Aging impairs electrical conduction along endothelium of resistance arteries through enhanced Ca²⁺-activated K⁺ channel activation

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 (V_m) at site 2 (separation distance: 50-2000 μm). Across age groups, greatest differences were observed between Young and Old. Resting V_m 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 (ΔV _m ≈-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.