Pu J, Boyden P A
Department of Pharmacology, Columbia University, New York, NY, USA.
Circ Res. 1997 Jul;81(1):110-9. doi: 10.1161/01.res.81.1.110.
Previously, we have shown abnormalities in Vmax and in the recovery of Vmax in myocytes dispersed from the epicardial border zone (EBZ) of the 5-day infarcted canine heart (myocytes from the EBZ [IZs]). Thus, we sought to determine the characteristics of the whole-cell Na+ current (INa) in IsZs and compare them with the INa of cells from noninfarcted hearts (myocytes from noninfarcted epicardium [NZs]). INa was recorded using patch-clamp techniques under conditions that eliminated contaminating currents and controlled INa for measurement (19 degrees C, 5 mmol/L [Na+]zero). Peak INa density (at -25 mV) was significantly reduced in IZs (4.9 +/- 0.44 pA/pF, n = 36) versus NZs (12.8 +/- 0.55 pA/pF, n = 54; P < .001), yet the half-maximal activation voltage (V0.5), time course of decay, and time to peak INa were no different. However, in IZs, V0.5 of the availability curve (I/Imax curve) was shifted significantly in the hyperpolarizing direction (-80.2 +/- 0.48 mV in NZs [n = 45] versus -83.9 +/- 0.59 mV in IZs [n = 27], P < .01). Inactivation of INa directly from a depolarized prepotential (-60 mV) was significantly accelerated in IZs versus NZs (fast and slow time constants [T1 and T2, respectively] were as follows: NZs [n = 28], T1 = 71.5 +/- 5.6 ms and T2 = 243.7 +/- 17.1 ms; IZs [n = 21], T1 = 36.3 +/- 2.4 ms and T2 = 153 +/- 11.3 ms; P < .001). Recovery of INa from inactivation was dependent on the holding potential (VH) in both cell types but was significantly slower in IZs. At (VH) = -90 mV, INa recovery had a lag in 18 (82%) of 22 IZs (with a 17.6 +/- 1.5-ms lag) versus 2 (9%) of 22 NZs (with 5.9- and 8.7-ms lags); at VH = -100 mV, T1 = 60.9 +/- 2.6 ms and T2 = 352.8 +/- 28.1 ms in NZs (n = 41) versus T1 = 76.3 +/- 4.8 ms and T2 = 464.4 +/- 47.2 ms in IZs (n = 26) (P < .002 and P < .03, respectively); at VH = -110 mV, T1 = 33.4 +/- 1.8 ms and T2 = 293.5 +/- 33.6 ms in NZs (n = 21) versus T1 = 44.3 +/- 2.9 ms and T2 = 388.4 +/- 38 ms in IZs (n = 18) (P < .002 and P < .07, respectively). In sum, INa is reduced, and its kinetics are altered in IZs. These changes may underlie the altered excitability and postrepolarization refractoriness of the ventricular fibers of the EBZ, thus contributing to reentrant arrhythmias in the infarcted heart.
此前，我们已证明，从梗死5天的犬心的心外膜边界区（EBZ）分离出的心肌细胞中，Vmax及Vmax的恢复存在异常（来自EBZ的心肌细胞[IZs]）。因此，我们试图确定IZs中全细胞钠电流（INa）的特征，并将其与未梗死心脏细胞（来自未梗死心外膜的心肌细胞[NZs]）的INa进行比较。在消除污染电流并控制INa以进行测量的条件下（19℃，细胞外[Na⁺]为5 mmol/L），使用膜片钳技术记录INa。与NZs（12.8±0.55 pA/pF，n = 54；P <.001）相比，IZs中峰值INa密度（在-25 mV时）显著降低（4.9±0.44 pA/pF，n = 36），但半数最大激活电压（V0.5）、衰减时间进程和INa达到峰值的时间并无差异。然而，在IZs中，可用性曲线（I/Imax曲线）的V0.5显著向超极化方向偏移（NZs中为-80.2±0.48 mV [n = 45]，IZs中为-83.9±0.59 mV [n = 27]，P <.01）。与NZs相比，IZs中从去极化预电位（-60 mV）直接开始的INa失活显著加速（快速和慢速时间常数[分别为T1和T2]如下：NZs [n = 28]，T1 = 71.5±5.6 ms，T2 = 243.7±17.1 ms；IZs [n = 21]，T1 = 36.3±2.4 ms，T2 = 153±11.3 ms；P <.001）。两种细胞类型中，INa从失活状态的恢复均取决于钳制电位（VH），但IZs中的恢复明显较慢。在VH = -90 mV时，22个IZs中有18个（82%）的INa恢复存在延迟（延迟17.6±1.5 ms），而22个NZs中只有2个（9%）存在延迟（延迟5.9 ms和8.7 ms）；在VH = -100 mV时，NZs（n = 41）的T1 = 60.9±2.6 ms，T2 = 352.8±28.1 ms，而IZs（n = 26）的T1 = 76.3±4.8 ms，T2 = 464.4±47.2 ms（分别为P <.002和P <. <.03）；在VH = -110 mV时，NZs（n = 21）的T1 = 33.4±1.8 ms，T2 = 293.5±33.6 ms，而IZs（n = 18）的T1 = 44.3±2.9 ms，T2 = 388.4±38 ms（分别为P <.002和P <.07）。总之，IZs中的INa减少，其动力学发生改变。这些变化可能是EBZ心室纤维兴奋性改变和复极后不应期改变的基础，从而导致梗死心脏中的折返性心律失常。
