Noble Gas Xenon Is a Novel Adenosine Triphosphate-sensitive Potassium Channel Opener

Background: Adenosine triphosphate-sensitive potassium (K-ATP) channels in brain are involved in neuroprotective mechanisms. Pharmacologic activation of these channels is seen as beneficial, but clinical exploitation by using classic K+ channel openers is hampered by their inability to cross the blood-brain barrier. This is different with the inhalational anesthetic xenon, which recently has been suggested to activate K-ATP channels; it partitions freely into the brain. Methods: To evaluate the type and mechanism of interaction of xenon with neuronal-type K-ATP channels, these channels, consisting of Kir6.2 pore-forming subunits and sulfonylurea receptor-1 regulatory subunits, were expressed in HEK293 cells and whole cell, and excised patch-clamp recordings were performed. Results: Xenon, in contrast to classic K-ATP channel openers, acted directly on the Kir6.2 subunit of the channel. It had no effect on the closely related, adenosine triphosphate (ATP)-regulated Kir1.1 channel and failed to activate an ATP-insensitive mutant version of Kir6.2. Furthermore, concentration-inhibition curves for ATP obtained from inside-out patches in the absence or presence of 80% xenon revealed that xenon reduced the sensitivity of the K-ATP channel to ATP. This was reflected in an approximately fourfold shift of the concentration causing half-maximal inhibition (IC50) from 26 +/- 4 to 96 +/- 6 mu M. Conclusions: Xenon represents a novel KATP channel opener that increases KATP currents independently of the sulfonylurea receptor-1 subunit by reducing ATP inhibition of the channel. Through this action and by its ability to readily partition across the blood-brain barrier, xenon has considerable potential in clinical settings of neuronal injury, including stroke.