Effects of anesthetics on ATP-sensitive K channels in rat substantia nigra

ATP-sensitive K (K_ATP) channels are widely expressed in cytoplasmic membranes of neurons and they couple cell metabolism to excitability. They are known to play important roles in neuroprotection during ischemia and excitotoxicity. We studied the effects of three anesthetics on surface K_ATP channels in principal neurons of rat substantia nigra pars compacta. Whole cell voltage- and current-clamp recordings were made using rat midbrain slices. When neurons were dialyzed with an ATP-free pipette solution during perfusion with a glucose-free external solution, a hyperpolarization and an outward current developed slowly in a tolbutamide-inhibitable manner. Ketamine and thiopental did not affect the membrane potential or current when intracellular ATP was preserved, however, isoflurane slightly depolarized the neurons and increased frequency of spontaneous firings. The hyperpolarization and outward current induced by intracellular ATP depletion were reversibly inhibited by ketamine and thiopental at 100 and 300 μM but not by 704 μM isoflurane. These results suggest that surface K_ATP channels in these neurons are inhibited by high concentrations of ketamine and thiopental but not by isoflurane when the channels are activated. Our findings do not support the idea that K_ATP channel activation is important for previously reported neuroprotective actions of isoflurane.