Isoflurane pretreatment preserves adenosine triphosphate-sensitive K(+) channel function in the human artery exposed to oxidative stress caused by high glucose levels.

Background: Adenosine triphosphate (ATP)-sensitive K(+) channels contribute to significant regulatory mechanisms related to organ blood flow in both physiological and pathological conditions. High glucose impairs arterial ATP-sensitive K(+) channel activity via superoxide production. However, the effects of anesthetics on this pathological process have not been evaluated in humans. In the present study, we investigated whether pretreatment with the volatile anesthetic isoflurane preserves ATP-sensitive K(+) channel activity in the human artery exposed to oxidative stress caused by high glucose.
Methods: All experiments were performed using human omental arteries without endothelium in the presence of d-glucose (5.5 mmol/L). Some arteries were treated with isoflurane (1.15% or 2.3%) in combination with d- or l-glucose (20 mmol/L) for 60 minutes, and then only isoflurane was discontinued. Relaxation and hyperpolarization of arterial segments in response to an ATP-sensitive K(+) channel opener levcromakalim were evaluated using the isometric force recording or electrophysiological study, respectively. Superoxide production was determined by dihydroethidium fluorescence. Immunohistochemical analysis for a subunit of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p47phox was performed. Data were evaluated using repeated-measures analysis of variance or a factorial analysis of variance as appropriate, followed by Scheffé test.
Results: The ATP-sensitive K(+) channel antagonist glibenclamide (10(-6) mol/L) abolished relaxation induced by cumulative addition of levcromakalim (10(-8) to 10(-5) mol/L) in arteries treated with l-glucose (20 mmol/L). Incubation with d-glucose (20 mmol/L) impaired the vasorelaxation induced by levcromakalim. The selective NADPH oxidase NOX2 inhibitor gp91ds-tat (10(-6) mol/L) and pretreatment with isoflurane (1.15% and 2.3%) restored relaxation in response to levcromakalim in arteries treated with d-glucose (20 mmol/L). Isoflurane (2.3%), gp91ds-tat (10(-6) mol/L), and their combination similarly restored hyperpolarization in response to levcromakalim (3 × 10(-6) mol/L) in arteries treated with d-glucose (20 mmol/L). Along with these results, isoflurane (2.3%) reduced superoxide production and the intracellular mobilization of the cytosolic NOX2 subunit p47phox toward smooth muscle cell membrane in arteries treated with d-glucose (20 mmol/L).
Conclusions: We have demonstrated for the first time a beneficial effect from the pretreatment with isoflurane on the isolated human artery. Pretreatment with isoflurane preserves ATP-sensitive K(+) channel activity in the human omental artery exposed to oxidative stress induced by high glucose, whereas the effect seems to be mediated by NADPH oxidase inhibition. Volatile anesthetics may protect human visceral arteries from malfunction caused by oxidative stress.