Aging Impairs Electrical Conduction Along Endothelium of Resistance Arteries Through Enhanced Ca2+-Activated K+ Channel Activation

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Abstract

Objective—

Intercellular conduction of electrical signals underlies spreading vasodilation of resistance arteries. Small- and intermediate-conductance Ca2+-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 Ca2+-activated K+ channels is altered with advancing age.

Approach and Results—

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 Ca2+-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 Ca2+-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.

Conclusions—

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.

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