Wang Y X, Zheng Y M, Zhou X B
Department of Pharmacology, Fourth Military Medical University, Xian, People's Republic of China.
Eur J Pharmacol. 1996 Dec 5;316(2-3):307-15. doi: 10.1016/s0014-2999(96)00663-2.
The effects of berberine on cardiac action potentials were measured in isolated guinea-pig papillary muscles exposed to hypoxia and cromakalim using the standard microelectrode technique. In addition, the patch clamp technique was used to determine the effects of berberine on cromakalim-induced outward currents in isolated ventricular myocytes and on ATP-sensitive K+ (KATP) channels in inside-out membrane patches. Berberine, at 3 microM significantly inhibited, while at 100 microM completely blocked the shortening of action potential duration and effective refractory period induced by hypoxia or cromakalim (100 microM). Under the whole-cell voltage clamp conditions, berberine (3-100 microM) attenuated or even abolished the cromakalim-elicited outward K+ currents. Berberine (3-100 microM) inhibited KATP channel activity in a concentration-dependent fashion in inside-out membrane patches exposed to 0.1 mM ATP. This inhibition appeared to be mainly due to a decrease in the open channel probability without affecting unitary conductance or the time constants for open and closed channel times. Glibenclamide (10 microM) partially blocked the hypoxia-evoked but fully reversed the cromakalim-evoked abbreviation of action potential duration and effective refractory period. Both the whole-cell outward K+ currents induced by cromakalim and the opening of single KATP channels induced by the low intracellular ATP concentration were also completely abolished by 10 microM glibenclamide. We conclude that berberine is a blocker of the cardiac KATP channel. The reported beneficial effect of berberine on ischemia-induced arrhythmias is likely attributed to its inhibition of KATP channel activation and subsequent shortening of action potential duration and effective refractory period during ischemia.
采用标准微电极技术，在暴露于缺氧环境并使用克罗卡林的豚鼠离体乳头肌中测量黄连素对心脏动作电位的影响。此外，采用膜片钳技术来确定黄连素对离体心室肌细胞中克罗卡林诱导的外向电流以及对内向外膜片中ATP敏感性钾（KATP）通道的影响。3微摩尔的黄连素显著抑制，而100微摩尔时则完全阻断由缺氧或克罗卡林（100微摩尔）诱导的动作电位时程缩短和有效不应期缩短。在全细胞电压钳制条件下，黄连素（3 - 100微摩尔）减弱甚至消除了克罗卡林引发的外向钾电流。在暴露于0.1毫摩尔ATP的内向外膜片中，黄连素（3 - 100微摩尔）以浓度依赖性方式抑制KATP通道活性。这种抑制似乎主要是由于开放通道概率降低，而不影响单位电导或通道开放和关闭时间的时间常数。格列本脲（10微摩尔）部分阻断缺氧诱发的，但完全逆转了克罗卡林诱发的动作电位时程和有效不应期缩短。10微摩尔的格列本脲也完全消除了克罗卡林诱导的全细胞外向钾电流以及低细胞内ATP浓度诱导的单个KATP通道开放。我们得出结论，黄连素是心脏KATP通道的阻滞剂。报道的黄连素对缺血性心律失常的有益作用可能归因于其对KATP通道激活的抑制以及随后在缺血期间动作电位时程和有效不应期的缩短。
