Differential Effects of Etomidate and Midazolam on Vascular Adenosine Triphosphate–sensitive Potassium Channels: Isometric Tension and Patch Clamp Studies

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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 (Kir6.2ΔC36 channels), and (4) mutant Kir6.2ΔC36 channels with reduced sensitivity to adenosine triphosphate (Kir6.2ΔC36-K185Q channels).Results:Etomidate (≥ 10−6 m), but not midazolam (up to 10−6 m), inhibited the levcromakalim-induced vasodilation, which was sensitive to glibenclamide (IC50: 7.21 × 10−8 m; maximum inhibitory concentration: 1.22 × 10−4 m). Etomidate (≥ 3 × 10−6 m), but not midazolam (up to 10−4 m), inhibited the native KATP channel activity in both cell-attached and inside-out configurations with IC50 values of 1.68 × 10−5 m and 1.52 × 10−5 m, respectively. Etomidate (10−5 m) also inhibited the activity of various types of recombinant SUR/Kir6.0KATP channels, Kir6.2ΔC36 channels, and Kir6.2ΔC36-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.

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