Differential effects of volatile and intravenous anesthetics on the activity of human TASK-1.
Volatile anesthetics have been shown to activate various two-pore (2P) domain K(+) (K(2P)) channels such as TASK-1 and TREK-1 (TWIK-related acid-sensitive K(+) channel), and mice deficient in these channels are resistant to halothane-induced anesthesia. Here, we investigated whether K(2P) channels were also potentially important targets of intravenous anesthetics. Whole cell patch-clamp techniques were used to determine the effects of the commonly used intravenous anesthetics etomidate and propofol on the acid-sensitive K(+) current in rat ventricular myocytes (which strongly express TASK-1) and selected human K(2P) channels expressed in Xenopus laevis oocytes. In myocytes, etomidate decreased both inward rectifier K(+) (K(ir)) current (I(K1)) and acid-sensitive outward K(+) current at positive potentials, suggesting that this drug may inhibit TASK channels. Indeed, in addition to inhibiting guinea pig Kir2.1 expressed in oocytes, etomidate inhibited human TASK-1 (and TASK-3) in a concentration-dependent fashion. Propofol had no effect on human TASK-1 (or TASK-3) expressed in oocytes. Moreover, we showed that, similar to the known effect of halothane, sevoflurane and the purified R-(-)- and S-(+)-enantiomers of isoflurane, without stereoselectivity, activated human TASK-1. We conclude that intravenous and volatile anesthetics have dissimilar effects on K(2P) channels. Human TASK-1 (and TASK-3) are insensitive to propofol but are inhibited by supraclinical concentrations of etomidate. In contrast, stimulatory effects of sevoflurane and enantiomeric isoflurane on human TASK-1 can be observed at clinically relevant concentrations.
Putzke
C
C
Department of Anesthesiology and Critical Care Medicine, Philipps-University Marburg, Baldingerstrasse 1, 35043, Marburg, Germany. carolineputzke@gmx.de
Hanley
P J
PJ
Schlichthörl
G
G
Preisig-Müller
R
R
Rinné
S
S
Anetseder
M
M
Eckenhoff
R
R
Berkowitz
C
C
Vassiliou
T
T
Wulf
H
H
Eberhart
L
L
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005045:Etomidate / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007530:Isoflurane / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008738:Methyl Ethers / Q000494:pharmacology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000235:genetics / Q000502:physiology*; D015742:Propofol / Q000494:pharmacology; D018075:RNA, Complementary / Q000235:genetics; D051381:Rats; D000077149:Sevoflurane; D014982:Xenopus laevis
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D001095:Arachidonic Acids; D008738:Methyl Ethers; D009419:Nerve Tissue Proteins; D026902:Potassium Channel Blockers; D024683:Potassium Channels, Tandem Pore Domain; D018075:RNA, Complementary; C088155:methanandamide; C420132:potassium channel subfamily K member 3; D000077149:Sevoflurane; D007530:Isoflurane; D011188:Potassium; D006221:Halothane; D015742:Propofol; D005045:Etomidate