Anesthetics lipid interaction

Boulanger, Y. Schreier, S. Smith, I. C.P., Molecular detailsof anesthetic-lipid interaction as seen by deuterium and phosphorus-31 nuclear magnetic resonance, Biochemistry 20, 6824-6830 (1981). 

Non-polm- and weakly polarizable molecules would be expected to interact mainly with the hydrophobic parts of the membrane lipids or proteins. Non-polar or weakly polar but highly polarizable anesthetics could interact with both hydrophobic and ionic or polar sites. 

Diethyl ether was the first general anesthetic used. The dentist Dr. William Morton is credited with its introduction in the 1800s. Diethyl ether functions as an anesthetic by interacting with the central nervous system. It appears that diethyl ether (and many other general anesthetics) functions by accumulating in the lipid material of the nerve cells, thereby interfering with nerve impulse transmission. This results in analgesia, a lessened perception of pain. 

It has been generally accepted that anesthetics interact with membrane lipids as a primary step of anesthesia. The detailed mechanism of the anesthetic action is, however, still controversial. This is mainly due to the absence of specific information on delivery sites in membranes. The NMR data for the delivery site of drugs in membranes are of great use. 

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal cellular function. Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane fluidization theory) or prevent the interconversion of membrane lipids from a gel to a liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis). 

No difference has been observed in the interactions of the two enantiomers of isoflurane with hpid bilayers. But the (5)-enantiomer of isoflurane is two times more active than the (7 )-enantiomer toward a calcium channel receptor, that is sensitive to volatile anesthetic agents, while nodifference in activity has been observed toward an anesthetic nonsensitive receptor. The (5)-enantiomer of isoflurane is also more active than the (R)-enantiomer toward acetylcholine nicotinic receptor and GABA receptor. These data strongly suggest that fluoroethers interact not only with cerebral membranous lipids but also with receptor proteins. 

Both the inhaled and the intravenous anesthetics can depress spontaneous and evoked activity of neurons in many regions of the brain. Older concepts of the mechanism of anesthesia evoked nonspecific interactions of these agents with the lipid matrix of the nerve membrane (the so-called Meyer-Overton principle)—interactions that were thought to lead to secondary changes in ion flux. More recently, evidence has accumulated suggesting that the modification of ion currents by anesthetics results from more direct interactions with specific nerve membrane components. The ionic mechanisms involved for different anesthetics may vary, but at clinically relevant concentrations they appear to involve interactions with members of the ligand-gated ion channel family. 

A general model for the interaction of drags and anesthetics with lipid membranes has been developed by Jorgensen el al. [49], The situation is best described by a multistate lattice model for the main transition of lipid bilayers. The foreign mole-... 

This question of direct interaction with nerve proteins or indirect interaction via membrane perturbation has also been tackled by ESR spectroscopy. Two types of labeling have been used fatty acids for lipid labeling and maleimide for frog nerve proteins. The anesthetics used were halothane as an example of a general anesthetic and procaine, lidocaine, and tetracaine as examples of local anesthetics. The latter interact primarily with head groups but can also merge into the hydrophobic hydrocarbon... 

Most of the examples published deal with the interaction of anesthetics with membranes, but calcium channel openers, [l-blockers, antimalarial drugs, anticancer drugs, antibiotics, and insecticides have also been examined. The NMR resonance signals of atoms and groups within the lipid, and of drag molecules, have been followed and described as a function of the interaction. For the interaction of anesthetics and the involved mechanism of action, the reader s attention is directed to a review [112],... 

The molecular mechanism of local anesthesia, the location of the local anesthetic dibucaine in model membranes, and the interaction of dibucaine with a Na+-channel inactivation gate peptide have been studied in detail by 2H- and 1H-NMR spectroscopy [24]. Model membranes consisted of PC, PS, and PE. Dibucaine was deuterated at H9 and H3 of the butoxy group and at the 3-position of the quinoline ring. 2H-NMR spectra of the multilamellar dispersions of the lipid mixtures were obtained. In addition, spectra of deuterated palmitic acids incorporated into mixtures containing cholesterol were obtained and the order parameter, SCD, for each carbon... 

There is a long history of controversy in the literature regarding the mode of action of general anesthetics. Experimental results derived from model systems of lipids alone or lipid-cholesterol are somewhat controversial. To mention just a few, using Raman spectroscopy it was found that, at clinical concentrations, halothane had no influence on the hydrocarbon chain conformations, and it was concluded that the interaction between halothane and the lipid bilayer occurs in the head group region [57]. This idea was also supported by 19F-NMR studies. The chemical shifts of halothane in a lipid suspension were similar to those in water and differed from those in hydrocarbons. In contrast, from 2H-NMR experiments, it was concluded that halothane is situated in the hydrocarbon region of the membrane (see also chapter 3.3). 

Interesting calculations have been carried out by others dealing with the interaction of anesthetic molecules on lipids and proteins. For example, at the MAC, the concentration of anesthetic molecules in the hydrophobic phase is approximately 50 mM. Assuming that the anesthetic molecules are uniformly distributed throughout the lipid bilayer of a cell membrane of thickness 50 A, there would be only one anesthetic molecule for every 60 lipid molecules (i.e., 1.5 percent of the molecules in the membrane and only 0.5 percent of the membrane volume). Under these circumstances, the anesthetic molecules would be distributed too diffusely to have a significant effect on membrane status. If, however, anesthetic molecules became preferentially located adjacent to a protein, then a local effect on protein function might occur. 

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