The effects of volatile anesthetics on recombinant adenosine triphosphate-sensitive potassium channels

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Background ; Recent evidence indicates that vascular adenosine triphosphate-sensitive potassium (K_<ATP>) channels in vascular smooth muscle cells are critical in the regulation of vascular tonus under both physiological and pathophysiological conditions. Studies of the interaction of volatile anesthetics with vascular K_<ATP> channels have been limited. In the present study, we investigated the molecular mechanism of isoflurane's action on vascular K_<ATP> channels.Methods ; Electrophysiologic experiments were performed using cell-attached and inside-out patch-clamp techniques to monitor native vascular K_<ATP> channels, and recombinant K_<ATP> channels comprised of inwardly rectifying potassium, channel subunits (Kir6. 1) and the sulfonylurea receptor (SUR2B). Isometric tension experiments were performed in rat thoracic aortic rings without endothelium.Results ; Application of isoflurane (0.5mM) to the bath solution during cell-attached recordings induced a significant increase in K_ … More <ATP> channel activity, which was greatly reduced by pretreatment with a selective inhibitor protein kinase A (PKA), Rp-cAMPS (100 μM). In inside-out patches, isoflurane failed to activate K_<ATP> channels. Isoflurane significantly activated wild type recombinant SUR2B/Kir6.1 in cell-attached patches. Isoflurane-induced activation of wild-type channels was diminished in the PKA-insensitive mutant SUR2B-T633A/Kir6.1, SUR2B-S1465A/Kir6. 1, and SUR2B/Kir6.1-S385A. In addition, we demonstrated that isoflurane-induced PKA activation was associated with isoflurane-induced decreases in isometric tension in the rat aorta.Conclusion ; Our results indicated that isoflurane activates K_<ATP> channels via PKA activation. PKA-dependent vasodilation induced by isoflurane also was observed in isometric tension experiments. Analysis of expressed vascular type K_<ATP>, channels suggested that PKA-mediated phosphorylation of both Kir6.1 and SUR2B subunits plays a pivotal role in isoflurane-induced vascular K_<ATP>, channel activation. Less