Endothelium-dependent cerebral artery dilation mediated by TRPA1 and Ca2+-Activated K+ channels

Circ Res. 2009 Apr 24;104(8):987-94. doi: 10.1161/CIRCRESAHA.108.189530. Epub 2009 Mar 19.


Although it is well established that changes in endothelial intracellular [Ca(2+)] regulate endothelium-dependent vasodilatory pathways, the molecular identities of the ion channels responsible for Ca(2+) influx in these cells are not clearly defined. The sole member of the ankyrin (A) transient receptor potential (TRP) subfamily, TRPA1, is a Ca(2+)-permeable nonselective cation channel activated by electrophilic compounds such as acrolein (tear gas), allicin (garlic), and allyl isothiocyanate (AITC) (mustard oil). The present study examines the hypothesis that Ca(2+) influx via TRPA1 causes endothelium-dependent vasodilation. The effects of TRPA1 activity on vascular tone were examined using isolated, pressurized cerebral arteries. AITC induced concentration-dependent dilation of pressurized vessels with myogenic tone that was accompanied by a corresponding decrease in smooth muscle intracellular [Ca(2+)]. AITC-induced dilation was attenuated by disruption of the endothelium and when the TRPA1 channel blocker HC-030031 was present in the arterial lumen. TRPA1 channels were found to be present in native endothelial cells, localized to endothelial cell membrane projections proximal to vascular smooth muscle cells. AITC-induced dilation was insensitive to nitric oxide synthase or cyclooxygenase inhibition but was blocked by luminal administration of the small and intermediate conductance Ca(2+)-activated K(+) channel blockers apamin and TRAM34. BaCl(2), a blocker of inwardly rectifying K(+) channels, also inhibited AITC-induced dilation. AITC-induced smooth muscle cell hyperpolarization was blocked by apamin and TRAM34. We conclude that Ca(2+) influx via endothelial TRPA1 channels elicits vasodilation of cerebral arteries by a mechanism involving endothelial cell Ca(2+)-activated K(+) channels and inwardly rectifying K(+) channels in arterial myocytes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ankyrins
  • Apamin / pharmacology
  • Calcium Channels / drug effects
  • Calcium Channels / metabolism*
  • Cells, Cultured
  • Cerebral Arteries / drug effects
  • Cerebral Arteries / metabolism*
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Isothiocyanates / pharmacology
  • Male
  • Membrane Potentials
  • Muscle, Smooth, Vascular / metabolism
  • Potassium Channel Blockers / pharmacology
  • Potassium Channels, Calcium-Activated / drug effects
  • Potassium Channels, Calcium-Activated / metabolism*
  • Potassium Channels, Inwardly Rectifying / drug effects
  • Potassium Channels, Inwardly Rectifying / metabolism*
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Time Factors
  • Vasodilation* / drug effects
  • Vasodilator Agents / pharmacology


  • Ankyrins
  • Calcium Channels
  • Isothiocyanates
  • Potassium Channel Blockers
  • Potassium Channels, Calcium-Activated
  • Potassium Channels, Inwardly Rectifying
  • Pyrazoles
  • TRAM 34
  • TRPA1 Cation Channel
  • TRPC Cation Channels
  • Trpa1 protein, rat
  • Vasodilator Agents
  • Apamin
  • allyl isothiocyanate