Abstract
Local anesthetics (LAs) are known to act on membrane level; however, the molecular mechanism of their activity is still not fully understood. One hypothesis holds that these drugs can incorporate into lipid membrane of nerve cells and in this way change conformation of channel proteins responsible for transport of sodium ions. However, the action of anesthetics is not limited to nerve cells. These drugs also affect other types of cells and organelles, causing severe side effects. In this paper, we applied Langmuir monolayers—as model of cellular membranes—and investigated interactions between selected amide-type local anesthetics (lidocaine prilocaine, mepivacaine and ropivacaine, in the form of hydrochlorides) and lipid components of natural membranes: cholesterol, POPC and cardiolipin (CL) and their mixtures (POPC/cholesterol and POPC/CL/cholesterol), which can serve as simplified models of nerve cell membranes, erythrocytes, and mitochondria. The influence of the drug was monitored by registering the surface pressure (π) as a function of surface area per molecule (A) in a monolayer in the presence of the drug in the subphase. The structure of lipid monolayers on subphases containing and devoid of the studied drugs were visualized with Brewster angle microscopy (BAM). Langmuir monolayer studies complemented with surface visualization technique reveal the expansion and fluidization of lipid monolayers, with the most pronounced effect observed for cardiolipin. In mixed systems, the effect of LAs was found to depend on cholesterol proportion. The observed fluidization of membranes by local anesthetics may negatively affect cells functioning and therefore can explain side effects of these drugs both on the cardiovascular and nervous systems.
Highlights
From the second half of the nineteenth century, when the pain-relief effect of cocaine was discovered, an intensive development of research on substances with local anesthetic activity began
To investigate the influence of local anesthetics on model lipid membrane, the monolayers were spread on pure water and aqueous solutions of particular drugs of the concentration 1 mM, which corresponds to their bloodstream concentration
It is important to mention that in preliminary experiments all the investigated Local anesthetics (LAs) were found to be incapable to adsorb at the air/water interface without the presence of lipid monolayer
Summary
From the second half of the nineteenth century, when the pain-relief effect of cocaine was discovered, an intensive development of research on substances with local anesthetic activity began. To get insight into their anesthetic activity as well as side effects it is of great importance to perform systematic investigations of the interactions between the drugs and model membranes mimicking various cells, namely nerve cells, erythrocytes and mitochondria.
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