Dun Wen, Baba Shigeo, Yagi Takuya, Boyden Penelope A
Department of Pharmacology, Center of Molecular Therapeutics, Columbia University, New York, New York 10032, USA.
Am J Physiol Heart Circ Physiol. 2004 Sep;287(3):H1046-54. doi: 10.1152/ajpheart.00082.2004. Epub 2004 Apr 15.
Action potentials (APs) of the epicardial border zone (EBZ) cells from the day 5 infarcted heart continue to be altered by day 14 postocclusion, namely, they shortened. However, by 2 mo, EBZ APs appear "normal," yet conduction of wave fronts remains abnormal. We hypothesize that the changes in transmembrane APs are due to a change in the distribution of ion channels in either density or function. Thus we focused on the changes in Ca2+ and K+ currents in cells isolated from the 14-day (IZ14d) and 2-mo (IZ2m) EBZ and compared them with those occurring in cells from the same hearts but remote (Rem) from the EBZ. Whole cell voltage-clamp techniques were used to measure and compare Ca2+ and K+ currents in cells from the different groups. Ca2+ current densities remain reduced in cells of the 14-day and 2-mo infarcted heart and the kinetic changes previously identified in the 5-day heart begin to, but do not recover to, cells from noninfarcted epicardium (NZ) values. Importantly, I(Ca,L) in both the EBZ and Rem regions still show a slowed recovery from inactivation. Furthermore, during the remodeling process, there is an increased expression of T-type Ca2+ currents, but only regionally, and only within a specific time window postmyocardial infarction (MI). Regional heterogeneity in beta-adrenergic responsiveness of I(Ca,L) exists between EBZ and remote cells of the 14-day hearts, but this regional heterogeneity is gone in the healed infarcted heart. In IZ14d, the transient outward K+ current (Ito) begins to reemerge and is accompanied by an upregulated tetraethylammonium-sensitive outward current. By 2-mo postocclusion, Ito and sustained outward K+ current have completed the reverse remodeling process. During the healing process post-MI, canine epicardial cells downregulate the fast Ito but compensate by upregulating a K+ current that in normal cells is minimally functional. For recovering I(Ca,L) of the 14-day and 2-mo EBZ cells, voltage-dependent processes appear to be reset, such that I(Ca,L) "window" current occurs at hyperpolarized potentials. Thus dynamic changes in both Ca2+ and K+ currents contribute to the altered AP observed in 14-day fibers and may account for return of APs of 2 mo EBZ fibers.
在第5天梗死心脏的心外膜边界区（EBZ）细胞的动作电位（APs）在闭塞后第14天仍持续改变，即它们缩短了。然而，到2个月时，EBZ的APs看起来“正常”，但波前传导仍然异常。我们推测跨膜APs的变化是由于离子通道在密度或功能上的分布变化所致。因此，我们聚焦于从第14天（IZ14d）和2个月（IZ2m）的EBZ分离的细胞中Ca2+和K+电流的变化，并将它们与来自同一心脏但远离EBZ（Rem）的细胞中的变化进行比较。采用全细胞电压钳技术来测量和比较不同组细胞中的Ca2+和K+电流。在第14天和2个月梗死心脏的细胞中，Ca2+电流密度仍然降低，并且先前在第5天心脏中确定的动力学变化开始出现，但并未恢复到非梗死心外膜（NZ）细胞的值。重要的是，EBZ和Rem区域中的I（Ca，L）从失活状态恢复仍然缓慢。此外，在重塑过程中，T型Ca2+电流的表达增加，但仅在局部，且仅在心肌梗死（MI）后的特定时间窗口内。在第14天心脏的EBZ和远离区域的细胞之间，I（Ca，L）的β-肾上腺素能反应性存在区域异质性，但在愈合的梗死心脏中这种区域异质性消失了。在IZ14d中，瞬时外向K+电流（Ito）开始重新出现，并伴有上调的四乙铵敏感外向电流。到闭塞后2个月时，Ito和持续外向K+电流已经完成了反向重塑过程。在MI后的愈合过程中，犬心外膜细胞下调快速Ito，但通过上调在正常细胞中功能最小的K+电流来进行补偿。对于第14天和2个月的EBZ细胞中I（Ca，L）的恢复，电压依赖性过程似乎被重置，使得I（Ca，L）“窗口电流”出现在超极化电位。因此，Ca2+和K+电流的动态变化导致了在第14天纤维中观察到的AP改变，并可能解释了2个月EBZ纤维中AP的恢复。
