Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.
Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1892-901. doi: 10.1161/ATVBAHA.113.301514. Epub 2013 May 30.
Intercellular conduction of electrical signals underlies spreading vasodilation of resistance arteries. Small- and intermediate-conductance Ca(2+)-activated K(+) channels of endothelial cells serve a dual function by initiating hyperpolarization and modulating electrical conduction. We tested the hypothesis that regulation of electrical signaling by small- and intermediate-conductance Ca(2+)-activated K(+) channels is altered with advancing age.
Intact endothelial tubes (60 µm wide; 1-3 mm long) were freshly isolated from male C57BL/6 mouse (Young: 4-6 months; Intermediate: 12-14 months; Old: 24-26 months) superior epigastric arteries. Using dual intracellular microelectrodes, current was injected (± 0.1-3 nA) at site 1 while recording membrane potential (Vm) at site 2 (separation distance: 50-2000 µm). Across age groups, greatest differences were observed between Young and Old. Resting Vm in Old (-38 ± 1 mV) was more negative (P<0.05) than Young (-30 ± 1 mV). Maximal hyperpolarization to both direct (NS309) and indirect (acetylcholine) activation of small- and intermediate-conductance Ca(2+)-activated K(+) channels was sustained (ΔVm ≈-40 mV) with age. The length constant (λ) for electrical conduction was reduced (P<0.05) from 1630 ± 80 µm (Young) to 1320 ± 80 µm (Old). Inhibiting small- and intermediate-conductance Ca(2+)-activated K(+) channels with apamin+charybdotoxin or scavenging hydrogen peroxide (H2O2) with catalase improved electrical conduction (P<0.05) in Old. Exogenous H2O2 (200 µmol/L) in Young evoked hyperpolarization and impaired electrical conduction; these effects were blocked by apamin+charybdotoxin.
Enhanced current loss through Ca2+-activated K+ channel activation impairs electrical conduction along the endothelium of resistance arteries with aging. Attenuating the spatial domain of electrical signaling will restrict the spread of vasodilation and thereby contribute to blood flow limitations associated with advanced age.
细胞间电信号的传导是阻力血管扩张的基础。内皮细胞的小电导和中等电导钙激活钾通道具有双重功能，既能引发超极化，又能调节电传导。我们假设，小电导和中等电导钙激活钾通道对电信号的调节会随着年龄的增长而改变。
从雄性 C57BL/6 小鼠（年轻组：4-6 个月；中年组：12-14 个月；老年组：24-26 个月）的上腹动脉中分离出完整的内皮管（60µm 宽；1-3mm 长）。使用双细胞内微电极，在部位 1 注入电流（±0.1-3nA），同时在部位 2 记录膜电位（Vm）（分离距离：50-2000µm）。在不同年龄组中，年轻组和老年组之间的差异最大。老年组的静息 Vm（-38±1mV）比年轻组（-30±1mV）更负（P<0.05）。直接（NS309）和间接（乙酰胆碱）激活小电导和中等电导钙激活钾通道引起的最大超极化随年龄的增长而持续（ΔVm≈-40mV）。电传导的长度常数（λ）从年轻组的 1630±80µm 降低到老年组的 1320±80µm（P<0.05）。用阿帕米+糜蛋白酶抑制小电导和中等电导钙激活钾通道，或用过氧化氢酶清除过氧化氢（H2O2），均可改善老年组的电传导（P<0.05）。在年轻组中，外源性 H2O2（200µmol/L）引起超极化并损害电传导；这些作用被阿帕米+糜蛋白酶阻断。
随着年龄的增长，通过钙激活钾通道激活导致电流损耗增加，从而损害阻力血管内皮的电传导。电信号空间域的衰减将限制血管扩张的传播，从而导致与年龄相关的血流限制。
