Isoflurane Activates Sarcolemmal Adenosine Triphosphate-sensitive Potassium Channels in Vascular Smooth Muscle Cells: A Role for Protein Kinase A

Background: Recent evidence indicates that vascular adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells are critical in the regulation of vascular tonus under both physiologic and pathophysiologic conditions. Studies of the interaction of volatile anesthetics with vascular KATP channels have been limited. In the current study, the authors investigated the molecular mechanism of isoflurane's action on vascular KATP channels.

Methods: Electrophysiologic experiments were performed using cell-attached and inside-out patch clamp techniques to monitor native vascular KATP channels, and recombinant KATP 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 (0.5 mm) to the bath solution during cell-attached recordings induced a significant increase in KATP channel activity, which was greatly reduced by pretreatment with a selective inhibitor of protein kinase A (PKA), Rp-cAMPS (100 [mu]m). In inside-out patches, isoflurane did not activate KATP 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, the authors demonstrated that isoflurane-induced PKA activation was associated with isoflurane-induced decreases in isometric tension in the rat aorta.