%0 Journal Article
%T Inhibition of Membrane Effects of General Anesthetic Propofol by Benzodiazepine Inverse Agonist Tetrahydro-¦Â-carboline
%A H. Tsuchiya
%J International Journal of Pharmacology
%D 2012
%I Asian Network for Scientific Information
%X Propofol induces general anesthesia through binding to GABAA receptors. It is inhibited by interacting with benzodiazepine inverse agonist tetrahydro-¦Â-carbolines present in the human body. Aside from acting on receptor proteins, both propofol and tetrahydro-¦Â-carbolines act on membrane lipid bilayers. In this study, the hypothetical inhibitory relation on membrane biophysical modification was verified between propofol and tetrahydro-¦Â-carbolines. Lipid bilayer membranes were prepared with phospholipids and cholesterol. The membrane preparations were reacted with propofol, 1-methyl-1,2,3,4-tetrahydro-¦Â-carboline and its metabolites 6-hydroxy-1-methyl-1,2,3,4-tetrahydro-¦Â-carboline and 7-hydroxy-1-methyl-1,2,3,4-tetrahydro-¦Â-carboline, followed by measuring fluorescence polarization to determine their induced changes in membrane fluidity. In the pilot experiments using model membranes prepared with 100 mol% 1,2-dipalmitoyl phosphatidylcholine, 1-methyl-1,2,3,4-tetrahydro-¦Â-carboline showed a concentration-dependent biphasic effect to increase membrane fluidity at high micromolar concentrations but decrease at <50 ¦ÌM. In the lower concentration range of 0.01-0.5 ¦ÌM, 1-methyl-1,2,3,4-tetrahydro-¦Â-carboline was effective in rigidifying the membranes, whereas neither 6-hydroxyl nor 7-hydroxyl metabolite showed any membrane effects. Based on these results, biomimetic membranes consisting of 60 mol% 1-palmitoyl-2-oleoylphosphatidylcholine and 40 mol% cholesterol were pretreated with 1-methyl-1,2,3,4-tetrahydro-¦Â-carboline of physiologically presumable concentrations and then reacted with propofol of clinically relevant concentrations. Propofol fluidized the membranes at 0.125-1 ¦ÌM. However, the membrane-fluidizing effects of 0.125 and 0.25 ¦ÌM propofol were inhibited by 0.01-5 nM 1-methyl-1,2,3,4-tetrahydro-¦Â-carboline. In addition to their interaction at a receptor level, propofol and 1-methyl-1,2,3,4-tetrahydro-¦Â-carboline show the inhibitory relation on membrane fluidity changes. Such a relation may be hypothetically associated with the anesthetic tolerance.
%K interaction
%K inhibitory relation
%K membrane effect
%K Propofol
%U http://docsdrive.com/pdfs/ansinet/ijp/2012/542-548.pdf