Differential effects of etomidate and midazolam on vascular adenosine triphosphate-sensitive potassium channels: isometric tension and patch clamp studies.
BACKGROUND
The aim of this study was to investigate the effects of two imidazoline-derived intravenous anesthetics, etomidate and midazolam, on vascular adenosine triphosphate-sensitive potassium (KATP) channel activity.


METHODS
In isolated rat aorta, isometric tension was recorded to examine the anesthetic effects on vasodilator response to levcromakalim, a selective KATP channel opener. Using the patch clamp method, the anesthetic effects were also examined on the currents through (1) native vascular KATP channels, (2) recombinant KATP channels with different combinations of various types of inwardly rectifying potassium channel (Kir6.0 family: Kir6.1, 6.2) and sulfonylurea receptor (SUR1, 2A, 2B) subunits, (3) SUR-deficient channels derived from a truncated isoform of Kir6.2 subunit (Kir6.2DeltaC36 channels), and (4) mutant Kir6.2DeltaC36 channels with reduced sensitivity to adenosine triphosphate (Kir6.2DeltaC36-K185Q channels).


RESULTS
Etomidate (> or = 10 m), but not midazolam (up to 10 m), inhibited the levcromakalim-induced vasodilation, which was sensitive to glibenclamide (IC50: 7.21 x 10 m; maximum inhibitory concentration: 1.22 x 10 m). Etomidate (> or = 3 x 10 m), but not midazolam (up to 10 m), inhibited the native KATP channel activity in both cell-attached and inside-out configurations with IC50 values of 1.68 x 10 m and 1.52 x 10 m, respectively. Etomidate (10 m) also inhibited the activity of various types of recombinant SUR/Kir6.0KATP channels, Kir6.2DeltaC36 channels, and Kir6.2DeltaC36-K185Q channels with equivalent potency.


CONCLUSIONS
Clinical concentrations of etomidate, but not midazolam, inhibit the KATP channel activity in vascular smooth muscle cells. The inhibition is presumably through its effects on the Kir6.0 subunit, but not on the SUR subunit, with the binding site different from adenosine triphosphate at the amino acid level.
Nakamura
Akiyo
A
Department of Anesthesiology, University of Tokushima Graduate School, Tokushima, Japan.
Kawahito
Shinji
S
Kawano
Takashi
T
Nazari
Hossein
H
Takahashi
Akira
A
Kitahata
Hiroshi
H
Nakaya
Yutaka
Y
Oshita
Shuzo
S
D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000255:Adenosine Triphosphate / Q000378:metabolism*; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology / Q000379:methods; D005045:Etomidate / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D007537:Isometric Contraction / Q000187:drug effects*; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels / Q000187:drug effects*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000187:drug effects; D064233:Sulfonylurea Receptors; D014162:Transfection / Q000379:methods; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D018686:Anesthetics, Intravenous; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; D019806:Cromakalim; D000255:Adenosine Triphosphate; D008874:Midazolam; D005905:Glyburide; D005045:Etomidate