title: Aging impairs electrical conduction along endothelium of resistance arteries through enhanced Ca2+-activated K+ channel activation.
abstract: OBJECTIVE
  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.
  
  
  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 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.
  
  
  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.
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA.
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Behringer
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Shaw
authors.forename: Erika B
authors.initials: EB
authors.lastname: Westcott
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Socha
authors.forename: Steven S
authors.initials: SS
authors.lastname: Segal
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000375:Aging / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001030:Apamin / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D004553:Electric Conductivity; D004558:Electric Stimulation; D004730:Endothelium, Vascular / Q000502:physiology*; D019074:Epigastric Arteries / Q000502:physiology*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009498:Neurotoxins / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000502:physiology; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D009498:Neurotoxins; D016877:Oxidants; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; D018999:Charybdotoxin; D001030:Apamin; D006861:Hydrogen Peroxide; D002374:Catalase; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D000109:Acetylcholine
keywords: endothelial cells; ion channels; oxidative stress