Banyasz Tamas, Jian Zhong, Horvath Balazs, Khabbaz Shaden, Izu Leighton T, Chen-Izu Ye
Department of Pharmacology, University of California, 2221 Tupper Hall, 451 Health Science Drive, Davis, CA, 95616, USA.
Pflugers Arch. 2014 Nov;466(11):2067-76. doi: 10.1007/s00424-014-1465-7. Epub 2014 Feb 19.
β-Adrenergic stimulation differentially modulates different K(+) channels and thus fine-tunes cardiac action potential (AP) repolarization. However, it remains unclear how the proportion of I Ks, I Kr, and I K1 currents in the same cell would be altered by β-adrenergic stimulation, which would change the relative contribution of individual K(+) current to the total repolarization reserve. In this study, we used an innovative AP-clamp sequential dissection technique to directly record the dynamic I Ks, I Kr, and I K1 currents during the AP in guinea pig ventricular myocytes under physiologically relevant conditions. Our data provide quantitative measures of the magnitude and time course of I Ks, I Kr, and I K1 currents in the same cell under its own steady-state AP, in a physiological milieu, and with preserved Ca(2+) homeostasis. We found that isoproterenol treatment significantly enhanced I Ks, moderately increased I K1, but slightly decreased I Kr in a dose-dependent manner. The dominance pattern of the K(+) currents was I Kr > I K1 > I Ks at the control condition, but reversed to I Kr < I K1 < I Ks following β-adrenergic stimulation. We systematically determined the changes in the relative contribution of I Ks, I Kr, and I K1 to cardiac repolarization during AP at different adrenergic states. In conclusion, the β-adrenergic stimulation fine-tunes the cardiac AP morphology by shifting the power of different K(+) currents in a dose-dependent manner. This knowledge is important for designing antiarrhythmic drug strategies to treat hearts exposed to various sympathetic tones.
β-肾上腺素能刺激以不同方式调节不同的钾离子通道，从而精确调节心脏动作电位（AP）的复极化。然而，尚不清楚同一细胞中I Ks、I Kr和I K1电流的比例会如何因β-肾上腺素能刺激而改变，这会改变单个钾离子电流对总复极化储备的相对贡献。在本研究中，我们使用了一种创新的动作电位钳位顺序剖析技术，在生理相关条件下直接记录豚鼠心室肌细胞动作电位期间的动态I Ks、I Kr和I K1电流。我们的数据提供了在同一细胞自身的稳态动作电位下、在生理环境中且钙稳态得以保留的情况下，I Ks、I Kr和I K1电流的大小和时间进程的定量测量。我们发现，异丙肾上腺素处理以剂量依赖的方式显著增强I Ks，适度增加I K1，但略微降低I Kr。在对照条件下，钾离子电流的主导模式为I Kr＞I K1＞I Ks，但在β-肾上腺素能刺激后则逆转至I Kr＜I K1＜I Ks。我们系统地确定了在不同肾上腺素能状态下，动作电位期间I Ks、I Kr和I K1对心脏复极化的相对贡献的变化。总之，β-肾上腺素能刺激通过以剂量依赖的方式改变不同钾离子电流的作用来精确调节心脏动作电位形态。这一知识对于设计抗心律失常药物策略以治疗处于各种交感神经张力状态的心脏具有重要意义。
