Anaesthetic Preconditioning; The Role of ATP-Sensitive K+ Channels

Abstract

Stroke in general but especially in the postoperative period is a serious clinical problem that warrants new therapeutic approaches. Here neuroprotective strategies and especially preconditioning have recently emerged as promising. Preconditioning was originally demonstrated in the heart but was subsequently also found in other organs. Classically it describes a phenomenon where short periods of ischaemia render tissues less vulnerable to major infarcts. In addition to ischaemia neuronal preconditioning can be achieved pharmacologically as well as through inhalational anaesthetics or drugs that open ATP-sensitive K+(KATP) channels. However, the mechanisms through which anaesthetics produce protection remain elusive and the use of K+ channel openers is hampered by their inability to cross the blood-brain-barrier. This study was conducted to investigate the effects of inhalational anaesthetics on KATP channels and to explore whether their neuronal preconditioning properties were dependent on KATP channel opening. First, in whole-cell and excised patchclamp experiments the effects of inhalational anaesthetics on recombinant wild type neuronal (Kir6.2/SUR1) KATP and related as well as modified channels were evaluated. Secondly, the KATP channel dependence of anaesthetic preconditioning was tested in neuronal-glial co-cultures. Recombinant KATP channels were activated by xenon, but inhibited by halogenated volatiles. Moreover, it was shown that xenon acted directly on the Kir6.2 pore-forming subunit, reduced the ability of ATP to inhibit the channel and had no effect on the ATP-regulated Kir1.1 channel. Functionally both sevoflurane and xenon preconditioned neurons at clinically used concentrations but only the effect of xenon was dependent on KATP channel activation. Thus this study established xenon as a novel KATP channel opener. It interacts with the pore-forming Kir6.2 rather than the regulatory sulphonylurea receptor subunit and disinhibits the channel from the blocking actions of ATP. As a consequence xenon but not sevoflurane is able to precondition neurons in a KATP channel-dependent manner.