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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 332; no. 3; pp. 803 - 810
• Main Authors: Parelkar, Nikhil K., Silswal, Neerupma, Jansen, Kirsten, Vaughn, Joshua, Bryan, Robert M., Andresen, Jon
• Format: Journal Article
• Language: English
• Published: The American Society for Pharmacology and Experimental Therapeutics 01.03.2010
• Subjects: Cardiovascular
• DOI: 10.1124/jpet.109.162313
• ISSN: 0022-3565

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 + (K 2P ) 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.