Stereostructure-based differences in the interactions of cardiotoxic local anesthetics with cholesterol-containing biomimetic membranes

Amide-type pipecoloxylidide local anesthetics, bupivacaine, and ropivacaine, show cardiotoxic effects with the potency depending on stereostructures. Cardiotoxic drugs not only bind to cardiomyocyte membrane channels to block them but also modify the physicochemical property of membrane lipid bilayers in which channels are embedded. The opposite configurations allow enantiomers to be discriminated by their enantiospecific interactions with another chiral molecule in membranes. We compared the interactions of local anesthetic stereoisomers with biomimetic membranes consisting of chiral lipid components, the differences of which might be indicative of the drug design for reducing cardiotoxicity. Fluorescent probe-labeled biomimetic membranes were prepared with cardiolipin and cholesterol of varying compositions and different phospholipids. Local anesthetics were reacted with the membrane preparations at a cardiotoxically relevant concentration of 200 μM. The potencies to interact with biomimetic membranes and change their fluidity were compared by measuring fluorescence polarization. All local anesthetics acted on lipid bilayers to increase membrane fluidity. Chiral cardiolipin was ineffective in discriminating S(−)-enantiomers from their antipodes. On the other hand, cholesterol produced the enantiospecific membrane interactions of bupivacaine and ropivacaine with increasing its composition in membranes. In 40 mol % and more cholesterol-containing membranes, the membrane-interacting potency was S(−)-bupivacaine < racemic bupivacaine < R(+)-bupivacaine, and S(−)-ropivacaine < R(+)-ropivacaine. Ropivacaine (S(−)-enantiomer), levobupivacaine (S(−)-enantiomeric), and bupivacaine (racemic) interacted with biomimetic membranes in increasing order of intensity. The rank order of membrane interactivity agreed with that of known cardiotoxicity. The stereoselective membrane interactions determined by cholesterol with higher chirality appears to be associated with the stereoselective cardiotoxic effects of local anesthetics. The stereostructure and membrane interactivity relationship supports the clinical use and development of S(−)-enantiomers to decrease the adverse effects of pipecoloxylidide local anesthetics on the cardiovascular system.