RT Journal Article
SR Electronic
T1 2,2,2-Trichloroethanol Activates a Nonclassical Potassium Channel in Cerebrovascular Smooth Muscle and Dilates the Middle Cerebral Artery
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 803
OP 810
DO 10.1124/jpet.109.162313
VO 332
IS 3
A1 Parelkar, Nikhil K.
A1 Silswal, Neerupma
A1 Jansen, Kirsten
A1 Vaughn, Joshua
A1 Bryan, Robert M.
A1 Andresen, Jon
YR 2010
UL http://jpet.aspetjournals.org/content/332/3/803.abstract
AB 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.Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics