2,2,2-trichloroethanol activates a nonclassical potassium channel in cerebrovascular smooth muscle and dilates the middle cerebral artery.
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.
Parelkar
Nikhil K
NK
Basic Medical Science Department, University of Missouri-Kansas City School of Medicine, 2464 Charlotte St., HSB 2232, Kansas City, MO 64108, USA.
Silswal
Neerupma
N
Jansen
Kirsten
K
Vaughn
Joshua
J
Bryan
Robert M
RM
Andresen
Jon
J
D000818:Animals; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D014665:Vasodilator Agents / Q000494:pharmacology*
D006993:Hypnotics and Sedatives; C546314:Kcnk18 protein, rat; C503434:Kcnk4 protein, rat; D015221:Potassium Channels; D014665:Vasodilator Agents; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D007530:Isoflurane