K+ currents underlying the action of endothelium-derived hyperpolarizing factor in guinea-pig, rat and human blood vessels

J Physiol. 2001 Mar 1;531(Pt 2):359-73. doi: 10.1111/j.1469-7793.2001.0359i.x.


Membrane currents attributed to endothelium-derived hyperpolarizing factor (EDHF) were recorded in short segments of submucosal arterioles of guinea-pigs using single microelectrode voltage clamp. The functional responses of arterioles and human subcutaneous, rat hepatic and guinea-pig coronary arteries were also assessed as changes in membrane potential recorded simultaneously with contractile activity. The current-voltage (I-V) relationship for the conductance due to EDHF displayed outward rectification with little voltage dependence. Components of the current were blocked by charybdotoxin (30-60 nM) and apamin (0.25-0.50 microM), which also blocked hyperpolarization and prevented EDHF-induced relaxation. The EDHF-induced current was insensitive to Ba2+ (20-100 microM) and/or ouabain (1 microM to 1 mM). In human subcutaneous arteries and guinea-pig coronary arteries and submucosal arterioles, the EDHF-induced responses were insensitive to Ba2+ and/or ouabain. Increasing [K+]o to 11-21 mM evoked depolarization under conditions in which EDHF evoked hyperpolarization. Responses to ACh, sympathetic nerve stimulation and action potentials were indistinguishable between dye-labelled smooth muscle and endothelial cells in arterioles. Action potentials in identified endothelial cells were always associated with constriction of the arterioles. 18beta-Glycyrrhetinic acid (30 microM) and carbenoxolone (100 microM) depolarized endothelial cells by 31 +/- 6 mV (n = 7 animals) and 33 +/- 4 mV (n = 5), respectively, inhibited action potentials in smooth muscle and endothelial cells and reduced the ACh-induced hyperpolarization of endothelial cells by 56 and 58 %, respectively. Thus, activation of outwardly rectifying K+ channels underlies the hyperpolarization and relaxation due to EDHF. These channels have properties similar to those of intermediate conductance (IKCa) and small conductance (SKCa) Ca2+-activated K+ channels. Strong electrical coupling between endothelial and smooth muscle cells implies that these two layers function as a single electrical syncytium. The non-specific effects of glycyrrhetinic acid precludes its use as an indicator of the involvement of gap junctions in EDHF-attributed responses. These conclusions are likely to apply to a variety of blood vessels including those of humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arteries / metabolism*
  • Arterioles / metabolism
  • Barium / pharmacology
  • Biological Factors / physiology*
  • Coronary Vessels / metabolism
  • Electric Conductivity
  • Electrophysiology
  • Endothelium, Vascular / physiology
  • Female
  • Glycyrrhetinic Acid / pharmacology
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Male
  • Muscle, Smooth, Vascular / physiology
  • Ouabain / pharmacology
  • Potassium Channels / physiology*
  • Potassium Chloride / pharmacology
  • Rats


  • Biological Factors
  • Potassium Channels
  • endothelium-dependent hyperpolarization factor
  • Barium
  • Ouabain
  • Potassium Chloride
  • Glycyrrhetinic Acid