Anesthetic activity of monoketones in mice: Relationship to hydrophobicity and in vivo effects on Na+/K+-ATPase activity and membrane fluidity

The in vivo anesthetic activity of monoketones in mice was examined in relation to their hydrophobicity and to the in vivo effects on Na+/K+-adenosine triphosphatase (Na+/K+-ATPase) activity and membrane fluidity. Anesthetic potency (AD(50)) of monoketones was determined; AD(50) implys the dose required to anesthetize 50% of the animals from the treated group. The n-octanol/water partition coefficient (P) was used as an index of hydrophobicity. Membrane fluidity was determined by using 1,6-diphenyl-1,3,5-hexatriene (DPH) or 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH as fluorescence probes. Log(1/AD(50)) was the parabolic function of log P, log (1/AD(50)) = -0.167(log P)(2) + 0.698 log P - 1.365, and the log P that corresponds to the minimum AD(50) was estimated to be 2.09. Brain synaptosomes were prepared from mice that were considered anesthetized with each of the 4 monoketones (1.5-fold AD(50)), methyl n-propyl, methyl n-amyl, methyl 3-methylhexyl and methyl n-octyl ketone. The Na+/K+-ATPase activity was inhibited by methyl n-propyl ketone alone, membrane DPH fluidity was decreased by each of the 4 monoketones, and membrane TMA-DPH fluidity was decreased by methyl n-propylketone alone. These results suggest an involvement of the decreased DPH fluidity in monoketone-induced anesthesia.