title: Ketamine blocks voltage-gated K(+) channels and causes membrane depolarization in rat mesenteric artery myocytes.
abstract: Clinical doses of ketamine typically increase blood pressure, heart rate, and cardiac output. However, the precise mechanism by which ketamine produces these cardiovascular effects remains unclear. The voltage-gated K(+) (K(V)) channel is the major regulator of resting membrane potential (E (m)) and vascular tone in many arteries. Therefore, we sought to evaluate the effects of ketamine on K(V) currents using the standard whole-cell patch clamp recordings in single myocytes, enzymatically dispersed from rat mesenteric arteries. Ketamine [(+/-)-racemic mixture] inhibited K(V) currents reversibly and concentration dependently with a K ( d ) of 566.7 +/- 32.3 microM and Hill coefficient of 0.75 +/- 0.03. The inhibition of K(V) currents by ketamine was voltage independent, and the time courses of channel activation and inactivation were little affected. The effects of ketamine on steady-state activation and inactivation curves were also minimal. Use-dependent inhibition was not observed either. S(+)-ketamine inhibited K(V) currents with similar potency and efficacy as the racemic mixture. The average resting E (m) in rat mesenteric artery myocytes was -44.1 +/- 4.2 mV, and both racemic and S(+)-ketamine induced depolarization of E (m) (15.8 +/- 3.6 and 24.3 +/- 5.0 mV at 100 microM, respectively). We conclude that ketamine induces E (m) depolarization in vascular myocytes by blocking K(V) channels in a state-independent manner, which may contribute to the increased vascular tone and blood pressure produced by this drug under a clinical setting.
authors.affiliation: Department of Anesthesiology, College of Medicine, Konkuk University, Seoul, South Korea.
authors.forename: Seong Hyop
authors.initials: SH
authors.lastname: Kim
authors.forename: Young Min
authors.initials: YM
authors.lastname: Bae
authors.forename: Dong Jun
authors.initials: DJ
authors.lastname: Sung
authors.forename: Sang Woong
authors.initials: SW
authors.lastname: Park
authors.forename: Nam-Sik
authors.initials: NS
authors.lastname: Woo
authors.forename: Bokyung
authors.initials: B
authors.lastname: Kim
authors.forename: Sung Il
authors.initials: SI
authors.lastname: Cho
mesh_terms: D000465:Algorithms; D000818:Animals; D003627:Data Interpretation, Statistical; D066298:In Vitro Techniques; D007649:Ketamine / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism
chemical_list: D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D007649:Ketamine