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 (AD50) of monoketones was determined; AD50 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/AD50) was the parabolic function of log P, log ((1/AD50) = -0.167(log P)2 + 0.698 log P - 1.365, and the log P that corresponds to the minimum AD50 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 AD50), 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.
Tanii
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Department of Hygiene, Kanazawa University School of Medicine, Japan.
D000777:Anesthetics / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016880:Anisotropy; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D005456:Fluorescent Dyes; D007274:Injections, Intraperitoneal; D007659:Ketones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects*; D051379:Mice; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000201:enzymology; D014867:Water / Q000737:chemistry
D000777:Anesthetics; D005456:Fluorescent Dyes; D007659:Ketones; D014867:Water; D000254:Sodium-Potassium-Exchanging ATPase