Beneficial effect of propofol on arterial adenosine triphosphate-sensitive K+ channel function impaired by thromboxane.
BACKGROUND
It is not known whether thromboxane A2 impairs adenosine triphosphate (ATP)-sensitive K channel function via increased production of superoxide in blood vessels and whether propofol as a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor restores this modification.


METHODS
Rat aortas without endothelium were used for isometric force recording, measurements of membrane potential, and superoxide production and Western immunoblotting. Vasorelaxation to an ATP-sensitive K channel opener levcromakalim was obtained during contraction to phenylephrine (3 x 10(-7) M) or a thromboxane A2 analogue U46619 (3 x 10(-7) M). In some experiments, aortas were incubated with an ATP-sensitive K channel antagonist glibenclamide, a superoxide inhibitor Tiron, a nonselective NADPH oxidase inhibitor apocynin, a hydrogen peroxide scavenger catalase, a xanthine oxidase inhibitor allopurinol, a thromboxane receptor antagonist SQ29548 or propofol (3 x 10(-7) to 3 x 10(-6) M).


RESULTS
Levcromakalim-induced vasorelaxation was abolished by glibenclamide in rings contracted with either vasoconstrictor agent. Tiron, apocynin, and propofol, but not catalase, augmented the vasodilator response as well as the hyperpolarization by levcromakalim in aortas contracted with U46619. Tiron, apocynin, SQ29548, and propofol, but not allopurinol, similarly reduced in situ levels of superoxide within aortic vascular smooth muscle exposed to U46619. Protein expression of a NADPH oxidase subunit p47phox increased in these arteries, and this augmentation was abolished by propofol.


CONCLUSIONS
Thromboxane receptor activation induces vascular oxidative stress via NADPH oxidase, resulting in the impairment of ATP-sensitive K channel function. Propofol reduces this stress via inhibition of a NADPH oxidase subunit p47phox and, therefore, restores ATP-sensitive K channel function.
Haba
Masanori
M
Department of Anesthesiology, Wakayama Medical University, Wakayama, Japan.
Kinoshita
Hiroyuki
H
Matsuda
Naoyuki
N
Azma
Toshiharu
T
Hama-Tomioka
Keiko
K
Hatakeyama
Noboru
N
Yamazaki
Mitsuaki
M
Hatano
Yoshio
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D018686:Anesthetics, Intravenous / Q000627:therapeutic use*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D015153:Blotting, Western; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000187:drug effects*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010656:Phenylephrine / Q000494:pharmacology; D015742:Propofol / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
D018686:Anesthetics, Intravenous; D054086:KATP Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D019806:Cromakalim; D013481:Superoxides; D010656:Phenylephrine; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D019255:NADPH Oxidases; D015742:Propofol