冲从-50 mV的钳制电位延长至+10 mV，并不影响I(Kr)的阻断程度。卡维地洛还抑制L型钙电流（I(Ca)）、瞬时外向钾电流（I(to)）和延迟整流钾电流的缓慢激活成分（I(Ks)），IC50分别为3.59、3.34和12.54 microM。卡维地洛（0.3 - 30 microM）对内向整流钾电流无显著影响。在用利血平预处理的兔乳头肌中，在0.1 - 3.0 Hz的刺激频率下，1 microM卡维地洛可使动作电位时程延长7 - 12%，3 microM卡维地洛可使其延长12 - 24%。在高于3 microM的浓度下，未观察到动作电位时程进一步延长。这些结果表明，卡维地洛同时阻断钾电流和钙电流导致动作电位时程适度延长，且逆频率依赖性最小。卡维地洛的这种电生理效应在室性快速性心律失常的治疗中可能是有益的。
