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Electrical conduction along endothelial cell tubes from mouse feed arteries: confounding actions of glycyrrhetinic acid derivatives.

ABSTRACT: Electrical conduction along endothelium of resistance vessels has not been determined independently of the influence of smooth muscle, surrounding tissue or blood. Two interrelated hypotheses were tested: (i) Intercellular conduction of electrical signals is manifest in endothelial cell (EC) tubes; and (ii) Inhibitors of gap junction channels (GJCs) have confounding actions on EC electrical and Ca(2+) signalling.Intact EC tubes were isolated from abdominal muscle feed (superior epigastric) arteries of C57BL/6 mice. Hyperpolarization was initiated with indirect (ACh) and direct (NS309) stimulation of intermediate- and small-conductance Ca(2+) -activated K(+) channels (IK(Ca) /SK(Ca) ). Remote membrane potential (V(m) ) responses to intracellular current injection defined the length constant (?) for electrical conduction. Dye coupling was evaluated following intracellular microinjection of propidium iodide. Intracellular Ca(2+) dynamics were determined using Fura-2 photometry. Carbenoxolone (CBX) or ?-glycyrrhetinic acid (?GA) was used to investigate the role of GJCs.Steady-state V(m) of ECs was -25?mV. ACh and NS309 hyperpolarized ECs by -40 and -60?mV respectively. Electrical conduction decayed monoexponentially with distance (??1.4?mm). Propidium iodide injected into one EC spread into surrounding ECs. CBX or ?GA inhibited dye transfer, electrical conduction and EC hyperpolarization reversibly. Both agents elevated resting Ca(2+) while ?GA inhibited responses to ACh.Individual cells were effectively coupled to each other within EC tubes. Inhibiting GJCs with glycyrrhetinic acid derivatives blocked hyperpolarization mediated by IK(Ca) /SK(Ca) channels, regardless of Ca(2+) signalling, obviating use of these agents in distinguishing key determinants of electrical conduction along the endothelium.

SUBMITTER: Behringer EJ

PROVIDER: S-EPMC3417504 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Electrical conduction along endothelial cell tubes from mouse feed arteries: confounding actions of glycyrrhetinic acid derivatives.

Behringer Erik J EJ Socha Matthew J MJ Polo-Parada Luis L Segal Steven S SS

British journal of pharmacology 20120501 2

<h4>Background and purpose</h4>Electrical conduction along endothelium of resistance vessels has not been determined independently of the influence of smooth muscle, surrounding tissue or blood. Two interrelated hypotheses were tested: (i) Intercellular conduction of electrical signals is manifest in endothelial cell (EC) tubes; and (ii) Inhibitors of gap junction channels (GJCs) have confounding actions on EC electrical and Ca(2+) signalling.<h4>Experimental approach</h4>Intact EC tubes were is ...[more]

PMID: 22168386

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Project description: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 (?Vm ?-40 mV) with age. The length constant (?) 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.

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Electrical conduction along endothelial cell tubes from mouse feed arteries: confounding actions of glycyrrhetinic acid derivatives.

Publications

Electrical conduction along endothelial cell tubes from mouse feed arteries: confounding actions of glycyrrhetinic acid derivatives.

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