Predictions of the EC50 for action potential block for aliphatic solutes

Experiments were conducted to test the hypothesis that aliphatic hydrocarbons bind to pockets/crevices of sodium (Na(+)) channels to cause action potential (AP) block. Aliphatic solutes exhibiting successively greater octanol/water partitition coefficients (K (ow)) were studied. Each solute blocked Na(+) channels. The 50% effective concentration (EC(50)) to block APs could be mathematically predicted as a function of the solute's properties. The solutes studied were methyl ethyl ketone (MEK), cyclohexanone, dichloromethane, chloroform and triethylamine (TriEA); the K (ow) increased from MEK to TriEA. APs were recorded from frog nerves, and test solutes were added to Ringer's solution bathing the nerve. When combined with EC(50)s for solutes with log K (ow)s < 0.29 obtained previously, the solute EC(50)s could be predicted as a function of the fractional molar volume (dV/dm = [dV/dn]/100), polarity (P) and the hydrogen bond acceptor basicity (beta) by the following equation: EC(50) = 2.612({-2.117[dv/dm]+0.6424P+2.628 beta}) Fluidity changes cannot explain the EC(50)s. Each of the solutes blocks Na(+) channels with little or no change in kinetics. Na(+) channel block explains much of the EC(50) data. EC(50)s are produced by a combination of effects including ion channel block, fluidity changes and osmotically induced structural changes. As the solute log K (ow) increases to values near 1 or greater, Na(+) channel block dominates in determining the EC(50). The results are consistent with the hypothesis that the solutes bind to channel crevices to cause Na(+) channel and AP block.