Drug-induced surface potential changes of lipid vesicles and the role of calcium

The effects of four different drugs with local anesthetic properties were investigated on the surface potential of phospholipid vesicles composed of electrostatically neutral lipids (phosphatidylcholine), negatively charged lipids (phosphatidylserine) and a mixture of acidic and neutral lipids (soy bean lipids). Propranolol, tetracaine, lidocaine and procaine decrease the negative surface potential of phosphatidylserine and soy bean liposomes and increase that of phosphatidylcholine liposomes. The drugs interact with the liposomes in such a way that the protonated amine groups point towards the polar head groups of the phospholipids and the rest of the molecule is probably incorporated into the hydrophobic core of the lipid bilayer. The same sequence in drug activity normally measured in biological tissues (propranolol greater than tetracaine greater than lidocaine greater than procaine) is found for the surface potential change of the phospholipids. Calcium prevents the binding of the drugs to phosphatidylserine, especially the binding of lidocaine and procaine. Because of its high affinity for negative surface charges, Ca2+ chelates with phosphatidylserine and blocks the incorporation of the drug molecule. Vice versa, when incorporated into the liposomal bilayer, the drug blocks the interaction of calcium. These antagonistic effects are only observed in liposomes made from acidic phospholipids and not in those made from pure electrostatically neutral lipids like phosphatidylcholine.