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Research ArticleCARDIOVASCULAR

2,2,2-Trichloroethanol Activates a Nonclassical Potassium Channel in Cerebrovascular Smooth Muscle and Dilates the Middle Cerebral Artery

Nikhil K. Parelkar, Neerupma Silswal, Kirsten Jansen, Joshua Vaughn, Robert M. Bryan Jr. and Jon Andresen
Journal of Pharmacology and Experimental Therapeutics March 2010, 332 (3) 803-810; DOI: https://doi.org/10.1124/jpet.109.162313
Nikhil K. Parelkar
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Neerupma Silswal
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Kirsten Jansen
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Joshua Vaughn
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Robert M. Bryan Jr.
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Jon Andresen
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Abstract

Trichloroacetaldehyde monohydrate [chloral hydrate (CH)] is a sedative/hypnotic that increases cerebral blood flow (CBF), and its active metabolite 2,2,2-trichloroethanol (TCE) is an agonist for the nonclassical two-pore domain K+ (K2P) channels TREK-1 and TRAAK. We sought to determine whether TCE dilates cerebral arteries in vitro by activating nonclassical K+ channels. TCE dilated pressurized and perfused rat middle cerebral arteries (MCAs) in a manner consistent with activation of nonclassical K+ channels. Dilation to TCE was inhibited by elevated external K+ but not by an inhibitory cocktail (IC) of classical K+ channel blockers. Patch-clamp electrophysiology revealed that, in the presence of the IC, TCE increased whole-cell currents and hyperpolarized the membrane potential of isolated MCA smooth muscle cells. Heating increased TCE-sensitive currents, indicating that the activated channel was thermosensitive. Immunofluorescence in sections of the rat MCA demonstrated that, like TREK-1, TRAAK is expressed in the smooth muscle of cerebral arteries. Isoflurane did not, however, dilate the MCA, suggesting that TREK-1 was not functional. These data indicate that TCE activated a nonclassical K+ channel with the characteristics of TRAAK in rat MCA smooth-muscle cells. Stimulation of K+ channels such as TRAAK in cerebral arteries may therefore explain in part how CH/TCE increases CBF.

Footnotes

  • This work was supported by the National Institutes of Health [Grants P01-NS38660, R01-NS46666] (to R.M.B.); the National Institutes of Health [Grant F32-HL080916-01] (to J.A.); the American Heart Association [Grant SDG-0735053N] and University of Missouri-Kansas City School of Medicine start-up funds (to J.A.); and Sarah Morrison Research Awards (to K.J. and J.V.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.162313.

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    CH
    chloral hydrate
    TCE
    2,2,2-trichloroethanol
    IC
    inhibitory cocktail
    CBF
    cerebral blood flow
    VSMC
    vascular smooth muscle cell
    MCA
    middle cerebral artery
    BSA
    bovine serum albumin
    PBS
    phosphate-buffered saline
    DAPI
    4′,6-diamidino-2-phenylindole
    RT
    room temperature.

    • Received October 3, 2009.
    • Accepted December 1, 2009.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleCARDIOVASCULAR

2,2,2-Trichloroethanol Activates a Nonclassical Potassium Channel in Cerebrovascular Smooth Muscle and Dilates the Middle Cerebral Artery

Nikhil K. Parelkar, Neerupma Silswal, Kirsten Jansen, Joshua Vaughn, Robert M. Bryan and Jon Andresen
Journal of Pharmacology and Experimental Therapeutics March 1, 2010, 332 (3) 803-810; DOI: https://doi.org/10.1124/jpet.109.162313

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Research ArticleCARDIOVASCULAR

2,2,2-Trichloroethanol Activates a Nonclassical Potassium Channel in Cerebrovascular Smooth Muscle and Dilates the Middle Cerebral Artery

Nikhil K. Parelkar, Neerupma Silswal, Kirsten Jansen, Joshua Vaughn, Robert M. Bryan and Jon Andresen
Journal of Pharmacology and Experimental Therapeutics March 1, 2010, 332 (3) 803-810; DOI: https://doi.org/10.1124/jpet.109.162313
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