Ketamine blocks voltage-gated K(+) channels and causes membrane depolarization in rat mesenteric artery myocytes.
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.
Kim
Seong Hyop
SH
Department of Anesthesiology, College of Medicine, Konkuk University, Seoul, South Korea.
Bae
Young Min
YM
Sung
Dong Jun
DJ
Park
Sang Woong
SW
Woo
Nam-Sik
NS
Kim
Bokyung
B
Cho
Sung Il
SI
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
D026902:Potassium Channel Blockers; D024642:Potassium Channels, Voltage-Gated; D007649:Ketamine